ArticleNeuroscience2014
Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer's disease-linked presenilin 1 A246E mutation can be reversed with cAMP.
Article in Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers, 1 of them a synthesis that pooled it.
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Who cites it
119 citing papers in PubMed, 1 synthesis or guideline pooled it, 182 citations in OpenAlex.
- Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)Autophagy · 2021Guideline
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Estrogen deprivation exacerbates Alzheimer's disease pathology through neuronal CTSS signaling.Journal of neuroinflammation · 2026Article
- MRC2-mediated collagen internalization is reduced in fibrotic lung fibroblasts and increased upon phenotypic dedifferentiation.JCI insight · 2026Article
- Bridging autophagy and endolysosomal dysfunction: Role of bridging integrator 1 in Alzheimer's disease.Neural regeneration research · 2026Article
- Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson's disease.Cell death and differentiation · 2026Article
- Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.Translational neurodegeneration · 2026Article
- Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways.Acta neuropathologica communications · 2026Article
- A Highly Selective Fluorescent pH Probe in Red to NIR Region and its Application for the Monitoring Lysosomal pH Fluctuation in Living Cells.Journal of fluorescence · 2026Article
- Lysosomal pH Measurements via Dual-Imaging Microscopy.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Autophagy-lysosomal pathway in neurodegeneration.Molecular neurodegeneration advances · 2026Review
- Integration of cAMP and TRPV4 Signaling to Optimize Collagen Remodeling for Management of Fibrosis.Cells · 2025Review
- Exploratory Analysis of Autophagy-Lysosomal Pathway Proteins in Dermal Fibroblasts as Potential Peripheral Biomarkers for Alzheimer's Disease: A Pilot Study.Biomedicines · 2025Article
- Lipofuscin accumulation in aging and neurodegeneration: a potential "timebomb" overlooked in Alzheimer's disease.Translational neurodegeneration · 2025Review
- Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer's Disease: An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts.Psychiatry investigation · 2025Article
- Isomerization of bis(monoacylglycero)phosphate by acyl migration.Journal of lipid research · 2025Article
- Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer's disease.Translational psychiatry · 2025Article
- Article
- Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Hyperammonemia increases the release of pathological extracellular vesicles from monocytes by impairing lysosomal function and autophagy through the TNFα-cAMP-PKA-LC3 pathway.Frontiers in immunology · 2025Article
59 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
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.
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