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The P21 (also identified as P021) is a synthetic peptide designed to mimic the activity of ciliary neurotrophic factor (CNTF) on the brain without triggering an allergic response. CNTF is a protein that promotes the survival and differentiation of various neural cells, including neurons and oligodendrocytes. CNTF has been suggested to exhibit possible neuroprotective and neurodegenerative activity in animal models of neurodegenerative diseases and injuries. Scientists identified CNTF's most active regions based on epitope mapping of neutralizing antibodies to CNTF.(1) This led to the development of Peptide 6, made of 11 amino acids (Ac-VGDGGLFEKKL-NH(2)) and a subsequence of just 4 amino acids called Peptide 6c (Ac-DGGL-NH(2)).
These amino acids have been supposed to support enhanced hippocampus-dependent learning and memory, increased neurogenesis, and potentially boost neuronal plasticity in normal adult mice. To improve the stability of the peptide and boost its potential to pass through the blood-brain barrier, the scientists report that they "added adamantane building blocks to the C-terminus or both C- and N-termini of Peptide 6c”. The result is P21, which appears to have the potential to mimic the action of CNTF by activating the CNTF receptor complex and downstream signaling pathways, possibly leading to enhanced cognition, increased proliferation, and neuronal differentiation of adult hippocampal progenitors in mice.
Molecular Weight: 578.7 g/mol
Research and Clinical Studies
P21 and Cognitive impairment
One study presented P21 peptide to 3xTg-AD mice in their diet 6-9 months before the onset of amyloid beta (Aβ) or tau pathology and during the period of synaptic compensation.(2) The study suggested that P21 appeared to rescue dendritic and synaptic deficits, boost neurogenesis, and reverse cognitive impairment in the 3xTg-AD mice. The study suggests that P21 may contribute to a mitigation of synaptic deficits and cognitive impairment by providing appropriate neurotrophic support during synaptic compensation.
Another study suggested that the P21 may reduce the age-dependent decline in learning and memory in aged Fisher rats by inhibiting neurogenesis deficit and possibly increasing the expression of brain-derived neurotrophic factor and restoring synaptic deficits in both the cortex and hippocampus.(3) The study also indicated that P21 appeared to reduce the concentration of myoinositol, a metabolite that increases in aged rats. The study suggests that "stimulating endogenous neuroprotective mechanisms using P21 may be a promising therapeutic approach for cognitive aging, Alzheimer's disease, and associated neurodegenerative disorders."
P21 and Alzheimer's Disease
One study focusing on the potential of the P21 suggested that chronic presentation of P21 appeared to possibly reduce the brain level of total tau in aged Fisher rats, and possibly also reduce tau levels in the cerebrospinal fluid (CSF) to that of young adult rats.(4) The study also observed that "P21 is blood-brain-barrier-permeable and does not induce any detectable immune reaction in rats."
Another study investigated the potential of P21 on neurobehavior and AD-like pathology in a transgenic mouse model of AD.(5) The compound was presented during prenatal-to-early postnatal development. Results suggested that the peptide appeared to rescue cognitive deficits, reduce abnormal accumulation of tau and Aβ plaque load, ameliorate certain markers of postsynaptic deficits, and decrease neuroinflammation in the brain.
In another experiment, the researchers investigated the neurotrophic potential in the P21 compound in preventing neurodegeneration, amyloid-β, and tau pathologies in 3xTg-AD mice.(6) The researchers started P21 during the period of synaptic compensation several months before the appearance of any overt pathology. They observed that P21 initiated during this period might prevent neurodegeneration, Aβ and tau pathologies, rescue episodic memory impairment, and markedly reduce the mortality rate.
One trial also investigated the potential of P21 on cognitive function and synaptic plasticity in a transgenic mouse model of AD.(7) Results indicated that the peptide might possibly mitigate cognitive impairment, increase expressions of pCREB and BDNF, and ameliorate synaptic protein deficit in the mice. The study also suggests that P21 might potentially rescue synaptic deficits and cognitive impairment in familial AD and related tauopathies during early development.
P21 and Macular Degeneration
Age-related macular degeneration (AMD) affects the macula, which is the central part of the retina responsible for central vision. It is one of the most common neurodegenerative diseases among the elderly and can lead to vision loss at its end stage. Recent research has suggested that consistent presentation of the neurotrophic peptidergic compound may help prevent the occurrence of AMD pathology.
A study conducted in aged rats and 3xTg-AD mice reported that chronic presentation of P21 appeared to possibly prevent several pathological changes associated with AMD.(8) The study reported identifying photoreceptor degeneration, lipofuscin granules, vacuoles, atrophy in retinal pigment epithelium (RPE), and Bruch's membrane (BM) thickening. The study also reported a rosette-like structure formation in aged rats, a hallmark of AMD pathology. Microgliosis and astrogliosis, inflammatory responses in the retina, were also observed in different retinal layers. Furthermore, the study indicated that total tau, phosphorylated tau, Aβ/APP, and VEGF appeared to be widely distributed in the sub-retina of aged rats and 3xTg mice. These molecules are associated with Alzheimer's disease pathology, and their presence suggests that retinal changes associated with aging and Alzheimer's disease share some common features. Importantly, consistent treatment with P21 for three months in rats and 18 months in 3xTg mice appeared to ameliorate the pathological changes described above.
P21 peptide is available for research and laboratory purposes only. Please review and adhere to our Terms and Conditions before ordering.
- Li, B., Wanka, L., Blanchard, J., Liu, F., Chohan, M. O., Iqbal, K., & Grundke-Iqbal, I. (2010). Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice. FEBS letters, 584(15), 3359–3365. https://doi.org/10.1016/j.febslet.2010.06.025
- Baazaoui, N., & Iqbal, K. (2017). Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound. Alzheimer's research & therapy, 9(1), 45. https://doi.org/10.1186/s13195-017-0273-7
- Bolognin, S., Buffelli, M., Puoliväli, J., & Iqbal, K. (2014). Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic compound. Neurobiology of aging, 35(9), 2134–2146. https://doi.org/10.1016/j.neurobiolaging.2014.02.017
- Khatoon, S., Chalbot, S., Bolognin, S., Puoliväli, J., & Iqbal, K. (2015). Elevated Tau Level in Aged Rat Cerebrospinal Fluid Reduced by Treatment with a Neurotrophic Compound. Journal of Alzheimer's disease : JAD, 47(3), 557–564. https://doi.org/10.3233/JAD-142799
- Wei, W., Wang, Y., Liu, Y., Dai, C. L., Tung, Y. C., Liu, F., & Iqbal, K. (2020). Prenatal to early postnatal neurotrophic treatment prevents Alzheimer-like behavior and pathology in mice. Alzheimer's research & therapy, 12(1), 102. https://doi.org/10.1186/s13195-020-00666-7
- Baazaoui, N., & Iqbal, K. (2017). Prevention of Amyloid-β and Tau Pathologies, Associated Neurodegeneration, and Cognitive Deficit by Early Treatment with a Neurotrophic Compound. Journal of Alzheimer's disease : JAD, 58(1), 215–230. https://doi.org/10.3233/JAD-170075
- Wei, W., Liu, Y., Dai, C. L., Baazaoui, N., Tung, Y. C., Liu, F., & Iqbal, K. (2021). Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction. Journal of Alzheimer's disease : JAD, 82(2), 631–646. https://doi.org/10.3233/JAD-201599
- Liu, Y., Wei, W., Baazaoui, N., Liu, F., & Iqbal, K. (2019). Inhibition of AMD-Like Pathology With a Neurotrophic Compound in Aged Rats and 3xTg-AD Mice. Frontiers in aging neuroscience, 11, 309. https://doi.org/10.3389/fnagi.2019.00309