Carboxyl-terminal modulator protein, Aβ and brain aging

羧基末端调节蛋白、Aβ 和大脑衰老

• 批准号: 9816648
• 负责人: Ian Christopher Wenker
• 金额: $ 201.88万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816648
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-Dimensional; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Animals; Attenuated; Autophagocytosis; Binding Proteins; Binding Sites; Brain; Brain Diseases; Development; Down-Regulation; Elderly; Family; Health; Homeostasis; Impaired cognition; Impairment; In Vitro; Lead; Learning; Literature; Memory; Methods; Molecular; Mus; Neurodegenerative Disorders; Nuclear Translocation; Organelles; Pathology; Pathway interactions; Patients; Play; Process; Promoter Regions; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Rattus; Regulation; Research Personnel; Role; Societies; Structure; Technology; Testing; aging brain; brain cell; cell type; improved; in vivo; inhibition of autophagy; knock-down; mature animal; misfolded protein; neuropathology; novel; promoter; protein expression; protein phosphatase inhibitor-2; transcription factor; young adult

Brain aging is a significant health issue and a risk factor for Alzheimer’s disease (AD). Our published results showed that elderly mice had worse learning and memory than younger mice. Similar finding occurred in rats. We have also shown that carboxyl-terminal modulator protein (CTMP), an endogenous negative regulator of the pro-survival protein Akt, increased with aging and this increase may contribute to the decreased brain ischemic tolerance in rats. Our preliminary studies showed that autophagy was decreased with aging and that CTMP silencing increased autophagy in the brain of elderly rats. Decreased autophagy is considered a process of brain aging. Our preliminary study also showed that amyloid β peptide (Aβ) increased CTMP and that neutralizing Aβ attenuated CTMP increase in aging brain. Aβ is increased with aging and Aβ accumulation in the brain is considered a feature of AD. In addition, presumed CTMP promoter regions had binding sites for Zic2, Zic2 bound CTMP promoter regions and Zic2 was decreased with aging in our preliminary study. Thus, we hypothesize that aging-related CTMP increase participates in the aging-related cognitive decline via deceasing autophagy and that the aging-related CTMP increase may be regulated by Zic2, which is modulated by Aβ. In this project, we will test these hypotheses by using different ages of Fischer 344 rats. CTMP will be silenced in the brain of these rats. Their autophagy in the brain, learning and memory will be tested. The regulation of CTMP expression, especially the role of Aβ in regulating CTMP expression with aging will be determined by molecular technology under in vitro and in vivo conditions. These studies may not only improve our understanding of brain aging but also define a novel mechanism for Aβ to induce detrimental effects. Thus, these studies may identify potential targets for attenuating brain aging processes and reducing risks for AD.

大脑老化是一个重要的健康问题，也是阿尔茨海默病的危险因素 （AD）。我们发表的结果表明，老年小鼠的学习和记忆能力比老年小鼠差。 年轻的老鼠在大鼠中也有类似的发现。我们还表明，羧基末端 调节蛋白（CTMP），促存活蛋白的内源性负调节因子 Akt随年龄增长而增加，这种增加可能有助于减少脑缺血 大鼠的耐受性我们的初步研究表明，自噬随着年龄的增长而减少 CTMP沉默增加老年大鼠脑中的自噬。降低 自噬被认为是大脑老化的一个过程。我们的初步研究还表明， 淀粉样β肽（Aβ）使CTMP升高，中和Aβ则使CTMP降低 增加大脑老化。Aβ随着年龄的增长而增加，Aβ在大脑中的积累是 被认为是AD的一个特征。此外，推测的CTMP启动子区域具有结合活性。 Zic2结合CTMP启动子区的Zic2位点，Zic2随着年龄的增长而减少。 我们的初步研究。因此，我们假设与年龄相关的CTMP增加参与了 通过减少自噬作用，与衰老相关的认知能力下降， CTMP升高可能受Zic 2调节，而Zic 2受Aβ调节。在这个项目中，我们将 通过使用不同年龄的Fischer 344大鼠来检验这些假设。CTMP将在 这些老鼠的大脑他们在大脑中的自噬，学习和记忆将被测试。 CTMP表达的调控，特别是Aβ在CTMP调控中的作用 将通过分子技术在体外和体内条件下确定随衰老的表达 条件这些研究不仅可以提高我们对大脑衰老的理解， 定义了Aβ诱导有害作用的新机制。因此，这些研究可能 确定减缓大脑老化过程和降低AD风险的潜在目标。