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

阿尔茨海默病(AD)是痴呆症最常见的原因，其特征是淀粉样蛋白积聚 斑块和神经原纤维缠结的形成。治疗阿尔茨海默病是一项挑战，因为这种毁灭性的疾病 经常与其他由共病引起的脑损伤共存，包括肥胖、糖尿病、高血压和 心血管疾病。代谢综合征(METS)是这些共病的早期阶段，它很普遍 在退伍军人中。中年的蛋氨酸可与AD的无症状细胞期相互作用 加速疾病的发展。需要及早检查合并症的作用，因为 在疾病管理和使用的药物类型方面，人口可能采取不同的道路。因此， 流行病学研究有时会得出关于他们患痴呆症的易感性的混合结果。的研究 利用AD的共病模型，蛋氨酸和AD之间的早期相互作用可以确定汇聚的途径。 在蛋氨酸中，线粒体蛋白被过度乙酰化，导致其功能下降。这种蛋白质 修饰被脱乙酰酶逆转，被称为SIRT3，这是本研究的重点。SIRT3 下调调控是蛋氨酸的一个关键组成部分，因为(I)小鼠体内SIRT3的全局敲除导致 Mets的加速，(Ii)由单点突变(V208I)引起的人类SIRT3活性降低，与 与蛋氨酸和(Iii)长期摄入过多卡路里，这是蛋氨酸的一个原因，降低SIRT3水平和 活动。虽然SIRT3的研究普遍停留在外周组织领域，但它在大脑中的功能 线粒体新陈代谢开始出现。我们最近对以下问题进行了批判性观察 线粒体蛋白的高乙酰化/下调，线粒体呼吸受损，以及 神经炎症与SIRT3-/-小鼠的大脑样本。因此，我们让这些患有阿尔茨海默氏症的小鼠 转基因(APP/PS1)小鼠产生APP/PS1/SIRT3-/-小鼠，作为Mets的共病AD模型。加重 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 观察了这些小鼠脑内的表达模式(RNA-seq分析)。 我们的初步研究表明，蛋氨酸缺乏SIRT3可能导致代谢失调和 中年神经炎并加速易患阿尔茨海默病的人的认知能力下降。整体而言 本研究的目的是通过研究SIRT3缺乏在神经元中的作用来剖析其原因机制。 类AD小鼠脑内星形胶质细胞和小胶质细胞。我们假设SIRT3缺乏症和淀粉样蛋白 病理通过代谢紊乱和神经炎症的汇聚途径相互作用 合并症AD“。这一假设将以以下具体目标进行检验： 目的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功能下降 目的2.确定不同脑细胞类型SIRT3缺乏对基因表达的影响 共病阿尔茨海默病的代谢应激模式和标志物 目的3.确定小胶质细胞失调作为SIRT3缺乏症的关键成分的作用。 诱导性神经炎 这项研究的发现将确定蛋氨酸加速AD发病和定位的具体机制 线粒体蛋白高乙酰化位于神经炎症的上游。SIRT3靶向治疗阿尔茨海默病 当与以下治疗相结合时，可能会产生有益的效果 减少阿尔茨海默氏症的发病率。

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.