Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease.
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.
Yu
W Haung
WH
Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.
Cuervo
Ana Maria
AM
Kumar
Asok
A
Peterhoff
Corrinne M
CM
Schmidt
Stephen D
SD
Lee
Ju-Hyun
JH
Mohan
Panaiyur S
PS
Mercken
Marc
M
Farmery
Mark R
MR
Tjernberg
Lars O
LO
Jiang
Ying
Y
Duff
Karen
K
Uchiyama
Yasuo
Y
Näslund
Jan
J
Mathews
Paul M
PM
Cataldo
Anne M
AM
Nixon
Ralph A
RA
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
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