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Endocytic Pathway Abnormalities Precede Amyloid β Deposition in Sporadic Alzheimer’s Disease and Down Syndrome

Cataldo, Anne M., Peterhoff, Corrinne M., Troncoso, Juan C., Gomez-Isla, Teresa, Hyman, Bradley T., Nixon, Ralph A.·2000·The American Journal of Pathology
DOI 10.1016/s0002-9440(10)64538-5
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  • Endosomal dysfunction is an early event in carriers of the APOE4 allele appearing in human brains decades before the onset of AD symptoms, and is also observed in ApoE4-TR mouse brain sections.

    “Endosomal dysfunction is an early event in carriers of the APOE4 allele appearing in human brains decades before the onset of AD symptoms, and is also observed in ApoE4-TR mouse brain sections (Cataldo et al., 2000;Nuriel et al., 2017).”

    From ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes (2019) · cites this paper as Cataldo et al., 2000

    The APOE ε4 Genotype results report greater endosomal enlargement in early-stage AD cases carrying ε4, and the Tissue section describes those cases as cognitively normal (page numbers not supplied). The paper does not establish that this change appeared decades before symptom onset in APOE4 carriers; its “decades before” finding concerns Down syndrome and classical AD neuropathology. It does not report ApoE4-TR mouse sections, which the sentence also cites Nuriel et al. (2017) for. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • This agrees with neuropathological observations of enlarged endosomes (trapping ApoE complexed with other proteins such as ABCA1) appearing in the brains of APOE4 carriers decades before the onset of cognitive decline.

    “This agrees with neuropathological observations of enlarged endosomes (trapping ApoE complexed with other proteins such as ABCA1) appearing in the brains of APOE4 carriers decades before the onset of cognitive decline (Cataldo et al., 2000).”

    From ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes (2019) · cites this paper as Cataldo et al., 2000

    The “APOE ε4 Genotype Promotes EP Activation in Early-Stage SAD” section reports larger endosomes in early-stage cases carrying APOE ε4, and “EP Activation Precedes Other Known Neuropathology in SAD” describes the pre-AD group as cognitively normal (page numbers not provided). The paper does not report ApoE–ABCA1 complexes trapped in endosomes or establish that the changes in APOE4 carriers appeared decades before cognitive decline; its decades-earlier finding concerns Down syndrome and the development of classical AD neuropathology. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • The endosomal network is a key biological pathway affected in neurodegenerative pathology.

    “These studies, alongside clinical evidence [8][9][10][11][12][13][14], highlight the endosomal network as a key biological pathway affected in neurodegenerative pathology.”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [9]

    The paper reports early endocytic-pathway abnormalities in sporadic Alzheimer’s disease and Down syndrome, supporting the endosomal network’s importance in those conditions. However, the section “EP Abnormalities Are Not Observed in Other Neurodegenerative Disorders or Normal Aging” reports no comparable endosomal enlargement in the other neurodegenerative diseases examined, so the broader claim needs qualification. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Neuronal endosomal swelling is classed as an early hallmark of Alzheimer's disease indicative of a perturbation in endosomal cargo sorting.

    “In addition, neuronal endosomal swelling has been classed as an early hallmark of Alzheimer's disease indicative of a perturbation in endosomal cargo sorting [8,9,56].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [9]

    The section “EP Activation Precedes Other Known Neuropathology in SAD” reports swollen neuronal early endosomes in pre-AD brains, detectable before amyloid accumulation or neurofibrillary pathology. The Discussion links these changes to altered endosomal fusion and recycling, but the cited passages do not establish that the swelling specifically indicates a perturbation in cargo sorting. Page numbers are unavailable in our copy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • VPS35 dysfunction leads to enlarged axonal endosomes.

    “VPS35 dysfunction leads to APP accumulation in early endosomes, increased Aβ production and exosomal release, and enlarged axonal endosomes [9, 16, 20].”

    From Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer’s disease mouse model (2025) · cites this paper as [9]

    The section “EP Activation Precedes Other Known Neuropathology in SAD” reports enlarged early endosomes in neurons from pre-AD brains. It does not attribute the enlargement to VPS35 dysfunction or identify the endosomes as axonal (pages not provided). (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Metadata

Authors
Cataldo, A. M., Peterhoff, C. M., Troncoso, J. C., Gomez-Isla, T., Hyman, B. T., & Nixon, R. A.
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2000-07
Volume
157
Issue
1
Pages
277-286
ISSN
0002-9440
DOI
10.1016/s0002-9440(10)64538-5
Cited by
776
References
6
Language
en
Licence
Funders
National Institutes of Health (AG 10916, AG14762)

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