ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2007
Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed, 68 citations in OpenAlex.
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- G-protein coupled receptor, PI3K and Rho signaling pathways regulate the cascades of Tau and amyloid-β in Alzheimer's disease.Molecular biomedicine · 2021Review
- Small GTPases of the Rab and Arf Families: Key Regulators of Intracellular Trafficking in Neurodegeneration.International journal of molecular sciences · 2021Review
- APP Binds to the EGFR Ligands HB-EGF and EGF, Acting Synergistically with EGF to Promote ERK Signaling and Neuritogenesis.Molecular neurobiology · 2021Article
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- Upregulation of RIN3 induces endosomal dysfunction in Alzheimer's disease.Translational neurodegeneration · 2020Article
- The impact of proteostasis dysfunction secondary to environmental and genetic causes on neurodegenerative diseases progression and potential therapeutic intervention.Environmental science and pollution research international · 2020Review
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- Coxiella burnetii Type 4B Secretion System-dependent manipulation of endolysosomal maturation is required for bacterial growth.PLoS pathogens · 2019Article
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
Alzheimer's disease (AD) involves activation of apoptotic pathways that may be regulated through signaling cascades initiated by the amyloid precursor protein (APP). Enlarged endosomes have been observed in postmortem AD brains at very early stages of the disease. We show here that exogenous expression of a familial AD (FAD) mutant of APP or of the APP binding protein APP-BP1 in neurons causes enlargement of early endosomes, increased receptor-mediated endocytosis via a pathway dependent on APP-BP1 binding to APP, and apoptosis. Levels of both APP-BP1 and Rab5 are elevated in early endosomes in cortical embryonic neurons expressing APP(V642I) or APP-BP1, in cultured skin fibroblast cells from Down syndrome subjects, and in postmortem hippocampal tissue of individuals with AD. Indeed, Rab5 was found to bind specifically to APP-BP1, between amino acids 443 and 479. Inhibition of Rab5 or dynamin activity, but not of Eps15 (epidermal growth factor receptor pathway substrate 15) activity, rescued neurons from apoptosis induced by either APP(V642I) or APP-BP1, without affecting levels of intracellular or secreted amyloid-beta (Abeta). Induction of Rab5 activity via expression of a constitutively active mutant led to an increase in neuronal apoptosis more than twice that attributable to induction of endosome enlargement via a Rab5-independent mechanism, regardless of Abeta production. Together, these findings suggest that Rab5 activation via an APP/APP-BP1-initiated signaling pathway mediates neuronal apoptosis caused by FAD mutants of APP and that, within this pathway, Rab5 has a specific role in signaling that is distinct from, although not independent of, its role in trafficking.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.