Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations.
By A. Cataldo, Corrinne M. Peterhoff, J. Troncoso, T. Gómez-Isla, Bradley T. Hyman, Ralph A. Nixon. American Journal of Pathology, 2000
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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.
Subfields: Neurology, Physiology
View Paper: https://www.semanticscholar.org/paper/69f014b4806270f98c2ce75b9c2864ff9921c523
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Citations in the corpus
- Extensive Involvement of Autophagy in Alzheimer Disease: An Immuno-Electron Microscopy Study (2005, background): “The function of the endocytic pathway, one major route to the lysosome, is altered before any other known pathologies in AD brain (19, 20), and this dysfunction may promote b-amyloid peptide generation (20–23) and reduce neuronal survival (24).”
- Oxidative Stress and Autophagy (2006, neutral): “Changes in the endosome/lysosome system occur very early in the affected neurons of Alzheimer’s disease patients (13).”
- APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types (2018, neutral): “Further, increased number and/or size of early endosomes has been described in the brains of AD patients (Cataldo et al., 2000).”
- Autophagy, amyloidogenesis and Alzheimer disease (2007, background): “The increased expression of Rab5 and other effectors of early endosome fusion early in AD (Cataldo et al., 1996; Cataldo et al., 2000) elevates A production in endosomes when AD is modeled in cells (Grbovic et al.”