Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy.
Defective autophagy contributes to Alzheimer disease (AD) pathogenesis although evidence is conflicting on whether multiple stages are impaired. Here, for the first time, we have comprehensively evaluated the entire autophagic process specifically in CA1 pyramidal neurons of hippocampus from early and late-stage AD subjects and nondemented controls. CA1 neurons aspirated by laser capture microdissection were analyzed using a custom-designed microarray comprising 578 neuropathology- and neuroscience-associated genes. Striking upregulation of autophagy-related genes, exceeding that of other gene ontology groups, reflected increases in autophagosome formation and lysosomal biogenesis beginning at early AD stages. Upregulated autophagosome formation was further indicated by elevated gene and protein expression levels for autophagosome components and increased LC3-positive puncta. Increased lysosomal biogenesis was evidenced by activation of MiTF/TFE family transcriptional regulators, particularly TFE3 (transcription factor binding to IGHM enhancer 3) and by elevated expression of their target genes and encoded proteins. Notably, TFEB (transcription factor EB) activation was associated more strongly with glia than neurons. These findings establish that autophagic sequestration is both competent and upregulated in AD. Autophagosome-lysosome fusion is not evidently altered. Despite this early disease response, however, autophagy flux is progressively impeded due to deficient substrate clearance, as reflected by autolysosomal accumulation of LC3-II and SQSTM1/p62 and expansion of autolysosomal size and total area. We propose that sustained induction of autophagy in the face of progressively declining lysosomal clearance of substrates explains the uncommonly robust autophagic pathology and neuritic dystrophy implicated in AD pathogenesis.
a Center for Dementia Research, Nathan Kline Institute , Orangeburg , NY , USA.|b Department of Psychiatry , New York University Langone Medical Center , New York , NY , USA.
Matteo
M
Bordi
a Center for Dementia Research, Nathan Kline Institute , Orangeburg , NY , USA.
Martin J
MJ
Berg
a Center for Dementia Research, Nathan Kline Institute , Orangeburg , NY , USA.|b Department of Psychiatry , New York University Langone Medical Center , New York , NY , USA.
Panaiyur S
PS
Mohan
a Center for Dementia Research, Nathan Kline Institute , Orangeburg , NY , USA.
Corrinne M
CM
Peterhoff
a Center for Dementia Research, Nathan Kline Institute , Orangeburg , NY , USA.|b Department of Psychiatry , New York University Langone Medical Center , New York , NY , USA.
Melissa J
MJ
Alldred
a Center for Dementia Research, Nathan Kline Institute , Orangeburg , NY , USA.|b Department of Psychiatry , New York University Langone Medical Center , New York , NY , USA.
Shaoli
S
Che
a Center for Dementia Research, Nathan Kline Institute , Orangeburg , NY , USA.|b Department of Psychiatry , New York University Langone Medical Center , New York , NY , USA.|d Department of Neuroscience and Physiology , New York University Langone Medical Center , New York , NY , USA.
Stephen D
SD
Ginsberg
a Center for Dementia Research, Nathan Kline Institute , Orangeburg , NY , USA.|b Department of Psychiatry , New York University Langone Medical Center , New York , NY , USA.|c Department of Cell Biology , New York University Langone Medical Center , New York , NY , USA.
Ralph A
RA
Nixon
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology*; D002402:Cathepsin D / Q000378:metabolism; D003710:Demography; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D016501:Neurites / Q000378:metabolism / Q000473:pathology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C069203:TFE3 protein, human; C064972:TFEB protein, human; D002402:Cathepsin D
Alzheimer disease; CA1 pyramidal neurons; MTOR; TFE3; TFEB; autophagosomes; autophagy; dystrophic neurites; hippocampus; lysosomes