title: Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease.
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 beta-amyloid (Abeta) deposits extracellularly in the presenilin (PS) 1/Abeta precursor protein (APP) mouse model of beta-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 Abeta. Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-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 Abeta production. Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.
authors.affiliation: Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.
authors.forename: W Haung
authors.initials: WH
authors.lastname: Yu
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
authors.forename: Asok
authors.initials: A
authors.lastname: Kumar
authors.forename: Corrinne M
authors.initials: CM
authors.lastname: Peterhoff
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Panaiyur S
authors.initials: PS
authors.lastname: Mohan
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.forename: Mark R
authors.initials: MR
authors.lastname: Farmery
authors.forename: Lars O
authors.initials: LO
authors.lastname: Tjernberg
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Karen
authors.initials: K
authors.lastname: Duff
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Jan
authors.initials: J
authors.lastname: Näslund
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Anne M
authors.initials: AM
authors.lastname: Cataldo
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nixon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001343:Autophagy / Q000502:physiology*; D001921:Brain / Q000473:pathology; D010450:Endopeptidases / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D053764:Presenilin-1; D015398:Signal Transduction; D014617:Vacuoles / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse