Scientists pinpointed the most active regions of CNTF through epitope mapping using neutralizing antibodies against CNTF.(1) This discovery paved the way for the creation of Peptide 6, composed of 11 amino acids (Ac-VGDGGLFEKKL-NH(2)), and a shorter sequence of just 4 amino acids known as Peptide 6c (Ac-DGGL-NH(2)).
These amino acids were hypothesized to promote improved hippocampus-dependent learning and memory, heightened neurogenesis, and potentially enhanced neuronal adaptability in normal adult mice. In an effort to enhance the peptide’s stability and its ability to traverse the blood-brain barrier, the scientists introduced adamantane building blocks to the C-terminus or both C- and N-termini of Peptide 6c. The result was P21, which seems to possess the capability to emulate the actions of CNTF through activating the CNTF receptor complex and subsequent signaling pathways. This activation holds the promise of bolstering cognition, increasing the proliferation of hippocampal progenitors, and promoting neuronal differentiation in mice.
Mechanism of Action
P21 is hypothesized to exert its primary potential within the central nervous system, with a particular focus on the dentate gyrus. Situated in the temporal lobe as part of the hippocampal formation, this region is said to contribute to the formation of fresh episodic memories and is suggested to facilitate spontaneous exploration and learning in novel environments. Additionally, the dentate gyrus plays a pivotal role in information preprocessing and pattern separation, the cognitive process that enables mammals to distinguish one memory from another. Notably, it stands out in the realm of neuroscience due to its significant rates of neurogenesis.
In mouse model studies, P21’s mechanism of action is said to deviate from the direct binding to the CNTF receptor, distinguishing it from a true analog of CNTF. Instead, P21 appears to function by inhibiting antibodies or other molecules that neutralize CNTF. Consequently, even though P21 does not appear to replicate CNTF’s effects directly, it has been suggested in research findings to mimic them by elevating the concentration of this powerful promoter of neurogenesis.
Further research in mice reveals that P21 possibly enhances the presence of BrdU-positive cells in the dentate gyrus. BrdU, a synthetic nucleoside akin to thymidine, reportedly serves as a marker for proliferating cells within living tissues. In experiments, BrdU is concentrated in the dentate gyrus of mice receiving P21, in contrast to control mice, suggesting that P21 possibly fosters cell proliferation in this region. To discern whether these cells are neurons, researchers assess NeuN expression, a marker indicative of mature neurons. The significant increase in NeuN levels in mice exposed to P21, particularly in the area displaying heightened BrdU presence, supports the researchers’ speculations that P21 may indeed promote increased neurogenesis.(2)
Research and Scientific Studies
P21 Peptide and Cognitive Enhancement
In one study, P21 peptide was introduced into the diets of 3xTg-AD mice approximately 6-9 months before the onset of amyloid beta (Aβ) or tau pathology, a period coinciding with synaptic compensation.(3) Remarkably, this research revealed that P21 seemingly rescued deficits in dendritic and synaptic function, promoted neurogenesis, and reversed cognitive impairment in the 3xTg-AD mice. These findings propose that P21 may potentially lead to the “prevention of dendritic and synaptic deficits and reversal of cognitive impairment” and also “did not show any weight loss, tumors, or signs of pain,” which indicates the potential effects of the P21 peptide.
In another study involving aged fisher rats, P21 emerged as an interesting study within the context of counteracting age-related declines in learning and memory.(4) It achieved a level of effectiveness, researchers suggested, by inhibiting deficits in neurogenesis and potentially upregulating the expression of brain-derived neurotrophic factor, thereby restoring synaptic function in both the cortex and hippocampus. Furthermore, the study indicated that P21 appeared to have reduced the concentration of myoinositol, a metabolite known to increase in aged rats. These results suggest that harnessing endogenous neuroprotective mechanisms through P21 may hold promise within the field of research addressing cognitive aging, Alzheimer’s disease, and related neurodegenerative disorders.
P21 Peptide and Macular Degeneration
Age-related macular degeneration (AMD) affects the macula, the central portion of the retina responsible for central vision. It ranks as one of the most prevalent neurodegenerative diseases and can ultimately result in vision loss. Recent research indicates that continuous exposure to a neurotrophic peptidergic compound may potentially prevent the development of AMD pathology.
In a study conducted on aged rats and 3xTg-AD mice, a sustained regimen of P21 appeared to hold promise in averting several pathological alterations linked to AMD.(5) The investigation noted the prevention of photoreceptor degeneration, the reduction of lipofuscin granules, the mitigation of vacuoles, and the amelioration of atrophy in the retinal pigment epithelium (RPE) and thickening of Bruch’s membrane (BM). Additionally, the study reported the inhibition of rosette-like structure formation in aged rats, a characteristic feature of AMD pathology. Furthermore, microgliosis and astrogliosis, inflammatory responses within the retina, were observed in various retinal layers. The study also highlighted the widespread distribution of total tau, phosphorylated tau, Aβ/APP, and VEGF in the sub-retina of aged rats and 3xTg mice, molecules associated with Alzheimer’s disease pathology.
This presence suggests shared features between retinal changes associated with aging and Alzheimer’s disease. Significantly, sustained exposure to P21 over three months in rats and 18 months in 3xTg mice appeared to alleviate the aforementioned pathological changes.
P21 Peptide and Alzheimer’s disease
A study examining the potential of P21 has intriguing implications for Alzheimer’s Disease (AD). It was found that sustained exposure to P21 seemed to have a noteworthy effect on aged Fisher rats by potentially reducing total tau levels in the brain, possibly bringing them closer to those observed in young adult rats. Furthermore, the study noted that P21 exhibited an ability to cross the blood-brain barrier without triggering any detectable immune responses in rats.(6)
Another study delved into P21’s influence on neurobehavior and AD-like pathology in a transgenic mouse model of AD. Introduced during prenatal-to-early postnatal development, the peptide appeared to hold promise in rescuing cognitive deficits, reducing abnormal tau accumulation, decreasing Aβ plaque load, ameliorating certain indicators of postsynaptic deficits, and mitigating neuroinflammation within the brain.(7)
In a separate experiment, researchers explored the neurotrophic potential of P21 in preventing neurodegeneration, amyloid-β, and tau pathologies in 3xTg-AD mice. P21 was initiated during the phase of synaptic compensation, several months prior to the emergence of overt pathology. Impressively, this approach seemed to avert neurodegeneration, Aβ and tau pathologies, restore episodic memory function, and significantly reduce mortality rates.(8)
Yet another trial investigated P21’s potential impact on cognitive function and synaptic plasticity in a transgenic mouse model of AD. The results indicated that the peptide held promise in potentially alleviating cognitive impairment, increasing the expression of pCREB and BDNF (brain-derived neurotrophic factor), and improving synaptic protein levels in these mice. This study also suggests 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.”
P21 Peptide and Appetite
While there haven’t been direct studies assessing the impact of P21 on food intake, there is a compelling rationale to suggest that it may potentially act as an appetite suppressant. This hypothesis stems from its proposed ability to stimulate the synthesis of alpha-melanocyte-stimulating hormone (alpha-MSH), a process initiated by elevated CNTF levels. By effectively raising CNTF levels through the reduction of neutralizing antibodies, P21 may activate the JAK/STAT pathway, leading to increased levels of alpha-MSH. Both alpha-MSH and neurogenesis have associations with reduced food intake, making it reasonable to anticipate that P21 may exhibit satiety-related effects in future research endeavors.(9)
In conclusion, the P21 peptide, a promising neurotrophic compound, has been suggested to exert multifaceted potential in various domains of neurobiology.
Research findings suggest its capacity to enhance neurogenesis, ameliorate cognitive deficits, and mitigate pathological changes associated with conditions such as Alzheimer’s disease and age-related macular degeneration. Its influence on appetite regulation, potentially through alpha-MSH synthesis, warrants further exploration. P21’s likely ability to traverse the blood-brain barrier without provoking immune responses adds to its appeal in extensive areas of research. As investigations into P21 continue, it holds significant promise in addressing neurological disorders and advancing our understanding of neuroprotection.
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- 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
- B. Li et al., “Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice,” FEBS Lett., vol. 584, no. 15, pp. 3359–3365, 2010. https://www.sciencedirect.com/science/article/pii/S001457931000520X
- 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
- 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
- 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
- B. Xu and X. Xie, “Neurotrophic factor control of satiety and body weight,” Nat. Rev. Neurosci., vol. 17, no. 5, pp. 282–292, May 2016. https://www.nature.com/articles/nrn.2016.24