Abstract
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.
Highlights
Alzheimer’s disease (AD) is still very challenging to treat; the current clinically prescribed medications treat the symptoms temporarily but cannot halt the progressive disorder
The test drugs that showed beneficial effects in the cellular assays were effective for memory recovery in AD model mice (Joyashiki et al, 2011; Tohda et al, 2012; Yang et al, 2017)
Three days after Aβ25–35 treatment, each peptide was added to cortical neurons at 1 and 10 nM
Summary
Alzheimer’s disease (AD) is still very challenging to treat; the current clinically prescribed medications treat the symptoms temporarily but cannot halt the progressive disorder. Since amyloid β (Aβ) oligomerization and/or deposition is the pathological cause of AD, lowering Aβ has been extensively studied as a strategy to inhibit AD. This strategy has not succeeded to date. In the brain of AD patients, Aβ deposition begins at an early stage, approximately 20–30 years before it is diagnosed. Aβ-driven neurite atrophy and synaptic loss begin at early stage and directly trigger memory deficit. Synaptic loss is majorly observed more than neuronal death in autopsy samples of AD patients (Bertoni-Freddari et al, 2003)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
