Autophagy failure in Alzheimer's disease and the role of defective lysosomal acidification

Abstract

Autophagy is a lysosomal degradative process to recycle cellular waste and eliminate potentially toxic damaged organelles and protein aggregates. The important cytoprotective functions of autophagy are evidenced by the diverse pathogenic consequences that may stem from autophagy dysregulation in a growing number of neurodegenerative disorders. In many of the diseases associated with autophagy anomalies, it is the final stage of autophagy-lysosomal degradation that is disrupted. In several disorders, including AD, defective lysosomal acidification contributes to this proteolytic failure. The complex regulation of lysosomal pH makes this process vulnerable to disruption by many factors and reliable lysosomal pH measurements have become increasingly important in investigations of disease mechanisms. Although various reagents for pH quantification have been developed over several decades, they are not all equally well-suited for measuring the pH of lysosomes. Here, we evaluate the most commonly used pH probes for sensitivity and localization and identify Lysosensor Yellow/Blue-Dextran, among currently used probes, as having the most optimal profile of properties for measuring lysosomal pH. In addition, we review evidence that lysosomal acidification is defective in Alzheimer’s disease (AD) and extend our original findings of elevated lysosomal pH in presenilin 1 (PS1)-deficient blastocysts and neurons to additional cell models of PS1- and PS1/2-deficiency, to fibroblasts from AD patients with PS1 mutations, and to neurons in the PS/APP mouse model of AD.

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

“…In the current study, we found that V 0 ATPase is both oxidized and polyubiquitinated (DS vs. Ctr Y and Ctr O vs. Ctr Y), and we hypothesize that these modifications decrease the V 0 -ATPase proton pump activity consistent with autophagy dysfunction. Accordingly, the Nixon group has demonstrated reduced acidification of lysosomes in AD (73), and genetic mutation of lysosomal ATPase is among the risk factors recognized to contribute to autophagy-related neurodegenerative diseases (37,52). Furthermore, disturbance of autophagosome formation coupled with hyperactivation of the mTOR pathway is observed in DS brain, before and after development of AD pathology (59).…”

The Na+/H+ Exchanger NHE6 Modulates Endosomal pH to Control Processing of Amyloid Precursor Protein in a Cell Culture Model of Alzheimer Disease

“…Enlarged endosomes are the earliest neuronal pathology described in AD, and recent intriguing studies have implicated endocytic dysfunction, perturbations of vesicle trafficking, and lysosomal pH deficits in the mechanism of neurodegeneration (7,8). Several genes identified in genome-wide association studies of AD risk, including BIN1, PICALM, CD2AP, EPHA1, and SORL1, are known to be involved in endosomal mechanisms (9).…”

Identification and expression analysis of the zebrafish orthologues of the mammalian MAP1LC3 gene family

“…Autophagy has been widely studied in relation to various diseases including AD. Failure in autophagy due to mutations in the PRESENILIN 1 gene has been implicated in AD [28]. To gain greater insight into autophagy, various animal models have been used to study the components of the autophagic pathway.…”