Sirtuin 3 attenuates amyloid-β induced neuronal hypometabolism
Autor: | Tanner Carcione, Shiping Li, Jiong Shi, Junxiang Yin, Winnie S. Liang, Megan Nielsen |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Genetically modified mouse Aging SIRT3 Amyloid Mice Transgenic Mitochondrion Hippocampal formation Hippocampus Cell Line 03 medical and health sciences Amyloid beta-Protein Precursor 0302 clinical medicine Adenosine Triphosphate Alzheimer Disease Memory Sirtuin 3 Animals Humans Maze Learning Neurons Amyloid beta-Peptides biology Behavior Animal Chemistry Wild type amyloid Acetylation Cell Biology NAD cerebral hypometabolism Cell biology Mitochondria Disease Models Animal 030104 developmental biology Sirtuin biology.protein NAD+ kinase Energy Metabolism Alzheimer’s disease 030217 neurology & neurosurgery Research Paper Signal Transduction |
Zdroj: | Aging (Albany NY) |
ISSN: | 1945-4589 |
Popis: | Alzheimer's disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-β (Aβ)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aβ-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aβ. Sirt3 plays an important role in regulating Aβ-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy. |
Databáze: | OpenAIRE |
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