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¹ Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962
² Department of Psychiatry, New York University School of Medicine, New York, NY 10016
³ Department of Cell Biology, New York University School of Medicine, New York, NY 10016
⁴ Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461
⁵ Johnson and Johnson/Janssen Pharmaceutica, B-2340 Beerse, Belgium
⁶ Neurotec, Karolinska Institutet, Novum-KASPAC, SE-141 57 Huddinge, Sweden
⁷ Department of Cell Biology and Neuroscience, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
⁸ McLean Hospital, Belmont, MA 02478

Correspondence to Ralph A. Nixon: nixon{at}nki.rfmh.org

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 ß-amyloid (Aß) deposits extracellularly in the presenilin (PS) 1/Aß precursor protein (APP) mouse model of ß-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 Aß. Purified AVs contain APP and ß-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent -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 Aß production. Our results, therefore, link ß-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

Abbreviations used in this paper: 3MA, 3-methyladenine; Aß, ß-amyloid; AD, Alzheimer's disease; APP, Aß precursor protein; AV, autophagic vacuole; ßCTF, ß–carboxy-terminal fragment; IEM, immuno-EM; KO, knockout; L/APP, murine L cell type + wild-type human alkaline phosphatase; LC3, light chain 3; mTOR, mammalian target of rapamycin; NTg, nontransgenic; PS, presenilin.

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