Section 01
What it's used for
Alzheimer's studies in mice only
In female mice bred to develop Alzheimer's-like disease, months of treatment reduced tau and amyloid buildup and improved memory and brain-cell growth. Both studies are from one lab; a foundation review found no human trial data exist.
▸Clinical wording
The Alzheimer's evidence rests on two long oral-dosing studies in female 3xTg-AD mice, both from the originating laboratory. Treatment begun at 9–10 months of age and continued for 12 months significantly reduced abnormal tau hyperphosphorylation at the major AD neurofibrillary sites and lowered soluble amyloid-β (plaque load in hippocampal CA1 showed only a trend), with increased BDNF expression, decreased GSK-3β activity, and rescue of cognition, neurogenesis and synaptic plasticity. Treatment begun earlier, at 3 months and continued about 18 months at 60 nmol P021 per gram of feed, rescued MAP2, GluR1 and synaptophysin deficits and restored doublecortin- and Ki-67-positive cell counts. There are no human data: the Alzheimer's Drug Discovery Foundation's Cognitive Vitality review of P021 states that no clinical trial data in humans are available.
New brain cells, rodents only
In healthy young mice and aged rats, this peptide increased growth of new brain cells and improved learning and memory. All findings are rodent studies from one group; no human imaging evidence of new cell growth exists.
▸Clinical wording
In normal adult C57BL/6 mice, peripherally administered P021 increased neurogenesis and the maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus, alongside improved learning and short-term and spatial reference memory. In 22–24-month-old Fischer rats, chronic oral P021 reversed the age-related deficit in neurogenesis, raised BDNF expression and restored synaptic markers in both cortex and hippocampus. In 3xTg-AD mice, doublecortin- and Ki-67-positive cell counts in treated animals matched or exceeded wild-type levels. All of this is rodent histology from the same research group; no imaging or biomarker evidence of neurogenesis in humans exists for this peptide.
Lowered tau buildup in rodents
In mice with Alzheimer's-like disease, a year of treatment reduced abnormal tau in the brain. In aged rats, it lowered spinal-fluid tau to young-adult levels, though an amyloid marker did not fall. Both are rodent studies; none in people.
▸Clinical wording
In 3xTg-AD mice treated orally for 12 months, P021 significantly reduced abnormally hyperphosphorylated and accumulated tau at the sites associated with AD neurofibrillary pathology, an effect the authors attributed to BDNF-mediated suppression of GSK-3β activity. In aged Fischer rats, chronic oral P021 lowered total tau in brain tissue and brought elevated cerebrospinal-fluid tau back to the level seen in young adult rats, while CSF Aβ/AβPP was not reduced. Both findings come from the same laboratory and both are in rodents; no tau PET, CSF or plasma tau measurements from humans given P021 have been published.
Slowed cognitive aging in rats
In aged rats, treatment slowed age-related decline in learning and memory and lowered a brain-aging metabolite. In Alzheimer's-model mice, it improved memory tasks and partly normalized brain scans (2026). All rodent work, never in people.
▸Clinical wording
The clearest cognitive-ageing result is in 22–24-month-old Fischer rats, where chronic oral P021 significantly reduced the age-dependent decline in learning and memory and also lowered hippocampal myo-inositol, a metabolite that had risen with age on in vivo magnetic resonance spectroscopy. In 3xTg-AD mice, P021 improved Morris water maze escape latency and restored discrimination of novel object locations at 18 months of age. A 2026 diffusion-MRI study in 3xTg-AD mice treated from 2.5 to 8 months found partial normalisation of fractional anisotropy in corpus callosum and external capsule. Every one of these is a rodent study with the originating group among the authors, so the direction has not been independently replicated and has never been tested in people.
Down syndrome mouse model
In a Down-syndrome mouse model, pups given the peptide before and after birth reached milestones earlier and, as adults, fully recovered one memory type and partly recovered another (25.7% to 38.8%). One mouse study; no human equivalent.
▸Clinical wording
Ts65Dn mice, a model of Down syndrome, were treated through the dams with P021 at 200 nmol per gram of diet from embryonic day 8 to postnatal day 21. Treated pups reached surface-righting, cliff-aversion and ear-twitch milestones significantly earlier than untreated trisomic pups, and as adults showed complete rescue of spatial reference memory in the Morris water maze and partial rescue of long-term object recognition (discrimination index rising from 25.7% to 38.8%); synaptophysin, BDNF, the pCREB/CREB ratio and inhibitory Ser9 phosphorylation of GSK-3β were increased at both 3 weeks and about 7 months of age. This is a single mouse study from the same laboratory, using dosing in utero and through lactation that has no direct human counterpart.
Section 02
Mechanism of Action
Built from a nerve growth protein
- P021 was engineered from a short active region of a human nerve-supporting protein (ciliary neurotrophic factor).
- A bulky chemical group was added to raise its stability and its ability to cross fatty barriers.
- Its longer precursor increased new neuron formation in the mouse hippocampus and improved water maze performance.
- The authors reported it works by blocking a signal that restrains progenitor cell division.
▸Clinical wording
CNTF-derived scaffold and inhibition of LIF signalling
P021 (also written P21, Ac-DGGL(A)G-NH2) was engineered from an active region of human ciliary neurotrophic factor, residues 148-151, with an adamantylated glycine added to raise stability and lipophilicity (Li 2010; Mottolese 2024). Its 11-mer precursor Peptide 6, taken from CNTF residues 146-156, increased dentate gyrus neurogenesis and improved Morris water maze performance in adult mice, and the authors reported that it acts by competitively inhibiting leukemia inhibitory factor signalling, lifting a brake that LIF places on progenitor proliferation (Chohan 2011).
Less tau damage in model mice
- In Alzheimer-model mice treated orally for 12 months, P021 reduced abnormal tau modification and soluble amyloid-beta.
- The authors attributed this to more growth factor (BDNF) lowering the activity of a tau-modifying enzyme.
- In cells from a different genetic disorder, P021 restored that enzyme's regulation along with growth, survival and maturation.
▸Clinical wording
BDNF induction and PI3K-Akt-driven GSK3beta inhibition
In 3xTg-AD mice treated orally for 12 months from 9-10 months of age, P021 reduced abnormal tau hyperphosphorylation at major neurofibrillary sites and lowered soluble amyloid-beta; the authors attributed this to increased BDNF expression decreasing glycogen synthase kinase-3beta activity, since BDNF-driven PI3K-Akt signalling inhibits GSK3beta through phosphorylation at Ser9 (Kazim 2014). In CDKL5-knockout neuroblastoma cells, P021 at 10 micromolar restored phospho-GSK3beta to control levels together with proliferation, survival and maturation (Mottolese 2024).
New neurons and stronger connections in rodents
- In adult mice P021 given peripherally improved learning and memory while increasing new neuron formation in the hippocampus.
- In 22-24-month-old rats, chronic oral dosing reduced the age-related decline in learning and memory.
- Those rats also regained neurogenesis, cortical and hippocampal synaptic markers, and higher growth factor levels.
- The precursor peptide restored neurogenesis and several synapse proteins in a separate rat disease model.
▸Clinical wording
Adult neurogenesis, dendritic and synaptic plasticity
Peripheral P021 in adult C57Bl6 mice improved learning and both short-term and spatial reference memory while increasing neurogenesis and maturation of newborn neurons in the dentate granule cell layer and subgranular zone (Li 2010). Chronic oral P021 in 22-24-month-old Fisher rats reduced the age-dependent decline in learning and memory, restored neurogenesis and cortical and hippocampal synaptic markers, raised BDNF, and lowered hippocampal myo-inositol on in vivo magnetic resonance spectroscopy (Bolognin 2014). The precursor peptide rescued neurogenesis and synapsin I, synaptophysin and MAP2 density in an I2NTF-CTF rat model (Bolognin 2012).
Several signalling routes activated at once
- Treating Alzheimer-model mice from birth prevented cognitive impairment and raised two memory-related signalling proteins.
- Three separate signalling branches were activated and synaptic protein deficits were rescued.
- The authors read this as several converging plasticity cascades rather than one single target.
- A review from the originating laboratory frames the compound as a brain-penetrating mimic of that nerve protein.
▸Clinical wording
CREB phosphorylation and convergent kinase cascades
Treating 3xTg-AD mice from birth to postnatal day 120 prevented cognitive impairment and raised pCREB and BDNF, with activation of the PLC/PKC, MEK/ERK and PI3K/Akt branches and rescue of synaptic protein deficits, suggesting the compound engages several convergent plasticity cascades rather than a single kinase (Wei 2021). A review from the originating laboratory frames P021 as a blood-brain-barrier permeable CNTF mimetic whose neurogenic and anti-tau effects run through LIF inhibition plus BDNF-mediated GSK3beta suppression (Kazim 2016).
What the evidence cannot yet show
- All of this work is in rodents or cell culture, and almost all of it from a single laboratory group.
- No clinical trial of P021 in humans appears in the indexed literature.
- In one mouse model the compound did not raise the growth factor and failed to improve survival or spine maturation.
- Claims of a beta-catenin-driven neurogenesis mechanism were not confirmed in these primary reports.
▸Clinical wording
Boundaries of the current evidence
All of the above is rodent or cell-culture work, and almost all of it comes from a single laboratory group; no clinical trial of P021 in humans appears in the indexed literature. The effect is also model-dependent: in Cdkl5-null mice the compound did not raise BDNF and failed to promote proliferation, neuronal survival or spine maturation, despite correcting phospho-GSK3beta in the matching cell model, which the authors read as compensation within the intact brain network (Mottolese 2024). Claims of beta-catenin-mediated neurogenesis were not confirmed in these primary reports.
Section 03
Biological Pathways
- CNTF-derived LIF-signaling inhibitionEngineered from a ciliary neurotrophic factor fragment, the precursor competitively inhibits leukemia inhibitory factor signaling, lifting a brake LIF places on progenitor proliferation in the dentate gyrus.
- BDNF-driven GSK3-beta inhibitionChronic treatment raises BDNF expression, and BDNF-driven PI3K-Akt signaling phosphorylates and inhibits GSK3-beta, linked to reduced tau hyperphosphorylation and lower soluble amyloid-beta in transgenic mice.
- Adult neurogenesis and synaptic plasticityIn adult and aged rodents the peptide increases dentate gyrus neurogenesis and newborn neuron maturation, restores hippocampal and cortical synaptic markers, and improves learning and spatial reference memory.
- Convergent CREB and kinase cascadesLong-term treatment from birth raises phosphorylated CREB and BDNF alongside activation of the PLC/PKC, MEK/ERK and PI3K/Akt branches, engaging several plasticity cascades rather than a single kinase.
- Model-dependent and unreplicated findingsIn Cdkl5-null mice the peptide failed to raise BDNF or promote neuronal survival despite correcting phospho-GSK3-beta in the matching cell model, and no human clinical trial appears in the indexed literature.
Section 04
Dosage Information
Ac-DGGL (tetrapeptide from CNTF active region)| Route / system | Context | Range studied | Limitation |
|---|---|---|---|
| Oral — P021 mixed into feed | Mice bred for Alzheimer's — the bulk of the research | 60 nmol per gram of feed — about 150–162 nmol per mouse a day, for 6 to 18 months; in one study from age 3 to 21 months. | Medicated chow eaten around the clock, not a dose. No human equivalent was ever calculated from it, and no person has swallowed P021 in any trial. |
| Intraperitoneal — into the abdomen | Mice bred without the Cdkl5 gene, age 4 months | 750 nmol per mouse a day for 30 days, in saline. A second group in the same study got the 60 nmol/g feed for 70 days. | A route with no human counterpart. The mouse-to-human conversion was never done, and how much P021 reaches a human brain has never been measured. |
| Intranasal — self-administration | Vendor and forum practice, outside any study | 500–750 µg once a day as a nasal spray, one spray per nostril — roughly 6–11 µg/kg for a 70–90 kg adult. No study used this route. | Circulating practice, not a finding. No controlled trial of any phase has ever given P021 to a person: no safety, dose or absorption data behind it. |
Results
Syringe Fill Level (100u syringe)
Set positive values for: Recommended dose per kg.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Section 05
Protocols
No protocols featuring this peptide yet. Browse All Protocols
Section 06
Stability & Storage
Lyophilised powder
The dry powder is kept dark and dry: 0–4 °C for short periods of days to weeks and −20 °C for long-term storage; the catalogue claims a shelf life of more than 3 years. The catalogue names DMSO as the solvent.
After reconstitution
Published experiments dissolved the peptide differently: deionised water for cell work, giving a 1 mM stock, and saline for systemic dosing in animals. The stock is held at 0–4 °C briefly or at −20 °C for longer.
Section 07
Side Effects & Precautions
P021 has never been given to a person; every safety observation comes from mice, rats, or cell culture, and no human dose has ever been established.
No human data exist at all
No clinical trial of P021 is registered, and there is no human data on how it behaves in the body, its toxicity, or immune reactions. P021 is not manufactured or sold as a product for people.
18 months in 3xTg-AD mice: no weight loss or tumors
In the longest study, 3xTg-AD mice received P021 in feed for about 18 months, with no weight loss, tumors, or signs of pain reported. The study was run by the peptide's developer, and adverse events were described narratively rather than measured against formal toxicology endpoints.
Immunogenicity is the top suspected risk
Reviewers flag immunogenicity, antibody formation against P021, as the most likely adverse event for this peptide, a hypothesis, not an observed finding. Chronic dosing found no immune reaction in aged rats, from the peptide's own lab and not independently reproduced. No human data exist.
No formal toxicology package exists
- No GLP repeat-dose toxicity, genotoxicity, safety pharmacology, or reproductive toxicity study has been published in any species.
- No maximum tolerated dose has been published.
- P021 was given to pregnant mice, but maternal health and pup survival were not reported as safety outcomes.
- No drug-interaction studies of any kind have been published.
Evidence is concentrated in the inventor's lab
Nearly all safety and efficacy studies come from the laboratory that holds patents on P021 and co-founded the company licensing it. The one substantially independent animal study did not reproduce the peptide's main biological effect, though it found no new safety signal.
Section 08
Regulatory Status
It remains a preclinical research peptide with an unusually thin evidence base: no approved label, indication, dose or established human safety profile exists for it.
FDA / United States
Not approved
P21 has never been nominated for the 503A bulk-substances process and is not on the 503A Bulks List, so section 503A opens no lawful route for a pharmacy to compound it for human use.
EU / EMA
Not approved
P21 has no EU marketing authorisation and does not appear among medicines evaluated by the CHMP.
WADA
Prohibited under S0
P21 is not individually named on the Prohibited List, but as a CNTF-derived peptide outside the growth-hormone/IGF-1 pathway covered by S2, it falls under the S0 catch-all for non-approved substances — banned at all times, with no therapeutic-use exemption.
Clinical trials
No human trial has ever been published
All evidence comes from a single research group's rodent studies, including safety data out to 12 months in animals; no IND, Phase 1 study or registration on ClinicalTrials.gov exists for P21 in humans.
A «research use only» label does not turn P21 into an approved medicine and says nothing about its purity. Regulatory status differs between jurisdictions and changes over time — check the current documents of your own regulator before relying on any of this.
Section 09
Research Studies
- [1]Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in miceLi B, Wanka L, Blanchard J, Liu F, Chohan MO, Iqbal K, Grundke-Iqbal I. · FEBS Letters · 2010
- [2]Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptideChohan MO, Li B, Blanchard J, Tung YC, Heaney AT, Rabe A, Iqbal K, Grundke-Iqbal I. · Neurobiology of Aging · 2011
- [3]An experimental rat model of sporadic Alzheimer's disease and rescue of cognitive impairment with a neurotrophic peptideBolognin S, Blanchard J, Wang X, Basurto-Islas G, Tung YC, Kohlbrenner E, Grundke-Iqbal I, Iqbal K. · Acta Neuropathologica · 2012
- [4]Rescue of cognitive-aging by administration of a neurogenic and/or neurotrophic compoundBolognin S, Buffelli M, Puoliväli J, Iqbal K. · Neurobiology of Aging · 2014
- [5]Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's diseaseKazim SF, Blanchard J, Dai CL, Tung YC, LaFerla FM, Grundke-Iqbal I, Iqbal K. · Neurobiology of Disease · 2014
- [6]Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's diseaseKazim SF, Iqbal K. · Molecular Neurodegeneration · 2016
- [7]Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic DysfunctionWei W, Liu Y, Dai CL, Baazaoui N, Tung YC, Liu F, Iqbal K. · Journal of Alzheimer's Disease · 2021
- [8]Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorderMottolese N, Loi M, Trazzi S, Tassinari M, Uguagliati B, Candini G, Iqbal K, Medici G, Ciani E. · Journal of Neurodevelopmental Disorders · 2024
Section 10
Frequently Asked Questions
P21 (also written P021, Ac-DGGL) is a synthetic tetrapeptide engineered from a small active region of ciliary neurotrophic factor (CNTF), modified with an adamantylated glycine so that, unlike full-length CNTF, it is described as orally bioavailable and able to cross the blood-brain barrier. It has never been given to a person: a cited review states no human clinical trial data exist for it, and every finding behind it comes from rodent studies run by the peptide's originating laboratory.
In 3xTg-AD mice dosed orally for 12-18 months, it reduced abnormal tau hyperphosphorylation, lowered soluble amyloid-beta, raised BDNF, and rescued cognition and neurogenesis measures; a hippocampal plaque-load reduction showed only a trend rather than significance. All of this evidence is rodent histology and behavior from a single research group, never independently replicated and never tested in a person.
Mouse studies mixed it into feed at 60 nmol per gram (roughly 150-162 nmol per mouse daily) for 6-18 months, or gave 750 nmol per mouse daily by intraperitoneal injection for 30 days in a separate model. Neither has a calculated human equivalent; outside any study, vendor and forum practice describes 500-750 µg once daily as an intranasal spray, a route no published research has used at all.
None have been documented - P21's own research record does not list a side-effect profile at all. That absence reflects the total lack of human exposure rather than a clean safety record: nobody has measured what it does to a person because nobody has given it to one.
It is not approved by any regulatory authority for any use, and its record describes it plainly as an experimental compound with very limited human data - in practice, none. There is no established legal framework around it because it has no history of human administration to regulate.
The lyophilised powder is kept dark and dry: 0-4 °C for days to weeks, or -20 °C for long-term storage, with a supplier-claimed shelf life beyond 3 years using DMSO as the solvent. Published research dissolved it differently - deionised water for cell-culture work (a 1 mM stock) and saline for dosing animals - with the stock held at 0-4 °C briefly or -20 °C for longer.
Full-length CNTF is a protein that does not cross into the brain well; P21 strips it down to a small active fragment (residues 148-151) and adds an adamantylated glycine specifically to raise its stability and lipophilicity. That modification is the basis for describing it as orally bioavailable and blood-brain-barrier permeable, but this property, like the rest of P21's profile, has only been characterised in animal and cell studies, not in people.