We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alcβ37 is generated from the neuronal protein alcadein β through cleavage of γ-secretase, similar to the generation of amyloid β (Aβ) derived from Aβ-protein precursor/APP. Neurotoxicity by Aβ oligomers (Aβo) is the prime cause prior to the loss of brain function in AD. We found that p3-Alcβ37 and its shorter peptide p3-Alcβ9-19 enhanced the mitochondrial activity of neurons and protected neurons against Aβo-induced toxicity. This is due to the suppression of the Aβo-mediated excessive Ca2+ influx into neurons by p3-Alcβ. Successful transfer of p3-Alcβ9-19 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 Aβ42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aβ and reduced p3-Alcβ37 levels, the administration of p3-Alcβ9-19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.
Keywords: AD therapy; Alzheimer's disease (AD); PET imaging; alcadein; mitochondria.
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.