Extensive Involvement of Autophagy in Alzheimer Disease: An Immuno-Electron Microscopy Study

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ID: 292140
2005
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Abstract
The accumulation of lysosomes and their hydrolases within neurons is a well-established neuropathologic feature of Alzheimer disease (AD). Here we show that lysosomal pathology in AD brain involves extensive alterations of macroautophagy, an inducible pathway for the turnover of intracellular constituents, including organelles. Using immunogold labeling with compartmental markers and electron microscopy on neocortical biopsies from AD brain, we unequivocally identified autophagosomes and other prelysosomal autophagic vacuoles (AVs), which were morphologically and biochemically similar to AVs highly purified from mouse liver. AVs were uncommon in brains devoid of AD pathology but were abundant in AD brains particularly, within neuritic processes, including synaptic terminals. In dystrophic neurites, autophagosomes, multivesicular bodies, multilamellar bodies, and cathepsin-containing autophagolysosomes were the predominant organelles and accumulated in large numbers. These compartments were distinguishable from lysosomes and lysosomal dense bodies, previously shown also to be abundant in dystrophic neurites. Autophagy was evident in the perikarya of affected neurons, particularly in those with neurofibrillary pathology where it was associated with a relative depletion of mitochondria and other organelles. These observations provide the first evidence that macroautophagy is extensively involved in the neurodegenerative/regenerative process in AD. The striking accumulations of immature AV forms in dystrophic neurites suggest that the transport of AVs and their maturation to lysosomes may be impaired, thereby impeding the suspected neuroprotective functions of autophagy.
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openalex_W1919353 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Ralph A. Nixon, Jerzy Węgiel, Asok Kumar, Wai Haung Yu, Corrinne M. Peterhoff, Anne M. Cataldo, Ana María Cuervo
Journal Journal of Neuropathology & Experimental Neurology
Year 2005
DOI
10.1093/jnen/64.2.113
URL
https://academic.oup.com/jnen/article-pdf/64/2/113/9555142/64-2-113.pdf
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