P-21

P21, published as P021 or Peptide 021, is a small synthetic peptidomimetic derived from ciliary neurotrophic factor (CNTF). Khalid Iqbal's laboratory at the New York State Institute for Basic Research in Developmental Disabilities found an active 11-residue CNTF fragment, Peptide 6, by epitope mapping. The group cut it down to four residues, Asp-Gly-Gly-Leu, and added an adamantylated glycine at the C-terminus to raise blood-brain barrier permeability (Kazim and Iqbal, 2016).

The first paper on the compound called it P21 (Li et al., 2010). Despite the "BDNF" in our product name, P21 is not brain-derived neurotrophic factor; it is studied for its effects on BDNF expression in rodent brain (Bolognin et al., 2014).

Those come from PubChem CID 56599151, whose structure matches the papers' Ac-DGGLAG-NH2. Papers list 578.3, which matches the monoisotopic mass, and place the four peptide residues at positions 148 to 151 of human CNTF (Kazim et al., 2017).

Published work on the P021 peptide falls into five areas, all in animals or cells. Every P021 study in PubMed lists Iqbal as an author, so independent replication is thin. He holds US patents on P021 and co-founded Phanes Biotech, which holds a worldwide license to develop it (Falangola et al., 2026). A 2011 study of the parent Peptide 6, led by another laboratory with Iqbal as a co-author, was retracted in 2026 (Rockenstein et al., 2011). No P021 paper carries a retraction or expression of concern in PubMed.

Neurogenesis and BDNF in normal and aged rodents

In normal adult C57Bl6 mice, P21 given peripherally enhanced learning and both short-term and spatial reference memory. It also increased neurogenesis and the maturation of newborn neurons in the dentate gyrus (Li et al., 2010). In 22- to 24-month-old Fischer rats, chronic oral P021 lessened the age-related decline in learning and memory, countered the fall in neurogenesis, raised BDNF expression, reversed synaptic deficits in cortex and hippocampus, and lowered hippocampal myo-inositol, which was elevated in aged rats (Bolognin et al., 2014).

A follow-up in aged rats reported that P021 crosses the blood-brain barrier, lowered total tau in the brain, and brought cerebrospinal fluid tau, but not Aβ/AβPP, back to young-adult levels (Khatoon et al., 2015). Models: mice and rats.

Tau and amyloid in Alzheimer's-model mice

Female 3xTg-AD mice, which carry Alzheimer's-linked APP, presenilin-1 and tau mutations, were fed a P021 diet for 12 months from 9 to 10 months of age. They showed less abnormal tau hyperphosphorylation, lower soluble Aβ and a trend toward fewer CA1 plaques, with rescued cognition, neurogenesis and synaptic plasticity. The authors linked the tau effect to higher BDNF and lower GSK-3β activity (Kazim et al., 2014).

Starting the diet at 3 months, before overt pathology, prevented neurodegeneration and Aβ and tau pathology, rescued episodic memory and markedly reduced mortality (Baazaoui and Iqbal, 2017a). The same schedule, continued to 21 months, rescued dendritic and synaptic deficits, increased neurogenesis and reversed cognitive impairment (Baazaoui and Iqbal, 2017b). Model: 3xTg-AD mice.

Early-life exposure in Down syndrome and Alzheimer's models

In Ts65Dn mice, a Down syndrome model, dams were fed P021 at 200 nmol per gram of diet from embryonic day 8 to weaning on postnatal day 21. Their trisomic pups showed less developmental delay and, as adults, better hippocampus-dependent memory. They also had no presynaptic protein deficit, lower GSK-3β activity and higher BDNF and phosphorylated CREB (Kazim et al., 2017).

The same prenatal-to-weaning window in 3xTg-AD mice rescued cognition at 4 months and lowered tau pathology and Aβ plaque load at 22 months (Wei et al., 2020). A P021 diet from birth to postnatal day 120 prevented the memory deficit at 4 months and raised phosphorylated CREB and BDNF (Wei et al., 2021). Models: Ts65Dn and 3xTg-AD mice.

Retina and brain imaging

Aged Fischer rats given P021 by gavage at 500 nmol/kg a day for 3 months, and 3xTg-AD mice fed it from 3 to 21 months, showed fewer age-related macular degeneration-like retinal changes: photoreceptor degeneration, lipofuscin, retinal pigment epithelium atrophy, Bruch's membrane thickening and glial activation (Liu et al., 2019).

In female 3xTg-AD mice fed P021 from 2.5 to 8 months of age, diffusional kurtosis MRI found fractional anisotropy in the corpus callosum, external capsule and cingulate cortex shifted toward wild-type values. The study had no histology or behavior testing (Falangola et al., 2026). Models: rats and mice.

CDKL5 deficiency: mixed findings

A University of Bologna group, with Iqbal as a co-author, tested P021 in models of CDKL5 deficiency disorder. In CDKL5-knockout human SH-SY5Y neuroblastoma cells, P021 at 1 or 10 µM restored proliferation, survival and maturation and corrected changes in GSK-3β signaling. In Cdkl5 knockout mice fed P021 from weaning for 70 days, or given it intraperitoneally for 30 days as adults, it did not raise brain BDNF or correct neuroanatomical defects, and effects on behavior were limited (Mottolese et al., 2024). Models: human cell line and mice.