ArticleAutophagy2025
Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction.
Article in Autophagy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Intravital pH Imaging using the sensor ApHID Reveals Incomplete Lysosomal Acidification in Resident Meningeal Phagocytes.bioRxiv : the preprint server for biology · 2026Article
- Review
- Lipid Metabolism in Central Nervous System Diseases: Pathological Mechanisms and Therapeutic Advances.CNS neuroscience & therapeutics · 2026Review
- Compartmental pH regulation in cancer and antitumor immunity: therapeutic opportunities and challenges.Apoptosis : an international journal on programmed cell death · 2026Review
- APOE4 disrupts the central dogma by arresting neuronal proteome dynamics.bioRxiv : the preprint server for biology · 2026Article
- Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.International journal of molecular sciences · 2026Review
- Lysosomal homeostasis at the crossroads of neurodegeneration.The Journal of clinical investigation · 2026Review
- TREM2 contributes to central sensitization through PI3K/Akt/mTOR-mediated autophagic dysfunction in a rat model of vestibular migraine.The journal of headache and pain · 2026Article
- Alzheimer's Disease: From Pathogenesis to Emerging Therapeutic Targets.Journal of clinical medicine · 2026Review
- Unravelling Synaptic and Metabolic Mechanisms of Cognitive Resilience in Asymptomatic Alzheimer's Disease Across Two Alzheimer's Disease Cohorts.Cellular and molecular neurobiology · 2026Article
- Apolipoprotein E4 in Alzheimer's Disease: Role in Pathology, Lipid Metabolism, and Drug Treatment.International journal of molecular sciences · 2026Review
- The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.Cell death discovery · 2025Review
- Spatiotemporal proteomics reveals the biosynthetic lysosomal membrane protein interactome in neurons.Nature communications · 2024Article
- Honokiol enhances the sensitivity of cetuximab in KRASTheranostics · 2024Article
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17 authors.
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Abstract
APOE4 is the primary risk factor for Alzheimer disease (AD). Early AD pathological events first affect the neuronal endolysosomal system, which in turn causes neuronal protein aggregation and cell death. Despite the crucial influence of lysosomes upon AD pathophysiology, and that APOE4 localizes to lysosomes, the influence of APOE4 on lysosomal function remains unexplored. We find that expression of APOE4 in neuronal cell lines results in lysosomal alkalinization and impaired lysosomal function. To identify driving factors for these defects, we performed quantitative lysosomal proteome profiling. This revealed that APOE4 expression results in differential regulation of numerous lysosomal proteins, correlating with APOE allele status and disease severity in AD brains. In particular, APOE4 expression results in the depletion of lysosomal LGALS3BP and the accumulation of lysosomal TMED5. We additionally validated that these lysosomal protein changes can be targeted to modulate lysosomal function. Taken together, this work thereby reveals that APOE4 causes widespread lysosomal defects through remodeling the lysosomal proteome, with the lysosomal TMED5 accumulation and LGALS3BP depletion manifesting as lysosomal alkalinization in APOE4 neurons.
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