Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

Abstract

Emerging data suggests that mitochondrial dysfunction is prominently involved in Alzheimer disease (AD) progression. Sirtuin-3 (Sirt3) is a member of the sirtuin family of nicotinamide adenine dinucleotide dependent deacetylases that regulates a variety of mitochondrial functions and suppresses mitochondria-related physiology. Here, we determined sirt3 expression in a mouse model of AD. Spatial learning and memory were tested by Morris water maze in APP/PS1 double transgenic mice. The expression of sirt3 was assayed by real-time quantitative PCR and western blotting. Age-and gender-matched wild-type (WT) littermates were used as controls. Cortical sirt3 localization was assessed using immunohistochemistry. The expression of sirt3 mRNA was significantly lower in the cortex of APP/PS1 double transgenic mice than in WT littermates (0.83 ± 0.24 vs. 1.10 ± 0.21, P < 0.05). A comparable reduction was found in sirt3 protein levels using western blotting. The ratio of mean optical density (MOD) of total sirt3/β-actin in the cortex was 0.77 ± 0.11 in APP/PS1 double transgenic mice and 1.34 ± 0.17 in the WT littermates (P < 0.01). Immunohistochemistry showed the same change as western blotting. The ratio of MOD of integral optical density/total area in APP/PS1 and WT littermates was 0.58 ± 0.02 and 0.71 ± 0.05 (P < 0.01). These data show that sirt3 was depleted in APP/PS1 double transgenic mice. The results suggest that mitochondrial sirt3 might participate in the development of AD via mitochondrial dysfunction.

A Newly Synthesized Rhamnoside Derivative Alleviates Alzheimer’s Amyloid-β-Induced Oxidative Stress, Mitochondrial Dysfunction, and Cell Senescence through Upregulating SIRT3

“…SIRT3 is the main mitochondrial sirtuin involved in protecting stress-induced mitochondrial integrity and energy metabolism and is highly associated with the pathogenesis of AD [13]. In the cortex of APP/PS1 double transgenic mice which are overproducing Aβ, both the mRNA and protein levels of SIRT3 are declined [42] and literature shows a negative association between SIRT3 expression and Aβ level in AD patients [17]. Thus, SIRT3 has been suggested as a molecular target for treating aging and age-related diseases [43,44].…”

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders

“…In vitro Aβ 1-42 treatment also led to increased SIRT-3, -4, and -5 [132]. However, overexpression of APP and presenilin 1 has led to reduction in SIRT3 mRNA and protein in a mouse model, suggesting more complex relations [133]. …”

Who watches the watchmen? Regulation of the expression and activity of sirtuins

“…In addition to metabolic diseases, changes in SIRT3 expression have been observed in neurodegenerative diseases and cancer. These alterations are assumed to be connected to the role of SIRT3 as part of the antioxidative protection machinery (168). Yang et al .…”

“…Yang et al . (168) reported reduced SIRT3 expression in APP/PS1 mouse model of Alzheimer's disease. On the other hand, Weir et al .…”