ArticleThe American journal of pathology2000
Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations.
Article in The American journal of pathology, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 491 papers, 1 of them a synthesis that pooled it.
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Who cites it
491 citing papers in PubMed, 1 synthesis or guideline pooled it, 837 citations in OpenAlex.
- Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites.Frontiers in neuroscience · 2022Pooled it
- Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.Nature communications · 2022Trial
- mTORC1 Activation Links Chronic Stress to Meso-Circuit Desynchronization and Accelerated Amyloid Pathology via Autophagic Dysfunction.CNS neuroscience & therapeutics · 2026Article
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Using Brain Organoids to Explore Human Neurobiology.Cellular and molecular neurobiology · 2026Review
- Rab5 hyperactivation: The central hub for endolysosomal dysfunction in Down syndrome.Neural regeneration research · 2026Article
- Endolysosomal inhibition uncouples tau uptake from intracellular seeding.The Journal of biological chemistry · 2026Article
- Review
- SORL1 variant links endosomal amyloid precursor protein mis-sorting to axonal transport defects and neuronal dysfunction.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Multiomics and proteomic insights into Alzheimer's disease biology in Down syndrome.Expert review of neurotherapeutics · 2026Review
- Bridging autophagy and endolysosomal dysfunction: Role of bridging integrator 1 in Alzheimer's disease.Neural regeneration research · 2026Article
- Protective mutations associated with APOE in Alzheimer's disease.Molecular psychiatry · 2026Review
- BIN1 gain-of-function in the presynaptic compartment leads to isoform-specific synaptotoxicity.Alzheimer's research & therapy · 2026Article
- Article
- Valosin-containing protein is cargo in Amyloid Precursor Protein extracellular vesicles.Cell communication and signaling : CCS · 2026Article
- BAG3 modulates clathrin-mediated endocytosis and tau uptake in astrocytes.American journal of physiology. Cell physiology · 2026Article
- Age-related behavioral and molecular landmarks in new mouse models for studying Alzheimer's disease in Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- A Question of Origins: Non-neuronal Sources of Amyloid-β.Neuroscience bulletin · 2026Review
- Maternal Choline Supplementation in a Mouse Model of Down Syndrome and Alzheimer's Disease Generates Unique Expression Profile Mosaics Within Three Hippocampal Excitatory Neuronal Populations.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Alzheimer's disease risk protein SorLA regulates ER homeostasis and lipid metabolism in human microglia, with conserved effects in neurons.Acta neuropathologica · 2026Article
431 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
Endocytosis is critical to the function and fate of molecules important to Alzheimer's disease (AD) etiology, including the beta protein precursor (betaPP), amyloid beta (Abeta) peptide, and apolipoprotein E (ApoE). Early endosomes, a major site of Abeta peptide generation, are markedly enlarged within neurons in the Alzheimer brain, suggesting altered endocytic pathway (EP) activity. Here, we show that neuronal EP activation is a specific and very early response in AD. To evaluate endocytic activation, we used markers of internalization (rab5, rabaptin 5) and recycling (rab4), and found that enlargement of rab5-positive early endosomes in the AD brain was associated with elevated levels of rab4 immunoreactive protein and translocation of rabaptin 5 to endosomes, implying that both endocytic uptake and recycling are activated. These abnormalities were evident in pyramidal neurons of the neocortex at preclinical stages of disease when Alzheimer-like neuropathology, such as Abeta deposition, was restricted to the entorhinal region. In Down syndrome, early endosomes were significantly enlarged in some pyramidal neurons as early as 28 weeks of gestation, decades before classical AD neuropathology develops. Markers of EP activity were only minimally influenced by normal aging and other neurodegenerative diseases studied. Inheritance of the epsilon4 allele of APOE, however, accentuated early endosome enlargement at preclinical stages of AD. By contrast, endosomes were normal in size at advanced stages of familial AD caused by mutations of presenilin 1 or 2, indicating that altered endocytosis is not a consequence of Abeta deposition. These results identify EP activation as the earliest known intraneuronal change to occur in sporadic AD, the most common form of AD. Given the important role of the EP in Abeta peptide generation and ApoE function, early endosomal abnormalities provide a mechanistic link between EP alterations, genetic susceptibility factors, and Abeta generation and suggest differences that may be involved in Abeta generation and beta amyloidogenesis in subtypes of AD.
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