Amyloid β hypothesis in Alzheimer’s disease and Cl⁻-ATPase―Neuronal cell death via PI4KIIα inhibition and recovery agents―

Abstract

In the brains of patients with Alzheimer’s disease, a decrease in phosphatidylinositol phosphate (PIP) requiring Cl⁻-ATPase activity was found. In cultured rat hippocampal neurons, pathophysiological concentrations of amyloid β proteins (Aβs≤10 nM) lowered PIP levels and Cl⁻-ATPase activity with an increase in intracellular Cl⁻ concentrations, resulting in Cl⁻-dependent enhancements in glutamate neurotoxicity and, ultimately, neuronal cell death. Pathophysiological concentrations of Aβs(0.1-10 nM) directly lowered phosphatidylinositol-4-kinase. Non-toxic peptide fragments of Aβ, such as Ile-Gly-Leu, recovered Aβ-induced inhibition of recombinant human phosphatidylinositol-4-kinase IIα (PI4KIIα) and the intrahippocampally administered Aβ-induced degeneration of hippocampal neurons and impairment of spatial memory in mice. Agents with the potential to block these neurotoxic mechanisms of Aβ were summarized herein as (1) Aβ antagonists, (2) substrates of PI4K, (3) PI4K product, (4) PI4K activators, and (5) GABAc receptor stimulants.