ArticleThe Journal of clinical investigation2016
Amyloid precursor protein-mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers.
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Who cites it
119 citing papers in PubMed, 183 citations in OpenAlex.
- Mechanisms of Brain Aging and Their Links to Alzheimer's and Parkinson's Disease Pathology.International journal of molecular sciences · 2026Review
- A Researcher's guide to rodent models of Down syndrome: Recent insights and translational perspectives.STAR protocols · 2026Review
- Endosome maturation is orchestrated by inside-out proton signaling through a NaNature communications · 2026Article
- The exocyst is an insulin-sensitive regulator of amyloid precursor protein trafficking and amyloid-beta generation in neurons.bioRxiv : the preprint server for biology · 2026Article
- Evaluating the peripheral nervous system pathology of Alzheimer's disease utilizing a functional human NMJ microphysiological system.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Functional Analysis of Late-Onset Alzheimer's Disease Risk Genes inbioRxiv : the preprint server for biology · 2026Article
- Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Impaired BDNF-TrkB trafficking and signalling in Down syndrome basal forebrain neurons.Cell death & disease · 2026Article
- Endosome maturation is orchestrated by inside-out proton signaling through a NaResearch square · 2026Article
- Brain-derived 5-hydroxymethylcytosine epigenetic scores are related to Alzheimer's disease pathology and cognitive decline.Acta neuropathologica · 2025Article
- Article
- Cholinotrophic basal forebrain connectome dysfunction in Down syndrome with and without dementia.iScience · 2025Article
- Increased Neuronal Expression of the Early Endosomal Adaptor APPL1 Replicates Alzheimer's Disease-Related Endosomal and Synaptic Dysfunction with Cholinergic Neurodegeneration.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- The history of Down syndrome-associated Alzheimer's disease; past, present, and future.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Neuronal Deletion ofBiomolecules · 2025Article
- Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS-AD-linked degenerative phenotypes in the Dp16 mouse model of Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Hyperactivation of RAB5 disrupts the endosomal Rab cascade leading to endolysosomal dysregulation in Down syndrome: A necessary role for increased APP gene dose.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Article
- APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer's disease.The Journal of clinical investigation · 2025Article
- Therapeutic and preventive strategies based on the maladaptive plasticity hypothesis for Alzheimer's disease.Frontiers in aging neuroscience · 2025Article
59 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
The endosome/lysosome pathway is disrupted early in the course of both Alzheimer's disease (AD) and Down syndrome (DS); however, it is not clear how dysfunction in this pathway influences the development of these diseases. Herein, we explored the cellular and molecular mechanisms by which endosomal dysfunction contributes to the pathogenesis of AD and DS. We determined that full-length amyloid precursor protein (APP) and its β-C-terminal fragment (β-CTF) act though increased activation of Rab5 to cause enlargement of early endosomes and to disrupt retrograde axonal trafficking of nerve growth factor (NGF) signals. The functional impacts of APP and its various products were investigated in PC12 cells, cultured rat basal forebrain cholinergic neurons (BFCNs), and BFCNs from a mouse model of DS. We found that the full-length wild-type APP (APPWT) and β-CTF both induced endosomal enlargement and disrupted NGF signaling and axonal trafficking. β-CTF alone induced atrophy of BFCNs that was rescued by the dominant-negative Rab5 mutant, Rab5S34N. Moreover, expression of a dominant-negative Rab5 construct markedly reduced APP-induced axonal blockage in Drosophila. Therefore, increased APP and/or β-CTF impact the endocytic pathway to disrupt NGF trafficking and signaling, resulting in trophic deficits in BFCNs. Our data strongly support the emerging concept that dysregulation of Rab5 activity contributes importantly to early pathogenesis of AD and DS.
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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.