SIRT3 Deficiency-mediated Metabolic Dysregulation in Comorbid Alzheimer's Disease

阿尔茨海默病 (AD) 是痴呆症最常见的病因，其特点是淀粉样蛋白的积累 斑块和神经原纤维缠结的形成。 AD 的治疗是一项挑战，因为这种毁灭性的疾病 通常与其他由合并症引起的脑部病变共存，包括肥胖、糖尿病、高血压和 心血管疾病。代谢综合征（MetS）是这些合并症的早期阶段，并且很普遍 在退伍军人群体中。中年的 MetS 可能与 AD 的无症状细胞期相互作用 加速疾病进展。需要及早检查合并症的作用，因为合并症 人群在疾病管理和使用药物类型方面可能采取不同的途径。因此， 流行病学研究有时会得出关于痴呆症易感性的不同结果。研究 使用 AD 共病模型，MetS 和 AD 之间的早期相互作用可以识别聚合途径。 在 MetS 中，线粒体蛋白过度乙酰化，导致其功能下降。这种蛋白质 修饰被脱乙酰酶（SIRT3）逆转，这是本研究的重点。 SIRT3 下调是 MetS 的一个关键组成部分，因为 (i) 小鼠中 Sirt3 的整体敲除会导致 MetS 的加速，(ii) 由单点突变 (V208I) 引起的人类 SIRT3 活性降低，与 与 MetS 相关，并且 (iii) 长期摄入过量热量（MetS 的一个原因）会降低 SIRT3 水平，并且 活动。虽然 SIRT3 研究通常停留在外周组织领域，但其在大脑中的功能 线粒体代谢开始出现。我们最近提出了批判性观察 线粒体蛋白的过度乙酰化/下调、线粒体呼吸受损以及线粒体标记物 Sirt3-/- 小鼠大脑样本的神经炎症。因此，我们将这些小鼠与阿尔茨海默氏症小鼠进行杂交 转基因 (APP/PS1) 小鼠产生 APP/PS1/Sirt3-/- 小鼠，作为与 MetS 共病的 AD 模型。恶化 胰岛素抵抗、淀粉样蛋白病理、神经炎症、小胶质细胞失调和差异基因 在这些小鼠中观察到大脑中的表达模式（RNA-seq 分析）。 我们的初步研究表明 MetS 中 SIRT3 缺乏可能导致代谢失调 中年时期的神经炎症，并加速易患 AD 个体的认知能力下降。整体 本研究的目的是通过检查 SIRT3 缺陷在神经元中的作用来剖析因果机制， 共病 AD 小鼠大脑的星形胶质细胞和小胶质细胞。我们假设“SIRT3 缺乏和淀粉样蛋白 病理学通过代谢失调和神经炎症的聚合途径相互作用 共病 AD”。该假设将通过以下具体目标进行检验： 目标 1. 确定 SIRT3 缺乏对脑线粒体代谢、胰岛素的影响 共病 AD 模型 APP/PS1/Sirt3-/- 小鼠的抵抗力和认知能力下降 目标 2. 确定不同脑细胞类型中 SIRT3 缺陷对基因表达的影响 共病 AD 的代谢应激模式和标志物 目标 3. 确定小胶质细胞失调作为 SIRT3 缺乏的关键组成部分的作用 - 诱发神经炎症 这项研究的结果将确定 MetS 加速 AD 发病机制的具体机制并定位 神经炎症上游线粒体蛋白过度乙酰化。 AD 中 SIRT3 的治疗靶向 与共存的病理学结合使用时，有可能产生有益的效果 减少阿尔茨海默病的病理。

Alzheimer's disease (AD), the most frequent cause of dementia, is characterized by accumulation of amyloid plaques and formation of neurofibrillary tangles. Treatment of AD is a challenge because this devastating disease often coexists with other brain lesions caused by comorbidities, including obesity, diabetes, hypertension and cardiovascular diseases. Metabolic syndrome (MetS) is the early stage of these comorbidities and it is prevalent among veteran population. MetS in mid-life could interact with the asymptomatic cellular phase of AD and accelerate the disease progression. The role of comorbidities needs to be examined early because the comorbid population may take diverse paths in terms of disease management and the type of medications used. Therefore, epidemiological studies can sometime yield mixed findings in terms of their susceptibility to dementia. Studies of early interactions between MetS and AD, using comorbid models of AD, can identify converging pathways. In MetS, mitochondrial proteins are hyperacetylated, leading to their decreased function. This protein modification is reversed by the deacetylase enzyme, known as SIRT3, the focus of this study. SIRT3 downregulation is a critical component of MetS because (i) global knockout of Sirt3 in mice leads to acceleration of MetS, (ii) reduced human SIRT3 activity, caused by a single point mutation (V208I), is associated with MetS and (iii) chronic consumption of excessive calories, a cause of MetS, decreases SIRT3 levels and activity. While SIRT3 research has generally remained in the domain of peripheral tissues, its function in brain mitochondrial metabolism is beginning to emerge. We recently made the critical observations of hyperacetylation/downregulation of mitochondrial proteins, impaired mitochondrial respiration, and markers of neuroinflammation with the brain samples of Sirt3-/- mice. Therefore, we crossed these mice with Alzheimer's transgenic (APP/PS1) mice to generate APP/PS1/Sirt3-/- mice, as a comorbid AD model with MetS. Exacerbation of insulin resistance, amyloid pathology, neuroinflammation, microglial dysregulation and differential gene expression patterns (RNA-seq analysis) in the brain were observed in these mice. Our preliminary studies suggested that SIRT3 deficiency in MetS may cause metabolic dysregulation and neuroinflammation in midlife and accelerates cognitive decline in individuals susceptible for AD. The overall objective of this study is to dissect the causal mechanisms by examining the roles of SIRT3 deficiency in neurons, astrocytes and microglia of comorboid AD mouse brain. We hypothesize that “SIRT3 deficiency and amyloid pathology interact through converging pathways of metabolic dysregulation and neuroinflammation in comorbid AD”. This hypothesis will be tested with the following Specific Aims: Aim 1. To determine the effects of SIRT3 deficiency on brain mitochondrial metabolism, insulin resistance and cognitive decline in APP/PS1/Sirt3-/- mice, a comorbid AD model Aim 2. To determine the effects of SIRT3 deficiency in different brain cell types on gene expression patterns and markers of metabolic stress in comorbid AD Aim 3. To determine the role of microglial dysregulation as a key component of SIRT3 deficiency- induced neuroinflammation Findings of this study will identify specific mechanisms by which MetS accelerates AD pathogenesis and place mitochondrial protein hyperacetylation upstream of neuroinflammation. Therapeutic targeting of SIRT3 in AD with coexisting pathologies has the potential to produce beneficial effects when combined with treatments that reduce Alzheimer's pathologies.