We investigated the effects of a heptapeptide, GPPGPAG, on memory improvement and neuritic regeneration in
Alzheimer's disease models to evaluate its potency as a new anti-
Alzheimer's disease (AD)
therapy. The anti-AD effects of GPPGPAG were evaluated in Aβ-treated cortical neurons and 5XFAD, a mouse model of AD. Exposure of cortical neurons to Aβ25-35 for 3 days resulted in
atrophy of axons and dendrites. Treatment with GPPGPAG improved the dendritic
atrophy of Aβ-treated cortical neurons, but not axonal
atrophy. Postsynaptic and presynaptic densities under Aβ1-42 exposure were increased by GPPGPAG post treatment.
Oral administration of GPPGPAG to 5XFAD mice for 15 days improved significantly object recognition memory and dendritic density. Direct infusion of GPPGPAG into the lateral ventricle of 5XFAD mice for 28 days improved object recognition memory. Following
oral administration of GPPGPAG in mice, the undigested heptapeptide was detected in the plasma and cerebral cortex. Analysis of target
protein of GPPGPAG in neurons by DARTS method identified 14-3-3ε as a bound
protein. The protective effect of GPPGPAG on Aβ1-42-induced dendritic
atrophy was canceled by knockdown of 14-3-3ε. Taken together, these results suggest that GPPGPAG is orally available, transfers to the brain, and ameliorates memory dysfunction in AD brain, which is possibly mediated by 14-3-3ε-related dendritic restoration.