Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

By W. H. Yu, A. Cuervo, Asok Kumar, Corrinne M. Peterhoff, S. Schmidt, Ju-Hyun Lee, P. Mohan, M. Mercken, M. Farmery, L. Tjernberg and 7 more. Journal of Cell Biology, 2005

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Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

Subfields: Cell Biology, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/113f37cb22c8ba33681dcb0a31e028d9c90906d5

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Citations in the corpus

Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease (2010, background): “It has been reported that autophagy is activated in AD brains[19].”
Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, positive): “However, Aβ may also be generated in autophagosomes, which appear to contain both APP and Presenilin-1 (PS-1), an enzyme involved in the cleavage of APP to Aβ (Boland et al., 2008; Yu et al., 2005).”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, positive): “These findings confirm conclusions from other studies that autophagosome may be an intracellular Ab reservoir which form when maturation of autophagosomes to autolysosomes is impaired (Yu et al., 2005).”
Eaten alive: a history of macroautophagy (2010, background): “Subsequent studies provided compelling evidence that activation of autophagy is a beneficial physiological response in nearly all neurodegenerative disease”
Autophagy, amyloidogenesis and Alzheimer disease (2007, background): “Under these conditions, A production rises twofold over that in autophagy-suppressed cells and A immunoreactivity appears within AVs (Yu et al., 2005).”