Alzheimer’s Disease

Acid and Alzheimer’s

Science Signaling  29 Jun 2010:
Vol. 3, Issue 128, pp. ec198
DOI: 10.1126/scisignal.3128ec198

Familial Alzheimer’s disease (FAD) is associated with mutations in the gene encoding presenilin 1 (PS1), a component of the γ-secretase complex, which cleaves type I membrane proteins, such as amyloid precursor protein. Mutations in PS1 are also associated with defects in autophagy in neurons; however, the mechanism involved is unknown. Lee et al. found that autophagy was impaired in blastocysts from PS1 knockout (PS1 KO) mice compared with that in wild-type (WT) blastocysts, which led to the accumulation of autophagic vacuoles (AVs) in PS1 KO cells. Fusion of autophagosomes with lysosomes was normal in PS1 KO cells, but degradation of autolysosomal components was blocked. The pH of lysosomes in PS1 KO cells was higher than that in lysosomes from WT cells, which was associated with the absence of the vacuolar ATPase Voa1 subunit (a proton pump that acidifies lysosomes) from the PS1 KO lysosomes. In WT cells, PS1 associated with Voa1 in the endoplasmic reticulum (ER) and was required for the formation of the mature, glycosylated form of Voa1, which was transported to lysosomes; in PS1 KO cells, unglycosylated Voa1 was retained in the ER. AVs accumulated in cortical and hippocampal neurons from PS1 conditional KO (PS1 cKO) mice, and lysosomes in neurons from PS1 CKO mice were less acidic than those of WT mice. Autophagy was impaired in fibroblasts from FAD patients compared with that in fibroblasts from normal donors, which correlated with the decreased acidification of lysosomes from FAD cells. As Annaert and De Strooper discuss, further investigation of the mechanisms by which PS1 affects subcellular trafficking and autophagic pathways will improve our understanding of the roles of PS1 in health and disease.

J.-H. Lee, W. H. Yu, A. Kumar, S. Lee, P. S. Mohan, C. M. Peterhoff, D. M. Wolfe, M. Martinez-Vicente, A. C. Massey, G. Sovak, Y. Uchiyama, D. Westaway, A. M. Cuervo, R. A. Nixon, Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158 (2010). [PubMed]

W. Annaert, B. De Strooper, Alzheimer’s disease neurons fail the acid test. Cell 141, 1112–1114 (2010). [Online Journal]