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• W1980054636 abstract "Mutation in presenilin 1 (PS1) is one of the leading causes of familial Alzheimer's disease (fAD). PS1 mutation exacerbates the autophagic and lysosomal pathology in AD patients, leading to accumulation of partially degraded material in bloated lysosomes and autophagosomes - a pathology that bears some resemblance to other diseases characterized by elevated lysosomal pH, like age-related macular degeneration. In this study, we examined the effect of the PS1-fAD mutation A246E on lysosomal pH and lysosomal function, and asked whether restoration of lysosomal pH could reverse some of these changes. Lysosomal pH was elevated by 0.2-0.3 pH units in human fibroblasts with the PS1-fAD mutation. The lysosomal alkalization in PS1-fAD fibroblasts was supported by a reduction in the pH-dependent cleavage of cathepsin D and by a reduction in binding of boron-dipyrromethene (BODIPY) FL-pepstatin A to the cathepsin D active site. PS1-fAD cells had increased LC3B-II/-I ratios and p62 levels, consistent with impaired lysosomal degradation and analogous to changes induced by lysosomal alkalinization with chloroquine. PS1-fAD fibroblasts had increased expression of ATP6V1B2, ATG5, BECN1 TFEB mRNA, and of ATP6V1B2, ATG5 and beclin at the protein level, consistent with chronic impairment of autophagic and lysosomal functions in the mutant cells. Critically, cyclic adenosine monophosphate (cAMP) treatment reacidified lysosomal pH in mutant PS1-fAD; cAMP also increased the availability of active cathepsin D and lowered the LC3B-II/-I ratio. These results confirm a small elevation in the lysosomal pH of human PS1-fAD fibroblasts, demonstrate that this lysosomal alkalization is associated with chronic changes in autophagy and degradation, and suggest that treatment to reacidify the lysosomes with cAMP can reverse these changes." @default.
• W1980054636 created "2016-06-24" @default.
• W1980054636 creator A5008478808 @default.
• W1980054636 creator A5047216342 @default.
• W1980054636 creator A5062141175 @default.
• W1980054636 creator A5071261150 @default.
• W1980054636 date "2014-03-01" @default.
• W1980054636 modified "2023-10-17" @default.
• W1980054636 title "Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer’s disease-linked presenilin 1 A246E mutation can be reversed with cAMP" @default.
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• W1980054636 doi "https://doi.org/10.1016/j.neuroscience.2014.01.001" @default.
• W1980054636 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4028113" @default.
• W1980054636 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/24418614" @default.
• W1980054636 hasPublicationYear "2014" @default.
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