P21 (P021)
Also known as: P021, Peptide 021, P-21, Ac-DGGL(A)G-NH2, CNTF-derived neurotrophic peptide, adamantane-modified Peptide 6 derivative
Experimental; not approved anywhere; no human trials identified.
5 notable studies · 7 references
TLDR
P21 (P021) is a small adamantane-modified peptide derived from ciliary neurotrophic factor that, in mouse and rat studies almost all from one laboratory, increased hippocampal neurogenesis, raised BDNF, reduced Alzheimer's-type tau pathology and improved memory, but it has never been tested in humans, its exact target is unknown, and it should not be confused with the unrelated cell-cycle protein p21.
At a Glance
Classification: Synthetic adamantane-modified short peptidomimetic derived from ciliary neurotrophic factor (CNTF); experimental neurogenic/neurotrophic compound
P21, also written P021, is a small experimental compound developed by Khalid Iqbal's group at the New York State Institute for Basic Research in Developmental Disabilities (Staten Island, NY). It comes from a line of work trying to get the brain-supporting effects of neurotrophic factors without using the large proteins themselves, which do not cross into the brain well and cause side effects. The family tree is roughly: Ciliary neurotrophic factor (CNTF, a large protein) ↓ Peptide 6, an 11-amino-acid fragment from an active region of CNTF ↓ P021, a shorter acetylated, amidated peptide built on the Asp-Gly-Gly-Leu (DGGL) core with an added adamantane-containing residue to improve stability and brain penetration. Its published structure is written Ac-DGGL(A)G-NH2, where (A) marks the adamantane-containing building block. P021 has been studied almost entirely in rodents, for: • Hippocampal neurogenesis • Learning and memory • Alzheimer's-type tau and amyloid pathology • Cognitive aging. Important naming note: "P21" is also the common name of p21 (CDKN1A), a well-known cell-cycle protein. That protein is unrelated. Searches and papers about "p21" are usually about the cell-cycle protein, not this peptide. No human studies of P021 were found.
What Is P21 (P021)?
P021 is a synthetic peptidomimetic, not a natural hormone. The original idea: CNTF can promote neuron survival and the birth of new neurons, but as a whole protein it is impractical as a brain drug. Iqbal's group identified Peptide 6, a short active region of CNTF, then shortened and chemically modified it. The resulting P021 was reported to work when given peripherally, including mixed into food (oral), in mice and rats. One later rat study reported that P021 crosses the blood–brain barrier and did not trigger a detectable immune reaction.
What Are Researchers Studying?
Neurogenesis and memory in normal animals
In the first P021 paper, peripheral administration to normal adult mice enhanced learning and short-term and spatial memory, together with more new neurons and better neuron maturation in the dentate gyrus.
Alzheimer's-type pathology
In 3xTg-AD mice (a model carrying human amyloid- and tau-related mutations), 12 months of P021 in the diet reduced abnormal tau hyperphosphorylation, modestly lowered soluble amyloid-β, and rescued deficits in cognition, neurogenesis and synaptic plasticity. A later study started treatment early, before pathology appeared, and reported prevention of neurodegeneration, tau and amyloid pathology, better memory and lower mortality in these mice. Transgenic mouse models capture only parts of human Alzheimer's disease, and many compounds that worked in them failed in people.
Cognitive aging
In 22–24-month-old Fisher rats, chronic oral P021 reduced age-related decline in learning and memory, improved neurogenesis and synaptic markers, increased BDNF, and normalized a brain metabolite (myo-inositol) that rises with age. A follow-up study in aged rats reported that P021 lowered elevated tau in brain and cerebrospinal fluid.
Brain injury and Down syndrome models
The parent compound, Peptide 6, has been tested in mouse models of traumatic brain injury and Down syndrome. Those findings belong to Peptide 6 and should not be assumed to apply to P021.
How Does It Work?
The proposed pathway, based on rodent studies: P021 (oral or peripheral) ↓ reaches the brain ↓ increased brain-derived neurotrophic factor (BDNF) expression ↓ reduced activity of glycogen synthase kinase-3β (GSK-3β), a major tau-phosphorylating enzyme ↓ more new neurons in the dentate gyrus (hippocampus), better synaptic markers, less abnormal tau phosphorylation ↓ improved performance on rodent memory tasks. The exact molecular target of P021 is not firmly established. The BDNF/GSK-3β link comes mainly from the same research group.
What Does the Research Show?
Human research
NOT ESTABLISHED No published human studies were found.
Animal research
MODERATE Several mouse and rat studies, including normal adult mice, a triple-transgenic Alzheimer's mouse model (3xTg-AD), and aged rats. Results are consistently positive, but nearly all come from one laboratory.
In-vitro research
LIMITED Most published work is in vivo; mechanistic cell-level characterization is limited.
Notable Studies
Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice
animalJournal: FEBS Letters. Introduced the adamantane-containing compound (called P21 in this paper). Given peripherally to normal adult C57BL/6 mice, it improved learning plus short-term and spatial reference memory, and increased neurogenesis and maturation of new neurons in the dentate gyrus.
Limitations: Healthy young mice, single laboratory, short report. Behavioral gains in mice do not establish cognitive effects in humans.
View publication →Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic compound
animalJournal: Neurobiology of Aging. Chronic oral P021 in 22–24-month-old Fisher rats reduced age-related learning and memory decline, countered the drop in neurogenesis, increased BDNF, restored synaptic markers, and lowered hippocampal myo-inositol measured by MR spectroscopy.
Limitations: Rat aging model from the originating group; no independent replication identified.
View publication →Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease
animalJournal: Neurobiology of Disease. Female 3xTg-AD mice received P021 in their diet for 12 months starting at 9–10 months of age. Treatment reduced tau hyperphosphorylation and accumulation, decreased soluble amyloid-β (with only a trend toward fewer plaques), increased BDNF, reduced GSK-3β activity, and rescued cognitive, neurogenesis and synaptic deficits.
Limitations: Transgenic mouse model, female mice only, single research group. Mouse "disease modification" has a poor record of predicting human Alzheimer's outcomes.
View publication →Elevated Tau Level in Aged Rat Cerebrospinal Fluid Reduced by Treatment with a Neurotrophic Compound
animalJournal: Journal of Alzheimer's Disease. Reported that P021 crosses the blood–brain barrier, and that chronic oral treatment lowered total tau in the brain and cerebrospinal fluid of aged rats toward young-adult levels, without affecting CSF amyloid-β/APP. No detectable immune reaction was observed.
Limitations: Biomarker study in rats; lowering CSF tau in rats does not establish clinical benefit.
View publication →Prevention of Amyloid-β and Tau Pathologies, Associated Neurodegeneration, and Cognitive Deficit by Early Treatment with a Neurotrophic Compound
animalJournal: Journal of Alzheimer's Disease. Continuous P021 treatment in 3xTg-AD mice starting at 3 months of age, before visible pathology, was followed for up to 18 months. The authors reported prevention of neurodegeneration and tau and amyloid pathology, rescue of episodic memory, and a marked reduction in mortality.
Limitations: Two-author, single-lab study in a transgenic mouse model; prevention in mice does not predict prevention in people.
View publication →What We Still Don't Know
• Any effect, safety or pharmacokinetics in humans; no human studies were identified • Its precise molecular target and receptor • Independent replication outside the Iqbal laboratory • Long-term toxicity, including whether stimulating growth-factor pathways carries tumor or other risks • Whether rodent memory and neurogenesis gains translate to human cognition • Effects in healthy adults versus disease models • Stability, purity and identity of material sold as "P21" outside research laboratories.
Related Compounds
Recent publications
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Sources & References
- Li B, Wanka L, Blanchard J, et al. Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice. FEBS Lett. 2010;584(15):3359–3365.
- Bolognin S, Buffelli M, Puoliväli J, Iqbal K. Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic compound. Neurobiol Aging. 2014;35(9):2134–2146.
- Kazim SF, Blanchard J, Dai CL, et al. Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2014;71:110–130.
- Khatoon S, Chalbot S, Bolognin S, Puoliväli J, Iqbal K. Elevated tau level in aged rat cerebrospinal fluid reduced by treatment with a neurotrophic compound. J Alzheimers Dis. 2015.
- Baazaoui N, Iqbal K. Prevention of amyloid-β and tau pathologies, associated neurodegeneration, and cognitive deficit by early treatment with a neurotrophic compound. J Alzheimers Dis. 2017;58(1):215–230.
- Kazim SF, Iqbal K. Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease. Mol Neurodegener. 2016.
- Chohan MO, Li B, Blanchard J, et al. Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide. Neurobiol Aging. 2011. (Parent compound Peptide 6.)
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