Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations

Topic: Brain proteins, microglia and lab models

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.

@article{cataldo2000-10880397,
  author  = {Cataldo, A. M. and Peterhoff, C. M. and Troncoso, J. C. and Gomez-Isla, T. and Hyman, B. T. and Nixon, R. A.},
  title   = {{Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations}},
  journal = {The American journal of pathology},
  year    = {2000},
  doi     = {10.1016/s0002-9440(10)64538-5},
  pmid    = {10880397},
  url     = {https://doi.org/10.1016/s0002-9440(10)64538-5}
}

Key findings

• 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.
• 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.
• These results identify EP activation as the earliest known intraneuronal change to occur in sporadic AD, the most common form of AD.

Why it matters

In brain tissue, neurons in sporadic Alzheimer's disease showed enlarged early endosomes, the compartments cells use to take in and recycle material. The change appeared before amyloid deposits had spread beyond the entorhinal region, was more pronounced in APOE ε4 carriers, and was seen in some neurons in Down syndrome as early as 28 weeks of gestation. The authors call it "the earliest known intraneuronal change" in sporadic AD (as of 2000), but endosomes were normal in familial AD caused by presenilin mutations, the record gives no case numbers, and the study tests no treatment or prevention.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/s0002-9440(10)64538-5
• PubMed: 10880397
• Original source →
• Free full text: PubMed Central →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• β-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE Science · 1999-10-22 · usefulness score 64/100 · Disease mechanisms
• Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families Science · 1993-08-13 · usefulness score 63/100 · Genetics
• The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neurology · 1991-04-01 · usefulness score 61/100 · Cognitive tests and assessment
• Neuropathological stageing of Alzheimer-related changes Acta Neuropathologica · 1991-09-01 · usefulness score 58/100 · Brain tissue and pathology
• APOE genotype and gender effects on Alzheimer disease in 100 adults with Down syndrome Neurology · 1999-07-01 · usefulness score 55/100 · Genetics
• Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis The Journal of neuroscience : the official journal of the Society for Neuroscience · 1997-08-01 · usefulness score 51/100 · Genetics
• Generation of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation Proceedings of the National Academy of Sciences of the United States of America · 1997-04-01 · usefulness score 48/100 · Risk genes beyond APOE
• Lysosomal proteinase antigens are prominently localized within senile plaques of Alzheimer's disease: evidence for a neuronal origin Brain research · 1990-04-01 · usefulness score 45/100 · Risk genes beyond APOE

Later studies that cite this one

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• Alzheimer's disease associated with Down syndrome: a genetic form of dementia The Lancet. Neurology · 2021-11-01 · usefulness score 59/100 · Prevention and risk
• Alzheimer's disease Lancet (London, England) · 2011-03-01 · usefulness score 59/100 · Getting a diagnosis
• ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias Neuron · 2022-03-16 · usefulness score 58/100 · Risk factors
• Down syndrome Nature reviews. Disease primers · 2020-02-06 · usefulness score 56/100 · How common it is
• Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport JAMA neurology · 2017-09-01 · usefulness score 56/100 · TREM2 and immune genetics
• Proteomic analysis of Down syndrome cerebrospinal fluid compared to late-onset and autosomal dominant Alzheimer´s disease Nature communications · 2025-07-01 · usefulness score 55/100 · Down syndrome and Alzheimer's
• Cell type-specific roles of APOE4 in Alzheimer disease Nature reviews. Neuroscience · 2024-01-08 · usefulness score 52/100 · Genetics
• ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response Cell stem cell · 2021-01-04 · usefulness score 52/100 · Genetics

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• Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1993-10-01 · usefulness score 53/100
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• Chronic PERK induction promotes Alzheimer-like neuropathology in Down syndrome: Insights for therapeutic intervention Progress in neurobiology · 2020-08-11 · usefulness score 44/100 · Down syndrome and Alzheimer's
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