Brain p3‐Alcβ peptide restores neuronal viability impaired by Alzheimer's amyloid β‐peptide

Abstract

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alcb37 is generated from the neuronal protein alcadein b through cleavage of c-secretase, similar to the generation of amyloid b (Ab) derived from Ab-protein precursor/APP. Neurotoxicity by Ab oligomers (Abo) is the prime cause prior to the loss of brain function in AD. We found that p3-Alcb37 and its shorter peptide p3-Alcb9-19 enhanced the mitochondrial activity of neurons and protected neurons against Abo-induced toxicity. This is due to the suppression of the Abo-mediated excessive Ca 2+ influx into neurons by p3-Alcb. Successful transfer of p3-Alcb9-19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Ab42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Ab and reduced p3-Alcb37 levels, the administration of p3-Alcb9-19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.

Enhancement of drug permeation across skin through stratum corneum ablation

“…Microporation and iontophoresis, when used together, significantly improved the efficacy of this delivery approach, resulting in a cumulative delivery of 722 ± 169 ng over the same time frame. Furthermore, Hata et al 39 used the PassPort™ device in order to treat Alzheimer's disease. They examine the impact of p3-Alcb9-19 on mitochondrial activity in monkeys, as mitochondrial dysfunction is prevalent in the brains of Alzheimer's disease patients and is known to decrease p3-Alcb37 levels.…”

Axonal transport of Frizzled5 by Alcadein α-containing vesicles is associated with kinesin-1

“…Among the Alcs, Alcα, and Alcβ are thought to be associated with AD pathophysiology ( Araki et al ., 2003 , 2004 ; Hata et al ., 2009 , 2011 ; Omori et al ., 2014). Alcα-KO mice facilitate the development of amyloid pathology in human APP transgenic AD model mice (Gotoh et al ., 2020), and Alcβ modulates AD progression ( Hata et al ., 2019 ; Gandy, 2023 ; Hata et al ., 2023 ).…”