Sirtuin 3 attenuates amyloid-β induced neuronal hypometabolism

Abstract

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.

Sirtuin 3 mRNA Expression is Downregulated in the Brain Tissues of Alzheimer’s Disease Patients: A Bioinformatic and Data Mining Approach

“…On the one hand, SIRT3 protein upregulation seems to be a protective factor in AD, and SIRT3 protein or mRNA upregulation was observed when many kinds of neuroprotective drugs were administered to animal and cell models of AD [ 12 – 14 , 32 ]. SIRT3 protein downregulation was found in the brain tissues of AD patients [ 7 , 9 ]. On the other hand, some evidence has shown that AD may affect the expression of SIRT3.…”

“…The oxidative stress associated with AD can activate poly (ADP-ribose) polymerase 1 (PARP-1), which can decrease NAD+ and promote ROS generation, leading to upregulation of SIRT3 expression [ 3 ]. Aβ can inhibit the activity of SIRT3 [ 9 ]. The detailed interaction between AD and SIRT3 has not been fully elucidated.…”

“…The detailed protective mechanism of SIRT3 in AD is still unclear, but to date, some experimental evidence has been published. First, Aβ can disrupt the metabolism and function of the mitochondria, leading to an insufficient energy supply [ 9 ] and brain aging. However, SIRT3 can post-translationally deacetylate many key enzymes in the Krebs cycle and fat metabolism, including complex I subunit NDUFA9 [ 33 ], lactate dehydrogenase A (LDHA) [ 34 ] and MnSOD [ 35 ], to improve mitochondrial metabolism and the ATP supply and ameliorate hypometabolism in the brain tissues of AD individuals.…”

“…Moreover, the SIRT3 protein levels in the brain tissues of AD patients were negatively correlated with the levels of tau tangles and amyloid plaques and positively correlated with cognitive function scores, including the 60-item Boston Naming Test and the Mattis dementia rating scale [ 7 , 8 ]. An in vitro study showed that inhibition of SIRT3 through short hairpin RNA interference in hippocampal HT22 cells led to the accumulation of tau protein [ 7 ], and SIRT3 overexpression rescued the Aβ protein-induced decrease in mitochondrial function in HT22 cells [ 9 ]. Supplementation with the SIRT3 cofactor NAD+ improved the cognitive function of a transgenic mouse model of AD [ 10 ].…”

Ketones improves Apolipoprotein E4-related memory deficiency via sirtuin 3

“…Our previous studies found that peripheral administration of ketones significantly reduced amyloid burden and greatly improved learning and memory ability in a symptomatic model of APP transgenic mice [16]. Sirt3 was involved in the pathogenesis of AD and was downregulated by Aβ [17, 18]. Further studies discovered that the Sirt3-related energy pathway played a critical role in neuronal hypometabolism [18].…”