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。 类似的发现也出现在大鼠身上。 调节蛋白（CTMP），促生存蛋白的内源性负调节因子 Akt 随着年龄的增长而增加，这种增加可能有助于减少脑缺血 我们的初步研究表明，自噬随着年龄的增长而减少。 CTMP 沉默增加了老年大鼠大脑中的自噬。 自噬被认为是大脑衰老的一个过程。我们的初步研究也表明。 淀粉样蛋白 β 肽 (Aβ) 增加 CTMP，而中和 Aβ 则减弱 CTMP 随着年龄的增长，大脑中的 Aβ 会增加，并且 Aβ 在大脑中的积累也会增加。 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。 Zic2 位点，Zic2 结合 CTMP 启动子区域，Zic2 随着年龄的增长而减少 因此，我们的初步研究表明，与衰老相关的 CTMP 增加参与其中。 通过减少自噬而导致与衰老相关的认知能力下降，并且与衰老相关的认知能力下降 CTMP 的增加可能受到 Zic2 的调节，Zic2 受 Aβ 的调节。 通过使用不同年龄的 CTMP 将被沉默的 Fischer 344 大鼠来测试这些假设。 这些老鼠的大脑自噬、学习和记忆能力将受到测试。 CTMP表达的调控，特别是Aβ对CTMP的调节作用 随衰老的表达将通过分子技术在体外和体内测定 这些研究不仅可以提高我们对大脑衰老的理解，还可以提高我们对大脑衰老的认识。 因此，这些研究可能确定了 Aβ 诱导疼痛作用的新机制。 确定减缓大脑衰老过程和降低 AD 风险的潜在目标。