Brain p3-Alc beta peptide restores neuronal viability impaired by Alzheimer's amyloid beta-peptide

We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alc beta 37 is generated from the neuronal protein alcadein beta through cleavage of gamma-secretase, similar to the generation of amyloid beta (A beta) derived from A beta-protein precursor/APP. Neurotoxicity by A beta oligomers (A beta o) is the prime cause prior to the loss of brain function in AD. We found that p3-Alc beta 37 and its shorter peptide p3-Alc beta 9-19 enhanced the mitochondrial activity of neurons and protected neurons against A beta o-induced toxicity. This is due to the suppression of the A beta o-mediated excessive Ca2+ influx into neurons by p3-Alc beta. Successful transfer of p3-Alc beta 9-19 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 A beta 42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased A beta and reduced p3-Alc beta 37 levels, the administration of p3-Alc beta 9-19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.