Alzheimer's disease (AD) often coexists with other aging-associated diseases including obesity, diabetes, hypertension, and cardiovascular diseases. The early stage of these comorbidities is known as metabolic syndrome (MetS) which is highly prevalent in mid-life. An important cause of MetS is the deficiency of SIRT3, a mitochondrial deacetylase which enhances the functions of critical mitochondrial proteins, including metabolic enzymes, by deacetylation. Deletion of Sirt3 gene has been reported to result in the acceleration of MetS. In a recently published study, we demonstrated in the brain of Sirt3^−/− mice, downregulation of metabolic enzymes, insulin resistance and elevation of inflammatory markers including microglial proliferation. These findings suggested a novel pathway that could link SIRT3 deficiency to neuroinflammation, an important cause of Alzheimer's pathogenesis. Therefore, we hypothesized that MetS and amyloid pathology may interact through converging pathways of insulin resistance and neuroinflammation in comorbid AD. To investigate these interactions, we crossed Sirt3^−/− mice with APP/PS1 mice and successfully generated APP/PS1/Sirt3^−/− mice with amyloid pathology and MetS. In these comorbid AD mice, we observed exacerbation of insulin resistance, glucose intolerance, amyloid plaque deposition, markers of neuroinflammation, including elevated expression of IL-1β, TNF-α and Cox-2 at 8 months of age. There was also increased microglial proliferation and activation. Our observations suggest a novel mechanism by which MetS may interact with amyloid pathology during the cellular phase of AD. Therapeutic targeting of SIRT3 in AD with comorbidities may produce beneficial effects.

阿尔茨海默病 (AD) 经常与其他与衰老相关的疾病共存，包括肥胖、糖尿病、高血压和心血管疾病。这些合并症的早期阶段被称为代谢综合征（MetS），在中年非常普遍。MetS 的一个重要原因是 SIRT3 的缺乏，SIRT3 是一种线粒体脱乙酰酶，可通过脱乙酰化增强关键线粒体蛋白（包括代谢酶）的功能。据报道，Sirt3 基因的缺失导致 MetS 的加速。在最近发表的一项研究中，我们在 Sirt3 的大脑中展示了^-/-小鼠，代谢酶下调，胰岛素抵抗和炎症标志物升高，包括小胶质细胞增殖。这些发现提出了一种新的途径，可以将 SIRT3 缺乏症与神经炎症联系起来，神经炎症是阿尔茨海默病发病机制的一个重要原因。因此，我们假设 MetS 和淀粉样蛋白病理学可能通过合并 AD 中的胰岛素抵抗和神经炎症的聚合途径相互作用。为了研究这些相互作用，我们将 Sirt3 ^-/-小鼠与 APP/PS1 小鼠杂交并成功生成了 APP/PS1/Sirt3 ^-/-患有淀粉样蛋白病理学和 MetS 的小鼠。在这些合并的 AD 小鼠中，我们观察到 8 个月大时胰岛素抵抗、葡萄糖耐受不良、淀粉样斑块沉积、神经炎症标志物的恶化，包括 IL-1β、TNF-α 和 Cox-2 的表达升高。小胶质细胞的增殖和活化也增加了。我们的观察表明，MetS 可能在 AD 的细胞期与淀粉样蛋白病理相互作用的新机制。在合并症的 AD 中 SIRT3 的治疗靶向可能会产生有益的效果。