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What is P21 and where does it come from?

Researchers at the New York State Institute for Basic Research in Developmental Disabilities developed P21, also known as P021 (Ac-DGGL(A)G-NH2), as a peptidergic compound derived from ciliary neurotrophic factor (CNTF). It was designed to be blood brain barrier permeable and active via oral administration. 1 2

Neurotrophic factors have been investigated as a therapeutic approach to shift the balance from neurodegeneration to neural regeneration. However, delivering these compounds effectively to the brain has historically been challenging. P21 was engineered as a neurotrophic peptide mimetic to bypass these limitations and act directly on underlying disease pathology. 1

Preclinical evidence for neurogenesis

In animal studies, P21 has been shown to rescue deficits in neurogenesis and synaptic plasticity. Researchers found that in 3xTg-AD mice, P21 increased the expression of brain derived neurotrophic factor (BDNF). This increase in BDNF mediated a decrease in glycogen synthase kinase-3-β (GSK3β) activity, which is believed to contribute to the compound's disease modifying effects. 1

The combination of increased BDNF expression and decreased GSK3β activity makes P21 a highly effective neurogenic agent in laboratory mice. However, it is necessary to remember that demonstrating this mechanism in a mouse model does not guarantee the same response in a human brain. 1

Research in Alzheimer's disease models

In models of Alzheimer's disease, which is characterised by amyloid beta plaques and neurofibrillary tangles, P21 has shown disease modifying potential. In one study, female 3xTg-AD mice and wild type mice were treated with an oral P021 or vehicle diet for 12 months, starting at 9 to 10 months of age. The researchers observed a significant reduction in the abnormal hyperphosphorylation and accumulation of tau at major pathology associated sites. 1

The treatment's effect on amyloid beta was limited to a significant decrease in soluble amyloid beta levels and a trend towards a reduced plaque load in the CA1 region of the hippocampus. This was consistent with a reduction in amyloid beta generation rather than clearance. Overall, the treatment rescued deficits in cognition, neurogenesis, and synaptic plasticity. 1

A separate study in aged Fisher rats confirmed that P21 is blood brain barrier permeable. Chronic oral treatment reduced the brain level of total tau. The researchers also found that while cerebrospinal fluid levels of both tau and Aβ/AβPP were elevated in the aged rats, P21 treatment reduced tau (but not Aβ/AβPP) to levels comparable to those found in young adult rats. Importantly, the compound did not induce any detectable immune reaction. 2

The gap between rodents and humans

The results observed in transgenic mice and aged rats are highly promising from a basic science perspective. However, they remain entirely restricted to preclinical models. The history of Alzheimer's disease research is filled with compounds that cleared pathology in mice but failed completely in human trials.

Transgenic mice are engineered to overexpress specific human genes rapidly. Their neurobiology, lifespan and cognitive functions are vastly different from those of a human patient who develops sporadic Alzheimer's disease over several decades. A drug that successfully clears plaques or stimulates neurogenesis in a mouse brain may be entirely ineffective in a human brain, or it may trigger unacceptable adverse events.

UK regulatory status

Under UK law, any substance presented as a treatment for a medical condition or intended to modify physiological functions requires regulatory approval. 3 The regulatory body responsible for this oversight is the MHRA. 4

P021

Preclinical only

Neuroactive · 8 cited studies

There is no human data of any kind (no Phase 1, no registered trial, no published exposure), and the substantial animal literature derives almost entirely from the single laboratory that developed the compound.

UK status. No UK marketing authorisation.

View the P021 evidence record See all BioRx studies for P021

The BioRx conclusion

In rodent models, P21 demonstrates a clear ability to rescue deficits in neurogenesis, elevate brain derived neurotrophic factor, and reduce tau pathology associated with Alzheimer's disease. These findings make it a valuable tool for studying brain plasticity and neurodegeneration in a laboratory setting. 1

Frequently asked questions

What is the P21 peptide?

P21, also known as P021, is a synthetic peptidergic compound derived from ciliary neurotrophic factor. It was engineered to be blood brain barrier permeable and active via oral administration. 1 2

What does P21 do in animal studies?

In rodent models, P21 has been shown to rescue deficits in neurogenesis, elevate brain derived neurotrophic factor, and reduce tau pathology associated with Alzheimer's disease. 1

Has P21 been tested in humans?

No. There are no published human clinical trials for P21. All current evidence regarding its effects on neurogenesis and cognitive function comes from animal studies.

More peptide questions

References

Studies marked "View study in BioRx" sit in the clinical studies index with their design and evidence grade.

  1. Kazim SF, Blanchard J, Dai CL, Tung YC, LaFerla FM, Grundke-Iqbal I, Iqbal K (2014). Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease. Neurobiology of Disease.PubMed · DOI · View study in BioRx
  2. Khatoon S, Chalbot S, Bolognin S, Puolivali J, Iqbal K (2015). Elevated Tau Level in Aged Rat Cerebrospinal Fluid Reduced by Treatment with a Neurotrophic Compound. Journal of Alzheimer's Disease.PubMed · DOI · View study in BioRx
  3. Human Medicines Regulations 2012, regulation 46: a medicinal product needs a marketing authorisation to be sold or supplied
  4. MHRA, the Medicines and Healthcare products Regulatory Agency