Lysosomal modulation ameliorates Alzheimer‐type pathology: Evidence of protective cleavage of Aβ1‐42 by modulated cathepsins

Abstract

Alzheimer's disease (AD) involves protein accumulation and progressive synaptic deterioration. Cathepsin proteases exhibit up‐regulation in response to accumulating proteins including Aβ1‐42, and they have been implicated in clearance of AD‐related deposits. Lysosomal modulation with Z‐Phe‐Ala‐diazomethylketone (PADK) involves 3‐8‐fold increases in cathepsin B in APPSwInd and APPswe/PS1dE9 mice, while neprilysin, IDE, and α‐secretase were unchanged. The PADK treatment reduced intracellular Aβ staining, decreased soluble Aβx‐42, and reduced extracellular‐enriched Aβ levels in the two AD models. The corresponding increase in Aβ1‐38 peptide as Aβ1‐42 was reduced indicates that intracellular proteolysis in lysosomes can detoxify peptides, likely through cathepsin cleavage. Associated with its effect on Aβ clearance, deficits in synaptic markers were eliminated in both mouse models by the lysosomal modulator. In addition, behavioral deficits were attenuated, reaching performance scores similar to those of age‐matched non‐transgenic mice. These findings indicate that intracellular processing of Aβ by lysosomes can be targeted to effectively offset the disruption of synaptic integrity and brain function. Lysosomal modulators represent an effective strategy for treating AD and other disorders involving pathogenic accumulations.