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

W. Haung Yu, Ana Maria Cuervo, Asok Kumar, Corrinne M. Peterhoff, Stephen D. Schmidt, Ju Hyun Lee, Panaiyur S. Mohan, Marc Mercken, Mark R. Farmery, Lars O. Tjernberg, Ying Jiang, Karen Duff, Yasuo Uchiyama, Jan Näslund, Paul M. Mathews, Anne M. Cataldo, Ralph A. Nixon

Research output: Contribution to journalArticle

691 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)87-98
Number of pages12
JournalJournal of Cell Biology
Volume171
Issue number1
DOIs
StatePublished - Oct 1 2005

ASJC Scopus subject areas

  • Cell Biology

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    Haung Yu, W., Cuervo, A. M., Kumar, A., Peterhoff, C. M., Schmidt, S. D., Lee, J. H., Mohan, P. S., Mercken, M., Farmery, M. R., Tjernberg, L. O., Jiang, Y., Duff, K., Uchiyama, Y., Näslund, J., Mathews, P. M., Cataldo, A. M., & Nixon, R. A. (2005). Macroautophagy - A novel β-amyloid peptide-generating pathway activated in Alzheimer's disease. Journal of Cell Biology, 171(1), 87-98. https://doi.org/10.1083/jcb.200505082