P21 is not a bodybuilding or wellness peptide - it is a research compound built by one Alzheimer's research lab to mimic a small active piece of CNTF (ciliary neurotrophic factor), a natural protein that helps brain cells grow and survive. Scientists shrank it down and chemically reinforced it so it could get into the brain and survive digestion when mixed into food. Every study on it so far has been done in mice or rats bred to develop Alzheimer's-like disease, plus a couple of dish (cell culture) experiments - nobody has tested it in a person. A quick warning: 'p21' is also the name of a completely different, very common cell-biology gene (it stops cells from dividing) and the name of an unrelated genetic-testing kit (MLPA P021) used to diagnose spinal muscular atrophy. Most search results that mention 'p21' are actually about that gene or that test, not this peptide - we filtered those out and only used the papers that are genuinely about the P021 peptide compound.
How strong is the evidence?
All real evidence on this exact peptide comes from animal experiments (mostly one Alzheimer's-focused research group, using genetically engineered 'triple transgenic' Alzheimer's mice) plus one cell-culture and mouse study on a rare pediatric brain disease. There are zero published human trials of this peptide. The animal results are fairly consistent - better memory, healthier brain connections, less Alzheimer's-type damage - across several studies from birth through old age in mice. But because it is almost all from the same lab and has never been tried in people, it should be treated as an early-stage research lead, not a proven treatment.
Uses
What people use it for
Experimental Alzheimer's disease research
Animal / labThe main reason this peptide exists: researchers designed it to boost a brain-protecting growth factor (BDNF) without the problems of giving the real growth-factor protein (it can't cross into the brain well and causes side effects). It has been tested at every life stage in Alzheimer's mice - starting treatment before birth, in youth, and in old age - to see if it can prevent or slow the disease.
Experimental treatment for a rare childhood brain disorder (CDKL5 deficiency)
Animal / labOne study tried it in a model of CDKL5 deficiency disorder, a severe genetic condition causing seizures and developmental delay in children. It helped brain cells grow and survive in a lab dish, but did not work as hoped when given to living mice.
General cognitive-aging research
Animal / labTested in healthy aged rats (not just disease models) to see if it could counter normal age-related memory decline.
Potential benefits
What it may help with
Improved memory and learning in Alzheimer's mice
Animal / labAcross several studies, mice bred to develop Alzheimer's disease and given P021 in their food performed better on memory and learning tests than untreated mice, whether treatment started before birth, in early life, or in adulthood.
Slowed age-related memory decline in normal aging
Animal / labIn old rats (roughly equivalent to a 70-80 year old person) without any disease model, daily P021 reduced the usual memory and learning decline seen with aging and normalized a brain chemical (myo-inositol) that rises with age.
Studies:24702821More new brain cell growth (neurogenesis)
Animal / labP021 increased the birth of new neurons in the hippocampus, the brain's memory center, in both aged rats and Alzheimer's mice - a process that normally slows down with age and disease.
Less amyloid plaque and tau tangle buildup
Animal / labIn Alzheimer's mice, P021 reduced the buildup of amyloid-beta plaques and abnormal tau protein - the two hallmark brain changes seen in Alzheimer's disease - when treatment started early, before symptoms appeared.
Healthier brain cell connections (synapses)
Animal / labTreated mice had better-preserved synapses and dendrites (the branches neurons use to connect to each other), which are what actually correlate with memory ability, rather than plaques themselves.
Mixed results in a rare pediatric brain disease model
Animal / labIn lab-grown cells from a CDKL5 deficiency disorder model, P021 restored normal cell growth and survival. But when given to live mice with the same condition, it did not raise brain BDNF levels as expected and gave only limited behavioral benefit - an important reminder that lab-dish results don't always hold up in a living animal, let alone a person.
Studies:39592934
What to watch for
Side effects & risks
- Mild
No side effects reported in animal studies
The research team designed P021 specifically to avoid the side effects seen with the natural growth-factor protein (CNTF), and review papers state it has shown no adverse effects in the preclinical studies done so far. This is based on the researchers' own summaries, not a dedicated safety/toxicology trial, and animal tolerability does not guarantee human safety.
- Moderate
No human safety data exists
Because nobody has given this peptide to a person in a published study, there is no real information on human side effects, allergic reactions, or long-term safety at all.
Dosing
Dosing — what studies used
There is no established human dose for P21/P021 - it has never been given to a person in a published study, so nothing here should be treated as a usable protocol. In the animal research, it was mixed into food (not injected) and given continuously over long stretches of the animals' lives, starting at different ages depending on the study. None of the abstracts report an exact milligram dose or a per-kilogram amount, so even the animal 'protocols' below are incomplete pictures of what researchers actually used.
Alzheimer's mouse model, early prevention starting in adulthood
Animal studyNot specified in the abstract (custom P021-supplemented diet)
Continuous, daily via food · From 3 months of age to 18-21 months of age · Oral (diet)
Started months before any brain damage appeared; treatment continued essentially for the animals' whole adult life.
Alzheimer's mouse model, treatment from birth
Animal studyNot specified in the abstract (custom P021-supplemented diet)
Continuous, daily via food · Birth to postnatal day 120 (about 4 months old) · Oral (diet)
Tested whether starting treatment in infancy, long before disease symptoms, could prevent them.
Alzheimer's mouse model, treatment starting before birth
Animal studyNot specified in the abstract (custom P021-supplemented diet)
Continuous, daily via mother's food then own food · Prenatal day 8 through postnatal day 21, then standard diet afterward · Oral (diet)
The earliest treatment window tested - starting while still in the womb.
Healthy aged rats (normal aging, not disease model)
Animal studyNot specified in the abstract (chronic oral administration)
Chronic, described as ongoing oral dosing · Not specified exactly; rats were 22-24 months old (elderly) at the time of testing · Oral
Used to test whether the peptide helps ordinary age-related memory decline, not just disease.
Because no dose has ever been tested in a human, anyone encountering 'P21' or 'P021' being sold or discussed as a self-use peptide should treat that as unsupported by the actual science - the research to date is animal-only lab work, not a usable regimen.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Your brain makes a natural protein called CNTF that helps brain cells grow, connect, and survive - think of it as plant food for neurons. The problem is that giving people the actual CNTF protein as a drug does not work well: it cannot get past the brain's protective barrier easily, breaks down fast in the body, and can cause side effects. Scientists identified the small, active piece of CNTF that does the real work, then built a tiny stripped-down copy of just that piece (six amino acids, chemically capped and reinforced) so it could survive the trip to the brain and last longer once there. Once inside the brain, this peptide appears to raise levels of BDNF, another growth factor that is critical for keeping brain cells and their connections healthy. Higher BDNF then triggers a cascade of other helpful brain chemistry, including calming down an enzyme called GSK-3-beta that is responsible for damaging tau protein (the substance that tangles up inside neurons in Alzheimer's disease). Net effect in mice: more new brain cells being born, stronger connections between neurons, and less of the toxic protein buildup seen in Alzheimer's disease.
Who should avoid it
- There is no approved or established human use, so there is no medically defined group who 'should' or 'shouldn't' take it - it simply has not been tested in people.
- Anyone considering an unregulated version of this peptide outside of a clinical trial should know it has no human safety, dosing, or interaction data at all.
- Not appropriate for use during pregnancy or in children outside of a supervised research setting, given the total absence of human data.
Interactions to know
- No drug or supplement interaction studies exist for this peptide in animals or humans - none of the abstracts studied it alongside other medications.
The papers that matter most
Key studies
Introduces P021 in detail (structure, how it was engineered for brain entry) and shows it rescued brain connections, boosted new neuron growth, and reversed memory problems when given long-term to Alzheimer's mice.
Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound
Showed benefits weren't limited to Alzheimer's mice - ordinary old rats given oral P021 had better memory, more new brain cells, and normalized brain chemistry markers of aging.
Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic compound
Starting treatment right after birth and continuing to 4 months old prevented cognitive problems and boosted brain growth-factor signaling, suggesting an early-life 'window' where the peptide works well.
Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction
Even earlier treatment - starting before birth - prevented memory problems at 4 months and reduced plaque and tangle buildup at 22 months, the longest-term result in the dataset.
Prenatal to early postnatal neurotrophic treatment prevents Alzheimer-like behavior and pathology in mice
Long-term treatment starting at 3 months old, followed for 18 months, prevented brain cell loss, amyloid and tau buildup, protected memory, and lowered death rates in Alzheimer's mice.
Prevention of Amyloid-Beta and Tau Pathologies, Associated Neurodegeneration, and Cognitive Deficit by Early Treatment with a Neurotrophic Compound
Worked well on brain cells in a dish but failed to raise BDNF or meaningfully help living mice with this condition - an honest negative result showing the peptide's benefits don't automatically transfer across every disease model or from lab dish to living animal.
Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder
Bottom line
P21/P021 is a genuinely interesting piece of Alzheimer's research - a lab-engineered mini growth-factor that has repeatedly helped mice at every life stage in a well-designed disease model - but it is still purely a laboratory compound with zero human testing, no defined dose, and no safety record in people. Treat it as a promising research direction to watch, not something to use.
Research papers
Studies we have on file for P21. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
40 papers
Delphinidin attenuates cognitive deficits and pathology of Alzheimer's disease by preventing microglial senescence via AMPK/SIRT1 pathway.
Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy. This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms. We employed APP/PS1 mice, naturally aged mice, and an in vitro model using Aβ42-induced senescent BV2 microglia. Delphinidin's effects were evaluated through assessments of cognitive function, synaptic integrity (synapse loss), Aβ plaque burden, senescent microglia gene signatures, and cellular senescence markers (including senescence-associated β-galactosidase activity, SASP factor expression, oxidative stress, and cyclin p21/p16 levels). Mechanistic studies involved analyzing the AMPK/SIRT1 signaling pathway, testing direct delphinidin-SIRT1 interaction, and using the AMPK inhibitor Compound C. Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, Aβ peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, cyclin p21 and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. In vitro, delphinidin treatment attenuated cell senescence induced by Aβ42 in BV2 microglia cells. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It's noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence. Our study reveals for the first time that delphinidin effectively improved cognitive deficits, alleviated synapse loss and Aβ pathology in APP/PS1 mice by mitigating microglial senescence. These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.
Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior.
Microglia and brain-derived neurotrophic factor (BDNF) are essential for the neuroplasticity that characterizes critical developmental periods. The experience-dependent development of social behaviors-associated with the medial prefrontal cortex (mPFC)-has a critical period during the juvenile period in mice. However, whether microglia and BDNF affect social development remains unclear. Herein, we aimed to elucidate the effects of microglia-derived BDNF on social behaviors and mPFC development. Mice that underwent social isolation during p21-p35 had increased Bdnf in the microglia accompanied by reduced adulthood sociability. Additionally, transgenic mice overexpressing microglial Bdnf-regulated using doxycycline at different time points-underwent behavioral, electrophysiological, and gene expression analyses. In these mice, long-term overexpression of microglial BDNF impaired sociability and excessive mPFC inhibitory neuronal circuit activity. However, administering doxycycline to normalize BDNF from p21 normalized sociability and electrophysiological function in the mPFC, whereas normalizing BDNF from later ages (p45-p50) did not normalize electrophysiological abnormalities in the mPFC, despite the improved sociability. To evaluate the possible role of BDNF in human sociability, we analyzed the relationship between adverse childhood experiences and BDNF expression in human macrophages, a possible proxy for microglia. Results show that adverse childhood experiences positively correlated with BDNF expression in M2 but not M1 macrophages. In summary, our study demonstrated the influence of microglial BDNF on the development of experience-dependent social behaviors in mice, emphasizing its specific impact on the maturation of mPFC function, particularly during the juvenile period. Furthermore, our results propose a translational implication by suggesting a potential link between BDNF secretion from macrophages and childhood experiences in humans.
GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21.
As a major neuron type in the brain, the excitatory neuron (EN) regulates the lifespan in C. elegans. How the EN acquires senescence, however, is unknown. Here, we show that growth differentiation factor 11 (GDF11) is predominantly expressed in the EN in the adult mouse, marmoset and human brain. In mice, selective knock-out of GDF11 in the post-mitotic EN shapes the brain ageing-related transcriptional profile, induces EN senescence and hyperexcitability, prunes their dendrites, impedes their synaptic input, impairs object recognition memory and shortens the lifespan, establishing a functional link between GDF11, brain ageing and cognition. In vitro GDF11 deletion causes cellular senescence in Neuro-2a cells. Mechanistically, GDF11 deletion induces neuronal senescence via Smad2-induced transcription of the pro-senescence factor p21. This work indicates that endogenous GDF11 acts as a brake on EN senescence and brain ageing.
Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease.
Alzheimer's disease (AD) is an incurable and debilitating chronic progressive neurodegenerative disorder which is the leading cause of dementia worldwide. AD is a heterogeneous and multifactorial disorder, histopathologically characterized by the presence of amyloid β (Aβ) plaques and neurofibrillary tangles composed of Aβ peptides and abnormally hyperphosphorylated tau protein, respectively. Independent of the various etiopathogenic mechanisms, neurodegeneration is a final common outcome of AD neuropathology. Synaptic loss is a better correlate of cognitive impairment in AD than Aβ or tau pathologies. Thus a highly promising therapeutic strategy for AD is to shift the balance from neurodegeneration to neuroregeneration and synaptic repair. Neurotrophic factors, by virtue of their neurogenic and neurotrophic activities, have potential for the treatment of AD. However, the clinical therapeutic usage of recombinant neurotrophic factors is limited because of the insurmountable hurdles of unfavorable pharmacokinetic properties, poor blood-brain barrier (BBB) permeability, and severe adverse effects. Neurotrophic factor small-molecule mimetics, in this context, represent a potential strategy to overcome these short comings, and have shown promise in preclinical studies. Neurotrophic factor small-molecule mimetics have been the focus of intense research in recent years for AD drug development. Here, we review the relevant literature regarding the therapeutic beneficial effect of neurotrophic factors in AD, and then discuss the recent status of research regarding the neurotrophic factor small-molecule mimetics as therapeutic candidates for AD. Lastly, we summarize the preclinical studies with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021). P021 is a neurogenic and neurotrophic compound which enhances dentate gyrus neurogenesis and memory processes via inhibiting leukemia inhibitory factor (LIF) signaling pathway and increasing brain-derived neurotrophic factor (BDNF) expression. It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3β (GSK-3β, major tau kinase) activity. P021 is a small molecular weight, BBB permeable compound with suitable pharmacokinetics for oral administration, and without adverse effects associated with native CNTF or BDNF molecule. P021 has shown beneficial therapeutic effect in several preclinical studies and has emerged as a highly promising compound for AD drug development.
Alzheimer's Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound.
Alzheimer's disease (AD) is a progressive neurodegenerative disease with an insidious onset and multifactorial nature. A deficit in neurogenesis and synaptic plasticity are considered the early pathological features associated with neurofibrillary tau and amyloid β pathologies and neuroinflammation. The imbalance of neurotrophic factors with an increase in FGF-2 level and a decrease in brain derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) in the hippocampus, frontal cortex and parietal cortex and disruption of the brain micro-environment are other characteristics of AD. Neurotrophic factors are crucial in neuronal differentiation, maturation, and survival. Several attempts to use neurotrophic factors to treat AD were made, but these trials were halted due to their blood-brain barrier (BBB) impermeability, short-half-life, and severe side effects. In the present review we mainly focus on the major etiopathology features of AD and the use of a small neurotrophic and neurogenic peptide mimetic compound; P021 that was discovered in our laboratory and was found to overcome the difficulties faced in the administration of the whole neurotrophic factor proteins. We describe pre-clinical studies on P021 and its potential as a therapeutic drug for AD and related neurodegenerative disorders. Our study is limited because it focuses only on P021 and the relevant literature; a more thorough investigation is required to review studies on various therapeutic approaches and potential drugs that are emerging in the AD field.
Hepatic Encephalopathy and Astrocyte Senescence.
Hepatic Encephalopathy (HE) is a severe complication of acute or chronic liver diseases with a broad spectrum of neurological symptoms including motor disturbances and cognitive impairment of different severity. Contrary to former beliefs, a growing number of studies suggest that cognitive impairment may not fully reverse after an acute episode of overt HE in patients with liver cirrhosis. The reasons for persistent cognitive impairment in HE are currently unknown but recent observations raise the possibility that astrocyte senescence may play a role here. Astrocyte senescence is closely related to oxidative stress and correlate with irreversible cognitive decline in aging and neurodegenerative diseases. In line with this, surrogate marker for oxidative stress and senescence were upregulated in ammonia-exposed cultured astrocytes and in post mortem brain tissue from patients with liver cirrhosis with but not without HE. Ammonia-induced senescence in astrocytes involves glutamine synthesis-dependent formation of reactive oxygen species (ROS), p53 activation and upregulation of cell cycle inhibitory factors p21 and GADD45α. More recent studies also suggest a role of ROS-induced downregulation of Heme Oxygenase (HO)1-targeting micro RNAs and upregulation of HO1 for ammonia-induced proliferation inhibition in cultured astrocytes. Further studies are required to identify the precise sequence of events that lead to astrocyte senescence and to elucidate functional implications of senescence for cognitive performance in patients with liver cirrhosis and HE.
The Role of the p21-Activated Kinase Family in Tumor Immunity.
The p21-activated kinases (PAKs) are a group of evolutionarily conserved serine/threonine protein kinases and serve as a downstream target of the small GTPases Rac and Cdc42, both of which belong to the Rho family. PAKs play pivotal roles in various physiological processes, including cytoskeletal rearrangement and cellular signal transduction. Group II PAKs (PAK4-6) are particularly closely linked to human tumors, such as breast and pancreatic cancers, while Group I PAKs (PAK1-3) are indispensable for normal physiological functions such as cardiovascular development and neurogenesis. In recent years, the association of PAKs with diseases like cancer and the rise of small-molecule inhibitors targeting PAKs have attracted significant attention. This article focuses on the analysis of PAKs' role in tumor progression and immune infiltration, as well as the current small-molecule inhibitors of PAKs and their mechanisms.
Developing forebrain synapses are uniquely vulnerable to sleep loss.
Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long-lasting changes in adult behavior. Divergent plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21 to P28), adolescent (P42 to P49), and adult (P70 to P100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition task. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of perineuronal nets. Our analysis further reveals the developing synapse as a putative node of convergence between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing insights for ASD susceptibility.
PAK signalling in neuronal physiology.
Group I p21-activated kinases are a family of key effectors of Rac1 and Cdc42 and they regulate many aspects of cellular function, such as cytoskeleton dynamics, cell movement and cell migration, cell proliferation and differentiation, and gene expression. The three genes PAK1/2/3 are expressed in brain and recent evidence indicates their crucial roles in neuronal cell fate, in axonal guidance and neuronal polarisation, and in neuronal migration. Moreover they are implicated in neurodegenerative diseases and play an important role in synaptic plasticity, with PAK3 being specifically involved in mental retardation. The main goal of this review is to describe the molecular mechanisms that govern the different functions of group I PAK in neuronal signalling and to discuss the specific functions of each isoform.
SARS-CoV-2 (MA10) Infection Aggravates Cerebrovascular Pathology in Endothelial Nitric Oxide Synthase-Deficient Mice.
SARS-CoV-2 can cause neurological issues, including cognitive dysfunction in COVID-19 survivors. Endothelial dysfunction, a key mechanism in COVID-19, is also a risk factor for vascular dementia (VaD). Reduced nitric oxide (NO) bioavailability is a pathogenic factor of endothelial dysfunction and platelet aggregation in COVID-19 patients, and endothelial NO synthase (eNOS) levels decline with advancing age, a risk factor for both COVID-19 morbidity and VaD. SARS-CoV-2 also induces cellular senescence and senescence-associated secretory phenotype (SASP). We hypothesized that eNOS deficiency would worsen neuroinflammation, senescence, blood-brain barrier (BBB) permeability, and hypercoagulability in eNOS-deficient mice. Six-month-old eNOS+/- (pre-cognitively impaired experimental VaD) and wild-type (WT) male mice were infected with mouse-adapted (MA10) SARS-CoV-2. Mice were evaluated for weight loss, viral load, and markers of inflammation and senescence 3 days post-infection. eNOS+/- mice showed more weight loss (~15%) compared to WT mice (~5%) and increased inflammatory markers (Ccl2, Cxcl9, Cxcl10, IL-1β, and IL-6) and senescence markers (p53 and p21). They also exhibited higher microglial activation (Iba1) and increased plasma coagulation and BBB permeability, despite comparable lung viral loads and absence of virus in the brain. This is the first experimental evidence demonstrating that eNOS deficiency exacerbates SARS-CoV-2-induced morbidity, neuroinflammation, and brain senescence, linking eNOS to COVID-19-related neuropathology.
Neurogenesis in the adult hippocampus: history, regulation, and prospective roles.
The hippocampus is one of the sites in the mammalian brain that is capable of continuously generating controversy. Adult neurogenesis is a remarkable process, and yet an intensely debatable topic in contemporary neuroscience due to its distinctiveness and conceivable impact on neural activity. The belief that neurogenesis continues through adulthood has provoked remarkable efforts to describe how newborn neurons differentiate and incorporate into the adult brain. It has also encouraged studies that investigate the consequences of inadequate neurogenesis in neuropsychiatric and neurodegenerative diseases and explore the potential role of neural progenitor cells in brain repair. The adult nervous system is not static; it is subjected to morphological and physiological alterations at various levels. This plastic mechanism guarantees that the behavioral regulation of the adult nervous system is adaptable in response to varying environmental stimuli. Three regions of the adult brain, the olfactory bulb, the hypothalamus, and the hippocampal dentate gyrus, contain new-born neurons that exhibit an essential role in the natural functional circuitry of the adult brain. Purpose/Aim: This article explores current advancements in adult hippocampal neurogenesis by presenting its history and evolution and studying its association with neural plasticity. The article also discusses the prospective roles of adult hippocampal neurogenesis and describes the intracellular, extracellular, pathological, and environmental factors involved in its regulation. Abbreviations AHN Adult hippocampal neurogenesis AKT Protein kinase B BMP Bone Morphogenic Protein BrdU Bromodeoxyuridine CNS Central nervous system DG Dentate gyrus DISC1 Disrupted-in-schizophrenia 1 FGF-2 Fibroblast Growth Factor 2 GABA Gamma-aminobutyric acid Mbd1 Methyl-CpG-binding domain protein 1 Mecp2 Methyl-CpG-binding protein 2 mTOR Mammalian target of rapamycin NSCs Neural stem cells OB Olfactory bulb; P21: cyclin-dependent kinase inhibitor 1 RBPj Recombination Signal Binding protein for Immunoglobulin Kappa J Region RMS Rostral migratory Stream SGZ Subgranular zone Shh Sonic hedgehog SOX2 SRY (sex determining region Y)-box 2 SVZ Subventricular zone Wnt3 Wingless-type mouse mammary tumor virus.
Corticosterone Impairs Hippocampal Neurogenesis and Behaviors through p21-Mediated ROS Accumulation.
Stress is known to induce a reduction in adult hippocampal neurogenesis (AHN) and anxiety-like behaviors. Glucocorticoids (GCs) are secreted in response to stress, and the hippocampus possesses the greatest levels of GC receptors, highlighting the potential of GCs in mediating stress-induced hippocampal alterations and behavior deficits. Herein, RNA-sequencing (RNA-seq) analysis of the hippocampus following corticosterone (CORT) exposure revealed the central regulatory role of the p21 (Cdkna1a) gene, which exhibited interactions with oxidative stress-related differentially expressed genes (DEGs), suggesting a potential link between p21 and oxidative stress-related pathways. Remarkably, p21-overexpression in the hippocampal dentate gyrus partially recapitulated CORT-induced phenotypes, including reactive oxygen species (ROS) accumulation, diminished AHN, dendritic atrophy, and the onset of anxiety-like behaviors. Significantly, inhibiting ROS exhibited a partial rescue of anxiety-like behaviors and hippocampal alterations induced by p21-overexpression, as well as those induced by CORT, underscoring the therapeutic potential of targeting ROS or p21 in the hippocampus as a promising avenue for mitigating anxiety disorders provoked by chronic stress.
The development of peptide- and oligonucleotide-based drugs to prevent the formation of abnormal tau in tauopathies.
Tauopathies represent clinicopathological entities with increased and abnormal glial and/or neuronal inclusions of tau, a microtubule-binding protein. Antisense oligonucleotides (ASOs) are a promising therapeutic approach for treating tauopathies as they can target tau mRNA to reduce total human tau expression or tau exon 10 expression and 4 R tau. Additionally, targeting the tau specifically with peptides may be a unique pharmacological approach, between small molecules and proteins. The present review investigates the chemical basis of designing ASOs and peptides currently known to treat tauopathies. Among ASOs targeting tau expression, BIIB080 was the first to enter clinical trial development for treating mild Alzheimer's disease (AD). Furthermore, the therapeutic potential of peptide 021 (P021, Ac-DGGLAG-NH2) in tauopathies is discussed based on preclinical studies. ASOs are a promising therapeutic approach for tauopathies, particularly because ASOs may suppress the expression of harmful genes and are directly delivered to the brain, showing little systemic side effects. However, whether a generalized brain tau decrease will produce positive clinical effects remains unclear. A Phase II trial of BIIB080 is ongoing in mild AD. Neurotrophic and neurogenic peptide mimetic compounds have also shown potential as treatment options for AD and other tauopathies.
Epigenetic processes associated with neonatal spinal transection.
In early development, the spinal cord in healthy or disease states displays remarkable activity-dependent changes in plasticity, which may be in part due to the increased activity of brain derived neurotrophic factor (BDNF). Indeed, BDNF delivery has been efficacious in partially ameliorating many of the neurobiological and behavioral consequences of spinal cord injury (SCI), making elucidating the role of BDNF in the normative developing and injured spinal cord a critical research focus. Recent work in our laboratory provided evidence for aberrant global and locus-specific epigenetic changes in methylation of the Bdnf gene as a consequence of SCI. In the present study, animals underwent thoracic lesions on P1, with cervical and lumbar tissue being later collected on P7, P14, and P21. Levels of Bdnf expression and methylation (exon IX and exon IV), in addition to global methylation levels were quantified at each timepoint. Results indicated locus-specific reductions of Bdnf expression that was accompanied by a parallel increase in methylation caudal to the injury site, with animals displaying increased Bdnf expression at the P14 timepoint. Together, these findings suggest that epigenetic activity of the Bdnf gene may act as biomarker in the etiology and intervention effort efficacy following SCI.
Zi Shen Wan Fang repaired blood-brain barrier integrity in diabetic cognitive impairment mice via preventing cerebrovascular cells senescence.
Blood-brain barrier (BBB) integrity disruption is a key pathological link of diabetes-induced cognitive impairment (DCI), but the detailed mechanism of how the diabetic environment induces BBB integrity disruption is not fully understood. Our previous study found that Zi Shen Wan Fang (ZSWF), an optimized prescription consisting of Anemarrhenae Rhizoma (Anemarrhena asphodeloides Bge.), Phellodendri Chinensis Cortex (Phellodendron chinense Schneid.) and Cistanches Herba (Cistanche deserticola Y.C.Ma) has excellent efficacy in alleviating DCI, however, whether its mechanism is related to repairing BBB integrity remains unclear. This study aims to reveal the mechanism of BBB integrity destruction in DCI mice, and to elucidate the mechanism by which ZSWF repairs BBB integrity and improves cognitive function in DCI mice. Diabetic mouse model was established by feeding a 60% high-fat diet combined with a single intraperitoneal injection of 120 mg/kg streptozotocin (STZ). DCI mice were screened with morris water maze (MWM) after 8 weeks of sustained hyperglycemic stimulation. ZSWF was administered daily at doses of 9.36 and 18.72 g/kg for 8 weeks. Cognitive function was evaluated using MWM, blood-brain-barrier (BBB) integrity was tested using immunostaining and western blot, the underlying mechanisms were explored using single-cell RNA sequencing (scRNA-seq), validation experiments were performed with immunofluorescence analysis, and the potential active ingredients of ZSWF against cerebrovascular senescence were predicted using molecular docking. Moreover, cerebral microvascular endothelial cells were cultured, and the effects of mangiferin on the expression of p21 and Vcam1 were investigated by immunofluorescence staining and RT-qPCR. ZSWF treatment significantly ameliorated cognitive function and repaired BBB integrity in DCI mice. Using scRNA-seq, we identified 14 brain cell types. In BBB constituent cells (endothelial cells and pericytes), we found that Cdkn1a and senescence-associated secretory phenotype (SASP) genes were significantly overexpressed in DCI mice, while ZSWF intervention significantly inhibited the expression of Cdkn1a and SASP genes in cerebrovascular cells of DCI mice. Moreover, we also found that the communication between brain endothelial cells and pericytes was decreased in DCI mice, while ZSWF significantly increased the communication between them, especially the expression of PDGFRβ in pericytes. Molecular docking results showed that mangiferin, the blood component of ZSWF, had a stronger affinity with the upstream proteins of p21. In vitro experiments showed that high glucose significantly increased the expression of p21 and Vcam1 in bEnd.3 cells, while mangiferin significantly inhibited the expression of p21 and Vcam1 induced by high glucose. Our study reveals that ZSWF can ameliorate cognitive function in DCI mice by repairing BBB integrity, and the specific mechanism of which may be related to preventing cerebrovascular cells senescence, and mangiferin is its key active ingredient.
Nobiletin restores HFD-induced enteric nerve injury by regulating enteric glial activation and the GDNF/AKT/FOXO3a/P21 pathway.
To explore whether nobiletin has a protective effect on high-fat diet (HFD)-induced enteric nerve injury and its underlying mechanism. An obesity model was induced by a HFD. Nobiletin (100 mg/kg and 200 mg/kg) and vehicle were administered by gastric gavage for 4 weeks. Lee's index, body weight, OGTT and intestinal propulsion assays were performed before sacrifice. After sampling, lipids were detected using Bodipy 493/503; lipid peroxidation was detected using MDA and SOD kits and the expression of PGP 9.5, Trem2, GFAP, β-tubulin 3, Bax, Bcl2, Nestin, P75 NTR, SOX10 and EDU was detected using immunofluorescence. The GDNF, p-AKT, AKT, p-FOXO3a, FOXO3a and P21 proteins were detected using western blotting. The relative mRNA expression levels of NOS2 were detected via qPCR. Primary enteric neural stem cells (ENSCs) were cultured. After ENSCs were treated with palmitic acid (PA) and nobiletin, CCK-8 and caspase-3/7 activity assays were performed to evaluate proliferation and apoptosis. HFD consumption caused colon lipid accumulation and peroxidation, induced enteric nerve damage and caused intestinal motor dysfunction. However, nobiletin reduced lipid accumulation and peroxidation in the colon; promoted Trem2, β-tubulin 3, Nestin, P75NTR, SOX10 and Bcl2 expression; inhibited Bax and GFAP expression; reduced NOS2 mRNA transcription; and regulated the GDNF/AKT/FOXO3a/P21 pathway. Nobiletin also promoted PA-induced impairment of ENSCs. Nobiletin restored HFD-induced enteric nerve injury, which may be associated with inhibiting enteric nerve apoptosis, promoting enteric nerve survival and regulating the GDNF/AKT/FOXO3a/P21 pathway.
MRKNs: Gene, Functions, and Role in Disease and Infection.
The makorin RING finger protein (MKRN) gene family encodes proteins (makorins) with a characteristic array of zinc-finger motifs present in a wide array from invertebrates to vertebrates. MKRNs (MKRN1, MKRN2, MKRN3, MKRN4) as RING finger E3 ligases that mediate substrate degradation are related with conserved RING finger domains that control multiple cellular components via the ubiquitin-proteasome system (UPS), including p53, p21, FADD, PTEN, p65, Nptx1, GLK, and some viral or bacterial proteins. MKRNs also served as diverse roles in disease, like MKRN1 in transcription regulation, metabolic disorders, and tumors; MKRN2 in testis physiology, neurogenesis, apoptosis, and mutation of MKRN2 regulation signals transduction, inflammatory responses, melanoma, and neuroblastoma; MKRN3 in central precocious puberty (CPP) therapy; and MKRN4 firstly reported as a novel E3 ligase instead of a pseudogene to contribute to systemic lupus erythematosus (SLE). Here, we systematically review advances in the gene's expression, function, and role of MKRNs orthologs in disease and pathogens infection. Further, MKRNs can be considered targets for the host's innate intracellular antiviral defenses and disease therapy.
FOXG1 Contributes Adult Hippocampal Neurogenesis in Mice.
Strategies to enhance hippocampal precursor cells efficiently differentiate into neurons could be crucial for structural repair after neurodegenerative damage. FOXG1 has been shown to play an important role in pattern formation, cell proliferation, and cell specification during embryonic and early postnatal neurogenesis. Thus far, the role of FOXG1 in adult hippocampal neurogenesis is largely unknown. Utilizing CAG-loxp-stop-loxp-Foxg1-IRES-EGFP (Foxg1fl/fl), a specific mouse line combined with CreAAV infusion, we successfully forced FOXG1 overexpressed in the hippocampal dentate gyrus (DG) of the genotype mice. Thereafter, we explored the function of FOXG1 on neuronal lineage progression and hippocampal neurogenesis in adult mice. By inhibiting p21cip1 expression, FOXG1-regulated activities enable the expansion of the precursor cell population. Besides, FOXG1 induced quiescent radial-glia like type I neural progenitor, giving rise to intermediate progenitor cells, neuroblasts in the hippocampal DG. Through increasing the length of G1 phase, FOXG1 promoted lineage-committed cells to exit the cell cycle and differentiate into mature neurons. The present results suggest that FOXG1 likely promotes neuronal lineage progression and thereby contributes to adult hippocampal neurogenesis. Elevating FOXG1 levels either pharmacologically or through other means could present a therapeutic strategy for disease related with neuronal loss.
27-Hydroxycholesterol triggers microglial senescence subsequent to iron over-loading contributes to brain aging, suppressed by Deferoxamine.
Brain aging is a major factor in cognitive decline and Alzheimer's disease (AD) progression. Aging-induced microglial senescence critically drives inflammaging and brain aging processes. Nevertheless, the underlying reasons and mechanisms that promote microglial aging remain unclear. This study explores how 27-hydroxycholesterol (27-OHC), a key oxysterol, accelerates brain aging by promoting microglial senescence, iron overload, and neuroinflammation. Clinically, we observed a significant inverse correlation between plasma 27-OHC levels and Mini-Mental State Examination (MMSE) scores in AD patients, accompanied by reduced 24S-OHC concentrations. Experimental studies revealed that 27-OHC administration in mice induced hippocampal-dependent cognitive impairment and anxiety-like behaviors, concurrent with elevated expression of cellular senescence markers (P21, P16, SA-β-Gal) and M1 microglial polarization. In BV-2 cells, 27-OHC disrupted iron homeostasis (DMT1/ferritin/GPX4 dysregulation), elevating ROS and impairing mitochondrial function. Deferoxamine (DFX) mitigated microglial senescence and ferroptosis. These findings establish the 27-OHC-iron axis as a novel therapeutic target for combating cholesterol-driven neurodegeneration.
Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction. To explore strategies for early intervention to prevent Alzheimer's disease. In the present study, we investigated the effect of treatment during early development with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLAG-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated. P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice. These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies.
Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound.
The use of neurotrophic factors to treat Alzheimer's disease (AD) is hindered by their blood-brain barrier impermeability, short half-life, and severe side effects. Peptide 021 (P021) is a neurotrophic/neurogenic tetra-peptide that was derived from the most active region of the ciliary neurotrophic factor (CNTF) by epitope mapping. Admantylated glycine was added to its C-terminal to increase its blood-brain barrier permeability and decrease its degradation by exopeptidases to make it druggable. Here, we report on the preventive effect of P021 in 3 × Tg-AD, a transgenic mouse model of AD. P021 was administered in the diet at 3 months, i.e., 6-9 months before any overt amyloid beta (Aβ) or tau pathology, and during the period of synaptic compensation, and was continued until 21 months in 3 × Tg-AD mice. The 3 × Tg-AD mice and wild-type (WT) mice were treated identically but with a vehicle-only diet serving as controls. The effects of P021 on neurogenesis, dendritic and synaptic markers, and cognitive performance were investigated. We found that P021 treatment was able to rescue dendritic and synaptic deficits, boost neurogenesis, and reverse cognitive impairment in 3 × Tg-AD mice. Availability of appropriate neurotrophic support during the period of synaptic compensation can prevent synaptic deficit and cognitive impairment, and P021 is a promising neurotrophic compound for this purpose.
Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic compound.
Aging is characterized by a progressive decline of cognitive performance, which has been partially attributed to structural and functional alterations of hippocampus. Importantly, aging is the major risk factor for the development of neurodegenerative diseases, especially Alzheimer's disease. An important therapeutic approach to counteract the age-associated memory dysfunctions is to maintain an appropriate microenvironment for successful neurogenesis and synaptic plasticity. In this study, we show that chronic oral administration of peptide 021 (P021), a small peptidergic neurotrophic compound derived from the ciliary neurotrophic factor, significantly reduced the age-dependent decline in learning and memory in 22 to 24-month-old Fisher rats. Treatment with P021 inhibited the deficit in neurogenesis in the aged rats and increased the expression of brain derived neurotrophic factor. Furthermore, P021 restored synaptic deficits both in the cortex and the hippocampus. In vivo magnetic resonance spectroscopy revealed age-dependent alterations in hippocampal content of several metabolites. Remarkably, P021 was effective in significantly reducing myoinositol (INS) concentration, which was increased in aged compared with young rats. These findings suggest that stimulating endogenous neuroprotective mechanisms is a potential therapeutic approach to cognitive aging, Alzheimer's disease, and associated neurodegenerative disorders and P021 is a promising compound for this purpose.
Qifuyin against CCL11-Induced cognitive impairment by inhibiting microglial senescence via CCR3 signaling.
The chemokine CCL11 is negatively correlated with cognitive function and is able to cause dysfunctions of synaptic plasticity. This research investigate whether CCL11 induce microglia senescence to damage synaptic plasticity and the protective role of Qifuyin. This study involved the intraperitoneal injection of CCL11 in C57BL/6 mice to create an ageing mouse model. Behavioral tests were conducted to evaluate the changes in cognitive function after Qifuyin treatment. LTP and Golgi staining were used to evaluate synaptic structure and function. Cellular senescence was assessed using SA-β-Gal staining, co-localization of p21 or p16 with Iba-1 was identified using multiplex immunofluorescence, and senescence-associated secretory phenotype (SASP) was evaluated via the Luminex. CCR3 knockout/overexpression HMC3 cells were treated with five brain-entering components of Qifuyin to observe protective effects of Qifuyin. Here we found that Qifuyin improved the ability of object recognition and memory, spatial learning and memory and conditional fear memory in CCL11-induced cognitive dysfunction of C57BL/6 mice. Qifuyin can improve synaptic plasticity, increase the expression of GAP-43, PSD-95 and SYN in the hippocampus of CCL11-induced mice. Cellular senescence of microglia and the amounts of SASP in the hippocampus were also reduced after Qifuyin treatment. Through the study of HMC3 cells with CCR3 gene knockout/overexpression, it was found that the brain components of Qifuyin could unlock the cell cycle arrest induced by CCL11/CCR3 pathway, reduce the proportion of G0 and G1 cells, reduce the expressions of p16, p21 and SASP, and enhance the synaptic connection of HT-22 cells damaged by HMC3 cells. This study discovered that CCL11 precipitates microglia senescence in brain, resulting in synaptic structural damage and impaired neuronal functional plasticity, hence causing disruptions in learning and memory functions. Qifuyin can mitigate microglial senescence, safeguard synaptic plasticity, and enhance cognitive function.
Histopathological and functional Characterization of a neonatal mouse model of intraventricular hemorrhage.
Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is a major neurological problem of premature infants that leads to white matter injury and posthemorrhagic hydrocephalus. There is no optimal treatment for IVH-induced complications. Several animal models of IVH have been developed, but they have significant limitations. We employed a one-day-old C57BL/6 mouse (P1) and injected hemolyzed whole blood or saline into both cerebral ventricles under hypothermia-induced anesthesia. The blood was obtained from one of the C57BL/6 inbred mouse strains. We evaluated a range of parameters, including apoptosis, cerebral inflammation, myelination, ventricle size, and neurobehavioral functions. The weight gain was comparable between blood- and saline-injected mouse pups. The ventricle size and head dimensions were larger in blood-injected pups compared to saline controls at P21 through P60. We demonstrated greater apoptotic cell death, neuronal degeneration, and microglia infiltration in the periventricular white matter of blood-treated pups relative to controls at P3 and P7. Myelination was reduced, and astrogliosis was increased in blood-injected mice relative to saline controls at P21. Post-hemorrhagic hydrocephalus was noted in blood-treated mice at both P21 and P60. Neurobehavior evaluation revealed motor and cognitive deficits in blood-injected animals relative to controls at P60. A comparison between hemolyzed and non-hemolyzed whole blood-treated pups showed that the hemolyzed blood produced more consistent hydrocephalus and reduction in myelination compared to non-hemolyzed blood injections. The study provides comprehensive analyses of a novel model of IVH that can be employed to understand the mechanisms and develop therapeutic strategies for white matter injury and hydrocephalus in IVH survivors.
Optimized MLPA workflow for spinal muscular atrophy diagnosis: identification of a novel variant, NC_000005.10:g.(70919941_70927324)del in isolated exon 1 of SMN1 gene through long-range PCR.
Spinal muscular atrophy (SMA) is a rare autosomal recessive hereditary neuromuscular disease caused by survival motor neuron 1 (SMN1) gene deletion or mutation. Homozygous deletions of exon 7 in SMN1 result in 95% of SMA cases, while the remaining 5% are caused by other pathogenic variants of SMN1. We analyzed two SMA-suspected cases that were collected, with no SMN1 gene deletion and point mutation in whole-exome sequencing. Exon 1 deletion of the SMN gene was detected using Multiplex ligation-dependent probe amplification (MLPA) P021. We used long-range polymerase chain reaction (PCR) to isolate the SMN1 template, optimized-MLPA P021 for copy number variation (CNV) analysis within SMN1 only, and validated the findings via third-generation sequencing. Two unrelated families shared a genotype with one copy of exon 7 and a novel variant, g.70919941_70927324del, in isolated exon 1 of the SMN1 gene. Case F1-II.1 demonstrated no exon 1 but retained other exons, whereas F2-II.1 had an exon 1 deletion in a single SMN1 gene. The read coverage in the third-generation sequencing results of both F1-II.1 and F2-II.1 revealed a deletion of approximately 7.3 kb in the 5' region of SMN1. The first nucleotide in the sequence data aligned to the 7385 bp of NG_008691.1. Remarkably, two proband families demonstrated identical SMN1 exon 1 breakpoint sites, hinting at a potential novel mutation hotspot in Chinese SMA, expanding the variation spectrum of the SMN1 gene and corroborating the specificity of isolated exon 1 deletion in SMA pathogenesis. The optimized-MLPA P021 determined a novel variant (g.70919941_70927324del) in isolated exon 1 of the SMN1 gene based on long-range PCR, enabling efficient and affordable detection of SMN gene variations in patients with SMA, providing new insight into SMA diagnosis to SMN1 deficiency and an optimized workflow for single exon CNV testing of the SMN gene.
Antidepressants and Cdk inhibitors: releasing the brake on neurogenesis?
It is now clear that neurogenesis occurs in the brain of adult mammals. Many studies have attempted to establish relationships among neurogenesis, depression and the mechanism of action of antidepressant drugs. Therapeutic effects of antidepressants appear to be linked to increased neurogenesis in the hippocampus. Cdk inhibitors are expressed in multiple brain regions, presumably maintaining quiescence in differentiated neurons. Recently, the abundant expression of p21(Cip1) was found in neuroblasts and in newly developing neurons in the subgranular zone of the hippocampus, a region where adult neurogenesis occurs. Chronic treatment with the tricyclic antidepressant imipramine markedly decreased p21(Cip1) mRNA and protein levels and stimulated neurogenesis in this region. These results suggest that p21(Cip1) restrains neurogenesis in the hippocampus, and antidepressant-induced stimulation of neurogenesis might be a consequence of decreased p21(Cip1) expression, with the subsequent release of neuronal progenitor cells from the blockade of proliferation. These findings suggest the potential for new therapeutic strategies for the treatment of depression that target cell cycle proteins. However, there is a possibility that long-term stimulation of neurogenesis might exhaust the proliferation potentials of neuronal progenitors.
Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.
Mutations in the X-linked CDKL5 gene underlie a severe epileptic encephalopathy, CDKL5 deficiency disorder (CDD), characterized by gross motor impairment, autistic features and intellectual disability. Absence of Cdkl5 negatively impacts neuronal proliferation, survival, and maturation in in vitro and in vivo models, resulting in behavioral deficits in the Cdkl5 KO mouse. While there is no targeted therapy for CDD, several studies showed that treatments enabling an increase in brain BDNF levels give rise to structural and behavioral improvements in Cdkl5 KO mice. P021, a tetra-peptide derived from the biologically active region of the human ciliary neurotrophic factor (CNTF), was found to enhance neurogenesis and synaptic plasticity by promoting an increase in BDNF expression in preclinical models of brain disorders, such as Alzheimer's disease and Down syndrome, resulting in a beneficial therapeutic effect. Considering the positive actions of P021 on brain development and cognition associated with increased BDNF expression, the present study aimed to evaluate the possible beneficial effect of treatment with P021 in an in vitro and in vivo model of CDD. We used SH-CDKL5-KO cells as an in vitro model of CDD to test the efficacy of P021 on neuronal proliferation, survival, and maturation. In addition, both young and adult Cdkl5 KO mice were used to evaluate the in vivo effects of P021, on neuroanatomical and behavioral defects. We found that P021 treatment was effective in restoring neuronal proliferation, survival, and maturation deficits, as well as alterations in the GSK3β signaling pathway, features that characterize a human neuronal model of CDKL5 deficiency. Unexpectedly, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 KO mice, resulting in limited behavioral benefit. At present, it remains to be understood whether initiating the treatment prenatally, or prolonging the duration of treatment will be necessary in order to achieve similar results in vivo in CDD mice to those obtained in vitro.
Prenatal to early postnatal neurotrophic treatment prevents Alzheimer-like behavior and pathology in mice.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of middle-aged to old individuals. The pathophysiological process of AD is believed to begin many years before the emergence of clinical symptoms. The important influence of congenital genetic aberrations on the development of AD provides a novel opportunity to initiate prenatal to early postnatal pharmacological treatment to address the role of this critical period of brain development in the disease. We investigated for the first time the effect of oral treatment during prenatal to early postnatal development with a neurotrophic compound, P021 (Ac-DGGLAG-NH2), on neurobehavior and AD-like pathology in 3xTg-AD, a transgenic mouse model of AD. The transgenic and control wild-type female mice were treated from prenatal day 8 to postnatal day 21 with a custom-made diet containing P021 or a vehicle diet, followed by a standard diet. AD-type cognitive function and pathological features were studied during adulthood and old age. The P021 treatment rescued cognitive deficits at 4 months, reduced abnormal hyperphosphorylation and accumulation of tau at known major AD neurofibrillary pathology-associated sites, and decreased Aβ plaque load at 22 months in 3xTg-AD mice. Prenatal to early postnatal treatment with P021 also ameliorated certain markers of postsynaptic deficits, including PSD-95 levels and CREB activity, and decreased one measure of neuroinflammation, GFAP level in the brain at 4 and 22 months in 3xTg mice. These findings suggest that neurotrophic impairment during early development can be one of the etiopathogenic factors of AD and that the neurotrophic peptide mimetic is a potential early prevention strategy for this disease.
Defective neurogenesis and schizophrenia-like behavior in PARP-1-deficient mice.
In the current study we present evidence suggesting that PARP-1 regulates neurogenesis and its deficiency may result in schizophrenia-like behavioral deficits in mice. PARP-1 knockout neural stem cells exhibited a marked upregulation of embryonic stem cell phosphatase that can suppress the proliferative signaling of PI3K-Akt and ERK. The suppressed activity of Akt and ERK in the absence of PARP-1 results in the elevation of FOXO1 activity and its downstream target genes p21 and p27, leading to the inhibition of neural stem cell proliferation. Moreover, expression of neurogenic factors and neuronal differentiation were decreased in the PARP-1 knockout neural stem cells whereas glial differentiation was increased. In accordance with the in vitro data, PARP-1 knockout mice exhibited reduced brain weight with enlarged ventricle as well as decreased adult neurogenesis in the hippocampus. Interestingly, PARP-1 knockout mice exhibited schizophrenia-like symptoms such as anxiety, depression, social interaction deficits, cognitive impairments, and prepulse inhibition deficits. Taken together, our results suggest that PARP-1 regulates neurogenesis during development and in adult and its absence may lead to the schizophrenia-like behavioral abnormality in mice.
PAK3 downregulation induces cognitive impairment following cranial irradiation.
Cranial irradiation is used for prophylactic brain radiotherapy as well as the treatment of primary brain tumors. Despite its high efficiency, it often induces unexpected side effects, including cognitive dysfunction. Herein, we observed that mice exposed to cranial irradiation exhibited cognitive dysfunction, including altered spontaneous behavior, decreased spatial memory, and reduced novel object recognition. Analysis of the actin cytoskeleton revealed that ionizing radiation (IR) disrupted the filamentous/globular actin (F/G-actin) ratio and downregulated the actin turnover signaling pathway p21-activated kinase 3 (PAK3)-LIM kinase 1 (LIMK1)-cofilin. Furthermore, we found that IR could upregulate microRNA-206-3 p (miR-206-3 p) targeting PAK3. As the inhibition of miR-206-3 p through antagonist (antagomiR), IR-induced disruption of PAK3 signaling is restored. In addition, intranasal administration of antagomiR-206-3 p recovered IR-induced cognitive impairment in mice. Our results suggest that cranial irradiation-induced cognitive impairment could be ameliorated by regulating PAK3 through antagomiR-206-3 p, thereby affording a promising strategy for protecting cognitive function during cranial irradiation, and promoting quality of life in patients with radiation therapy.
Chronic intestinal inflammation alters hippocampal neurogenesis.
Adult neurogenesis in the subgranular zone of the hippocampus is involved in learning, memory, and mood control. Decreased hippocampal neurogenesis elicits significant behavioral changes, including cognitive impairment and depression. Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the intestinal tract, and cognitive dysfunction and depression frequently occur in patients suffering from this disorder. We therefore tested the effects of chronic intestinal inflammation on hippocampal neurogenesis. The dextran sodium sulfate (DSS) mouse model of IBD was used. Mice were treated with multiple-cycle administration of 3% wt/vol DSS in drinking water on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26. Mice were sacrificed on day 7 (acute phase of inflammation) or day 29 (chronic phase of inflammation) after the beginning of the treatment. During the acute phase of inflammation, we found increased plasma levels of IL-6 and TNF-α and increased expression of Iba1, a marker of activated microglia, accompanied by induced IL-6 and IL-1β, and the cyclin-dependent kinase inhibitor p21(Cip1) (p21) in hippocampus. During the chronic phase of inflammation, plasma levels of IL-6 were elevated. In the hippocampus, p21 protein levels were continued to be induced. Furthermore, markers of stem/early progenitor cells, including nestin and brain lipid binding protein (BLBP), and neuronal marker doublecortin (DCX) were all down-regulated, whereas glial fibrillary acidic protein (GFAP), a marker for astroglia, was induced. In addition, the number of proliferating precursors of neuronal lineage assessed by double Ki67 and DCX staining was significantly diminished in the hippocampus of DSS-treated animals, indicating decreased production of new neurons. We show for the first time that chronic intestinal inflammation alters hippocampal neurogenesis. As p21 arrests early neuronal progenitor proliferation, it is likely that p21 induction during acute phase of inflammation resulted in the reduction of hippocampal neurogenesis observed later, on day 29, after the beginning of DSS treatment. The reduction in hippocampal neurogenesis might underlie the behavioral manifestations that occur in patients with IBD.
BDNF-TrkB Signaling Maintains Alveolar Epithelial Type 2 Cell Survival and Is Blocked in Hyperoxia-induced Neonatal Lung Injury.
Oxygen supplementation causes an arrest of alveolar formation and a depletion of alveolar epithelial type 2 (AT2) cells in preterm infants, both characteristics of bronchopulmonary dysplasia. BDNF (brain-derived neurotrophic factor) is a key integrator of cell homeostasis and contributes to chronic lung diseases. In this study, 1) wild-type mice were exposed to 85% O2 or 21% O2 from birth to postnatal day (P)28, followed by spatiotemporal profiling of pulmonary BDNF signaling on P3-P70; and 2) lung epithelial cells (MLE12), primary murine AT2, and precision-cut lung slices were treated with nonselective Trk inhibitor (K252a), selective TrkB antagonist (Ana12), and TrkB agonist (7,8-dihydroxyflavone). Single-cell transcriptomic profiling revealed an expression of Bdnf in mesenchymal cells but no changes during postnatal development. In contrast, immunofluorescent staining showed a predominant localization of TrkB in AT2 and ACTA2+ cells; its expression and phosphorylation were increased at P7-P21. Although hyperoxia induced a 40-fold upregulation of lung Bdnf and a 3-fold elevation of serum BDNF, TrkB abundance and activation decreased by 90%. This was related to a lower Sftpc and increased Acta2 in lungs. Blockade of Trk(B) reduced survival of MLE12 and murine AT2 with a loss of epithelial AT1 and AT2 markers, whereas the TrkB agonist increased survival and regulated AT2 maintenance in precision-cut lung slices after hyperoxia. Our data identified an important functional role of TrkB signaling in AT2 cells, a mechanism that is blocked in neonatal mouse lungs after hyperoxia and may contribute to a lack of regeneration and to arrest of alveolar growth in infants with bronchopulmonary dysplasia.
The Role of RAD6B and PEDF in Retinal Degeneration.
RAD6B is an E2 ubiquitin-conjugating enzyme, playing an important role in DNA damage repair, gene expression, senescence, apoptosis and protein degradation. However, the specific mechanism between ubiquitin and retinal degeneration requires more investigation. Pigment epithelium-derived factor (PEDF) has a potent neurotrophic effect on the retina, protecting retinal neurons and photoreceptors from cell death caused by pathological damage. In this study, we found that loss of RAD6B leads to retinal degeneration in mice, especially in old age. Affymetrix microarray analysis showed that the PEDF signal was changed in RAD6B deficient groups. The expression of γ-H2AX, β-Gal, P53, Caspase-3, P21 and P16 was increased significantly in retinas of RAD6B knockout (KO) mice. Our studies suggest that RAD6B and PEDF play an important role in the health of retina, whereas the absence of RAD6B accelerates the degeneration.
Variants located in intron 6 of SMN1 lead to misdiagnosis in genetic detection and screening for SMA.
Accurate genetic diagnosis is necessary for guiding the treatment of spinal muscular atrophy (SMA). An updated consensus for the diagnosis and management of SMA was published in 2018. However, clinicians should remain alert to some pitfalls of genetic testing that can occur when following a routine diagnosis. In this study, we report the diagnosis of three unrelated individuals who were initially misdiagnosed as carrying a homozygous deletion of SMN1 exon 7. MLPA (P060 and P021) and qPCR were used to detect the copy number of SMN. SMN1 variants were identified by SMN1 clone and next-generation sequencing (NGS). Transcription of SMN1 variants was detected using qRT-PCR and ex vivo splicing analysis. Among the three individuals, one was identified as a patient with SMA carrying a heterozygous deletion and a pathogenic variant (c.835-17_835-14delCTTT) of SMN1, one was a healthy carrier only carrying a heterozygous deletion of SMN1 exon 7, and the third was a patient with nemaline myopathy 2 carrying a heterozygous deletion of SMN1 exon 7. The misdiagnosis of these individuals was attributed to the presence of the c.835-17_835-14delCTTT or c.835-17C > G variants in SMN1 intron 6, which affect the amplification of SMN1 exon 7 during MLPA-P060 and qPCR testing. However, MLPA-P021 and NGS analyses were unaffected by these variants. These results support that additional detection methods should be employed in cases where the SMN1 copy number is ambiguous to minimize the misdiagnosis of SMA.
PAK1 Positively Regulates Oligodendrocyte Morphology and Myelination.
The actin cytoskeleton is crucial for oligodendrocyte differentiation and myelination. Here we show that p21-activated kinase 1 (PAK1), a well-known actin regulator, promotes oligodendrocyte morphologic change and myelin production in the CNS. A combination of in vitro and in vivo models demonstrated that PAK1 is expressed throughout the oligodendrocyte lineage with highest expression in differentiated oligodendrocytes. Inhibiting PAK1 early in oligodendrocyte development decreased oligodendrocyte morphologic complexity and altered F-actin spreading at the tips of oligodendrocyte progenitor cell processes. Constitutively activating AKT in oligodendrocytes in male and female mice, which leads to excessive myelin wrapping, increased PAK1 expression, suggesting an impact of PAK1 during active myelin wrapping. Furthermore, constitutively activating PAK1 in oligodendrocytes in zebrafish led to an increase in myelin internode length while inhibiting PAK1 during active myelination decreased internode length. As myelin parameters influence conduction velocity, these data suggest that PAK1 may influence communication within the CNS. These data support a model in which PAK1 is a positive regulator of CNS myelination.SIGNIFICANCE STATEMENT Myelin is a critical component of the CNS that provides metabolic support to neurons and also facilitates communication between cells in the CNS. Recent data demonstrate that actin dynamics drives myelin wrapping, but how actin is regulated during myelin wrapping is unknown. The authors investigate the role of the cytoskeletal modulator PAK1 during differentiation and myelination by oligodendrocytes, the myelinating cells of the CNS. They demonstrate that PAK1 promotes oligodendrocyte differentiation and myelination by modulating the cytoskeleton and thereby internode length, thus playing a critical role in the function of the CNS.
Liquid-liquid phase separation of RBM33 facilitates hippocampus aging by inducing microglial senescence by activating CDKN1A.
Microglia play an important role in hippocampus-dependent memory and cognitive function. Microglial aging contributes to hippocampal aging and influences neurodegenerative diseases, although the underlying mechanisms remain unclear. RBM33 was highly expressed in the hippocampus of naturally aged mice and senescent microglia. Hippocampus-specific genetic deletion of RBM33 alleviated age-related declines in learning and memory in aged RBM33 knockout (RBM33-/-) mice. In contrast, hippocampus-specific overexpression of RBM33 exacerbated these declines in aged RBM33 overexpression (RBM33Tg) mice, indicating that RBM33 acts as an age-promoting factor in the hippocampus. Mechanistically, RBM33 forms liquid-liquid phase separation (LLPS) both in vitro and in cells. RBM33 LLPS is required for its binding to the CDKN1A (p21cip1) promoter in a non-canonical transcriptional regulatory manner, leading to hippocampus-dependent declines in learning and memory by inducing microglial senescence. This study reveals that the RBM33 LLPS/ p21cip1 axis facilitates brain aging by inducing microglial senescence. Targeting the RBM33 LLPS/ p21cip1 axis may represent a therapeutic strategy to mitigate microglia senescence-mediated brain aging and hippocampus-dependent cognitive decline.
Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro.
Hippocampal neurons maintain the ability of proliferation throughout life to support neurogenesis. Deoxynivalenol (DON) is a mycotoxin that exhibits brain toxicity, yet whether and how DON affects hippocampal neurogenesis remains unknown. Here, we use mouse hippocampal neuron cells (HT-22) as a model to illustrate the effects of DON on neuron proliferation and to explore underlying mechanisms. DON exposure significantly inhibits the proliferation of HT-22 cells, which is associated with an up-regulation of cell cycle inhibitor p21 at both mRNA and protein levels. Global and site-specific m6A methylation levels on the 3'UTR of p21 mRNA are significantly increased in response to DON treatment, whereas inhibition of m6A hypermethylation significantly alleviates DON-induced cell cycle arrest. Further mechanistic studies indicate that the m6A readers YTHDF1 and IGF2BP1 are responsible for m6A-mediated increase in p21 mRNA stability. Meanwhile, 3'UTR of E3 ubiquitin ligase TRIM21 mRNA is also m6A hypermethylated, and another m6A reader YTHDF2 binds to the m6A sites, leading to decreased TRIM21 mRNA stability. Consequently, TRIM21 suppression impairs ubiquitin-mediated p21 protein degradation. Taken together, m6A-mediated upregulation of p21, at both post-transcriptional and post-translational levels, contributes to DON-induced inhibition of hippocampal neuron proliferation. These results may provide new insights for epigenetic therapy of neurodegenerative diseases.
Prevention of Amyloid-β and Tau Pathologies, Associated Neurodegeneration, and Cognitive Deficit by Early Treatment with a Neurotrophic Compound.
To date, neither any effective treatment nor prevention of Alzheimer's disease (AD), a major dementia causing disorder, are available. Herein, we investigated the secondary prevention of neurodegeneration, amyloid-β (Aβ) and tau pathologies with a neurotrophic compound P021 in 3xTg-AD mice. Previous work found that P021 can rescue at mild to moderate stages Aβ and tau pathologies in 3xTg-AD mice. To determine its potential clinical application, we sought to test the preventive effect of P021 on Aβ and tau pathologies by starting the treatment during the period of synaptic compensation several months before the appearance of any overt pathology in 3xTg-AD mice. We started a continuous treatment with P021 in 3-month-old female animals and followed its effect at 9-, 15- and 18-months post-treatment. Neurodegeneration at the above time points was studied using Fluorojade C staining, and tau and Aβ pathologies both immunohistochemically and by Western blots. Cognitive performance was studied by assessing episodic memory with Novel Object Recognition task at 16-17-months post-treatment. We found that P021 treatment initiated during the synaptic compensation period can prevent neurodegeneration, Aβ and tau pathologies, rescue episodic memory impairment, and markedly reduce mortality rate. These findings for the first time show effective prevention of AD changes with a neurotrophic compound that targets neurogenesis and synaptic plasticity, suggesting that improving the health of the neuronal network can prevent AD.
Stress and trauma: BDNF control of dendritic-spine formation and regression.
Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress. Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact. It seems then that CRF does have a role to play in determining BDNF control of dendritic spines.
BDNF mechanisms in late LTP formation: A synthesis and breakdown.
Unraveling the molecular mechanisms governing long-term synaptic plasticity is a key to understanding how the brain stores information in neural circuits and adapts to a changing environment. Brain-derived neurotrophic factor (BDNF) has emerged as a regulator of stable, late phase long-term potentiation (L-LTP) at excitatory glutamatergic synapses in the adult brain. However, the mechanisms by which BDNF triggers L-LTP are controversial. Here, we distill and discuss the latest advances along three main lines: 1) TrkB receptor-coupled translational control underlying dendritic protein synthesis and L-LTP, 2) Mechanisms for BDNF-induced rescue of L-LTP when protein synthesis is blocked, and 3) BDNF-TrkB regulation of actin cytoskeletal dynamics in dendritic spines. Finally, we explore the inter-relationships between BDNF-regulated mechanisms, how these mechanisms contribute to different forms of L-LTP in the hippocampus and dentate gyrus, and outline outstanding issues for future research. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.
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