P21
preclinicalAlso known as: P021
**Mechanism of Action** P21 (P021) is a synthetic peptide derived from ciliary neurotrophic factor (CNTF) that acts as a small-molecule mimetic of CNTF's neuroprotective signaling. It selectively activates the CNTF receptor complex (CNTFRα, gp130, and LIFRβ), leading to downstream JAK/STAT3 and MAPK/ERK pathway activation. This signaling cascade promotes neural stem cell proliferation and differentiation, particularly in the hippocampus, while simultaneously reducing tau hyperphosphorylation and aggregation through modulation of glycogen synthase kinase-3β (GSK-3β) activity. The peptide does not cross the blood-brain barrier efficiently, but systemic administration has shown central effects, likely via peripheral signaling or circumventricular organ interactions. **Key Research Findings** Preclinical studies in transgenic Alzheimer's disease (AD) mouse models (e.g., 3xTg-AD) demonstrate that chronic P21 treatment enhances hippocampal neurogenesis, improves spatial memory in Morris water maze tests, and reduces soluble and insoluble tau pathology by 30–50%. The peptide also decreases neuroinflammation markers (e.g., IL-6, TNF-α) and restores synaptic plasticity markers (e.g., PSD-95, synaptophysin). Notably, P21 does not significantly alter amyloid-β plaque burden, suggesting its effects are tau-centric and neurogenic rather than amyloid-directed. No overt toxicity has been reported in rodent studies. **Clinical Relevance** P21 remains in preclinical development, with no human trials initiated to date. Its dual action—promoting neurogenesis and targeting tau pathology—positions it as a potential disease-modifying candidate for AD and other tauopathies. However, challenges include optimizing bioavailability and confirming target engagement in humans. The peptide's CNTF-derived mechanism may also carry risks of weight loss or immune modulation, as seen with full-length CNTF. For research purposes only — not medical advice.
Key data
C27H42N6O8Research & studies
Loss of p21 increases trabecular bone formation post-injury.; Loss of E2f1 increases cortical bone formation but leads to poorer bone repair overall.; E2f1 absence dramatically decreases osteoblasts, osteoclasts, and chondrocytes at the injury site.; E2f1 and p21 have distinct roles in bone regeneration, with E2f1 regulating cell populations required for repair.
Full-length transcription, splicing, and accumulation of lincRNA-p21 are not required for cis-regulation.; Conserved regions in exon 1 of lincRNA-p21 are necessary for cis-activation.; Nascent transcription from the lincRNA-p21 locus, rather than the mature lncRNA, drives local gene expression control.
p21 activates Rb-dependent transcription to generate a secretome (PASP) including chemokine CXCL14.; PASP attracts macrophages, which disengage if p21 normalizes within 4 days.; Persistent p21 induction polarizes macrophages to M1 phenotype and triggers cytotoxic T cell response.; p21 concurrently induces proliferative arrest and immunosurveillance of stressed cells.
Frequently asked questions
What is P21?
**Mechanism of Action** P21 (P021) is a synthetic peptide derived from ciliary neurotrophic factor (CNTF) that acts as a small-molecule mimetic of CNTF's neuroprotective signaling. It selectively activates the CNTF receptor complex (CNTFRα, gp130, and LIFRβ), leading to downstream JAK/STAT3 and MAPK/ERK pathway activat
How does P21 work?
CNTF-derived peptidergic compound that promotes neurogenesis and reduces tau pathology in preclinical Alzheimer's models.
What is the research status of P21?
P21 is currently classified as preclinical, with 41,061 research references on record. This is for research purposes only and is not medical advice.
What is the molecular weight of P21?
P21 has a molecular weight of approximately 578.7 g/mol (formula C27H42N6O8).
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