Rates of brain acetylome remodeling in a mouse model of diabetes and tauopathy

糖尿病和 tau 蛋白病小鼠模型中脑乙酰组重塑率

• 批准号: 10807604
• 负责人: Takhar Kasumov
• 金额: $ 42.9万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807604
• 关键词: Acetyl Coenzyme A; Acetylation; Affect; Age Months; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer' s disease therapy; Behavior; Behavior assessment; Brain; Cause of Death; Clinical; Cognitive deficits; Collaborations; Computer software; Coupled; Cytosol; Deacetylation; Dementia; Development; Diabetic mouse; Diet; Elderly; Epigenetic Process; Exploratory/Developmental Grant; Fatty acid glycerol esters; Half-Life; Hippocampus; Histone H4; Histones; Human; Impaired cognition; In Vitro; Interdisciplinary Study; Isotopes; Label; Late Onset Alzheimer Disease; Link; Lysine; MAPT gene; Mass Spectrum Analysis; Measurement; Measures; Mediating; Memory impairment; Metabolic; Metabolism; Methods; Modeling; Molecular; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathologic; Pathway interactions; Peptides; Persons; Phenotype; Population; Post-Translational Protein Processing; Process; Protein Acetylation; Protein Isoforms; Proteins; Proteome; Proteomics; Reporting; Research; Resolution; Risk Factors; Role; Site; Tauopathies; United States; Validation; Work; abeta accumulation; age related; aged; amyloid pathology; behavioral phenotyping; clinically relevant; cofactor; diabetic; epidemiology study; epigenome; experimental study; frontal lobe; genome wide association study; hTau Mice; high risk; humanized mouse; in vivo; kinetic model; mind control; mouse model; multidisciplinary; neuroinflammation; non-diabetic; pre-clinical; protein degradation; response; stable isotope; sugar; tau Proteins; tau aggregation; tau-1; uptake

Alzheimer's disease (AD) is one of the top ten causes of death in the United States, and there is no cure. AD is characterized by tauopathy, the accumulation of hyperphosphorylated microtubule- associated protein tau (MAPT, tau), and is linked to metabolic dysregulation. Type 2 diabetes mellitus (T2DM) is a risk factor for late-onset AD, but the mechanistic link between the two is unclear. Post-translational protein lysine N(epsilon) acetylation by the central metabolite acetyl-CoA has been identified as an essential regulatory mechanism in intermediary metabolism, epigenetics, and protein stability. T2DM is characterized by altered substrate metabolism, which impacts acetylation and deacetylation co-factors NAD+ and acetyl-CoA. Dysregulated histone and tau acetylation have been linked with age-dependent memory impairment. In vitro studies suggest that acetylation contributes to tau aggregation. The in vivo impact of site-specific acetylation on brain protein, including tau turnover, is unknown. To investigate this, we developed a 2H2O (stable isotope)-based mass spectrometry method to quantify protein turnover and assess the effect of post-translational modifications (PTMs) on protein stability in vivo. The study aims to evaluate the role of acetylation on brain proteome dynamics in the htau mouse model of AD. The first aim quantifies proteome and acetylome dynamics in the hippocampus and frontal cortex of diet-induced diabetic and non-diabetic AD mice to determine the effect of T2DM-related dysregulated acetylation on brain protein stability in vivo. The second aim assesses the role of T2DM on the acetylation turnover of brain proteins in vivo. The research team will also determine how T2DM-related altered acetylation contributes to tauopathy and cognitive decline in AD. These experiments will establish the feasibility of the acetylome dynamics method and motivate the development of new AD therapies.

阿尔茨海默病（AD）是美国十大死亡原因之一， 无法治愈。 AD 的特点是 tau 蛋白病，即过度磷酸化微管的积累 相关蛋白 tau（MAPT，tau），与代谢失调有关。 2型糖尿病 糖尿病 (T2DM) 是迟发性 AD 的危险因素，但两者之间的机制联系是 不清楚。 翻译后蛋白质赖氨酸 N(ε) 被中心代谢物乙酰辅酶 A 乙酰化 被认为是中间代谢、表观遗传学、 和蛋白质稳定性。 T2DM 的特点是底物代谢改变，这会影响 乙酰化和脱乙酰化辅助因子 NAD+ 和乙酰辅酶 A。组蛋白和 tau 蛋白失调 乙酰化与年龄依赖性记忆障碍有关。体外研究表明 乙酰化有助于 tau 聚集。位点特异性乙酰化对体内的影响 脑蛋白，包括 tau 蛋白更新，尚不清楚。 为了研究这一点，我们开发了一种基于 2H2O（稳定同位素）的质谱方法 量化蛋白质周转并评估翻译后修饰 (PTM) 对蛋白质的影响 蛋白质在体内的稳定性。该研究旨在评估乙酰化对大脑蛋白质组的作用 AD 的 htau 小鼠模型中的动力学。第一个目标是量化蛋白质组和乙酰组 饮食诱发的糖尿病和非糖尿病 AD 的海马和额叶皮层动态 小鼠以确定 T2DM 相关乙酰化失调对脑蛋白稳定性的影响 体内。第二个目标评估 T2DM 对脑蛋白乙酰化周转的作用 体内。研究小组还将确定 T2DM 相关的乙酰化改变如何促进 AD 中的 tau 蛋白病和认知能力下降。这些实验将确定该方案的可行性 乙酰组动力学方法并激励新的 AD 疗法的开发。