A tiny protein fragment called P021, designed to act like a brain growth factor, was fed to Alzheimer‑model mice before any disease signs appeared. The treated mice kept healthier brain connections, grew new nerve cells, and performed better on memory tests compared to untreated mice.

The use of neurotrophic factors to treat Alzheimer's disease (AD) is hindered by their blood-brain barrier impermeability, short half-life, and severe side effects. Peptide 021 (P021) is a neurotrophic/neurogenic tetra-peptide that was derived from the most active region of the ciliary neurotrophic factor (CNTF) by epitope mapping. Admantylated glycine was added to its C-terminal to increase its blood-brain barrier permeability and decrease its degradation by exopeptidases to make it druggable. Here, we report on the preventive effect of P021 in 3 × Tg-AD, a transgenic mouse model of AD. P021 was administered in the diet at 3 months, i.e., 6-9 months before any overt amyloid beta (Aβ) or tau pathology, and during the period of synaptic compensation, and was continued until 21 months in 3 × Tg-AD mice. The 3 × Tg-AD mice and wild-type (WT) mice were treated identically but with a vehicle-only diet serving as controls. The effects of P021 on neurogenesis, dendritic and synaptic markers, and cognitive performance were investigated. We found that P021 treatment was able to rescue dendritic and synaptic deficits, boost neurogenesis, and reverse cognitive impairment in 3 × Tg-AD mice. Availability of appropriate neurotrophic support during the period of synaptic compensation can prevent synaptic deficit and cognitive impairment, and P021 is a promising neurotrophic compound for this purpose.