Assessing interactions between cerebrovascular and tau pathologies

评估脑血管和 tau 病理学之间的相互作用

• 批准号: 8929959
• 负责人: Holly Brothers
• 金额: $ 5.3万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929959
• 关键词: Address; Age-Months; Alzheimer' s Disease; Amino Acids; Attenuated; Behavioral; Biochemical; Blood Vessels; Cardiovascular Diseases; Cerebrovascular Disorders; Chronic; Clinical; Clinical Treatment; Cognitive; Cognitive deficits; Comorbidity; Data; Dementia; Development; Diagnosis; Diet; Enzymes; Foundations; Goals; Homocysteine; Homocystine; Human; Hyperhomocysteinemia; Impaired cognition; Individual; Intervention; Lead; Learning; Lithium; Magnetic Resonance Imaging; Measures; Memory impairment; Mentors; Mentorship; Metabolic Pathway; Metabolism; Methylation; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Outcome; Outcome Measure; Pathology; Pathway interactions; Patients; Pharmacological Treatment; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Process; Relative (related person); Research; Risk Factors; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Societies; Testing; Therapeutic; Time; Transgenes; Transgenic Mice; Transgenic Organisms; Vascular Dementia; cardiovascular risk factor; cerebrovascular; cognitive function; design; improved; innovation; mixed dementia; mouse model; novel; public health relevance; skills; spatial memory; tau Proteins; tau phosphorylation

DESCRIPTION (provided by applicant): Dementia is a loss of cognitive function that is extremely costly to individuals and society. Dementia is not defined by a single cause or pathology, and is most often attributed to Alzheimer's disease (AD, ~70%) and vascular dementia (VaD, ~17%), yet a considerable number of dementia cases (20-50%) share aspects of both. The broad objective of this proposal is to improve characterization of the commonalities and differences between these forms of dementia. Better understanding can improve diagnosis of dementias within this spectrum, interpretation of clinical results confounded by co-morbidity, and direction of therapeutic approaches. In order to better understand the overlap and differences between dementias within the spectrum between AD and VaD, this proposal focuses on two factors often shared between AD and VaD, hyperhomocysteinemia (HHcy) and tau pathology. HHcy is a risk factor for cardiovascular disease and related VaD, but is also frequently present in AD and other dementias. HHcy may play a causal role in the development of dementia. Tau pathology is a hallmark of AD, but is also present in a range of neurodegenerative diseases, including VaD, and may be promoted by HHcy. The focused objectives of this proposal are to understand the interactions between cerebrovascular and tau pathologies, identify mechanism by which HHcy may promote tau pathology and to address interventional approaches that may be useful in dementia patients with HHcy. In order to address these objectives, this proposal will utilize a model of diet-induced chronic HHcy developed by our lab and a recently developed transgenic mouse that expresses a suppressible human tau transgene. Aim 1 will evaluate the interactions between HHcy and tau, particularly the effects on cognitive deficit, and address dietary reversal of HHcy and pharmacological suppression of tau pathology as therapeutic approaches. Aim 2 will determine if changes in the metabolic pathway of homocysteine are likely pathway for an HHcy-induced increase in tau pathology. HHcy-induced vascular pathology (microhemorrhage), tau pathology (oligomers, hyperphosphorylated species and neurofibrillary tangles), cognitive impairment (spatial memory) and enzymes/metabolites of homocysteine metabolism will be evaluated. These aims investigate separate aspects of the relationship between HHcy, tau and cognitive impairment. Each aim will offer valuable information to determine the usefulness of intervention strategies to reduce HHcy and tau pathology in the substantial subset of dementia patients with comorbid HHcy. Finally, these studies provide the opportunity to broaden my repertoire of technical skills and develop intellectually under the mentorship of my sponsor and mentoring committee. In particular I will learn: magnetic resonance imaging in mice, use of transgenic mice, assessment of tau and vascular pathology, and how to address a need with the development of a novel model. These aims are designed to support my gradual progression toward autonomy and will provide the foundation for independent research.

描述（由申请人提供）：痴呆是认知功能的丧失，对个人和社会来说是极为昂贵的。痴呆症不是由单一原因或病理学来定义的，并且通常归因于阿尔茨海默氏病（AD，〜70％）和血管性痴呆（VAD，〜17％），但痴呆症病例大量（20-50％）两者的份额。该提案的广泛目标是改善这些痴呆症形式之间的共同点和差异的表征。更好的理解可以改善该范围内痴呆症的诊断，对合并症混淆的临床结果的解释以及治疗方法的方向。 为了更好地了解AD和VAD之间频谱中痴呆症之间的重叠和差异，该提案重点介绍了AD和VAD之间经常共享的两个因素，高脑结合结膜血症（HHCY）和TAU病理学。 HHCY是心血管疾病和相关VAD的危险因素，但在AD和其他痴呆症中也经常存在。 HHCY可能在痴呆症的发展中发挥因果作用。 Tau病理学是AD的标志，但也存在于包括VAD在内的一系列神经退行性疾病中，并且可以由HHCY促进。该提案的重点目标是了解脑血管和TAU病理学之间的相互作用，确定HHCY可以促进TAU病理学的机制，并解决可能对HHCY痴呆症患者有用的介入方法。 为了解决这些目标，该提案将利用我们实验室开发的饮食诱导的慢性HHCY的模型，以及最近开发的转基因小鼠，表达了可抑制的人tau转基因。 AIM 1将评估HHCY和TAU之间的相互作用，尤其是对认知缺陷的影响，并解决HHCY的饮食逆转和作为治疗方法的Tau病理学的药理抑制。 AIM 2将确定同型半胱氨酸代谢途径的变化是否可能是HHCY诱导的TAU病理增加的途径。 HHCY诱导的血管病理学（微生物病理），TAU病理学（低聚物，高磷酸化物种和神经原纤维缠结），认知障碍（空间记忆）和同型生长生成代谢的酶/代谢物。这些目的研究了HHCY，TAU和认知障碍之间关系的各个方面。每个目标都将提供有价值的信息，以确定降低HHCY和TAU病理学的干预策略的有用性，这些病理在痴呆症患者的大量痴呆症患者中。 最后，这些研究为扩大我对技术技能的曲目而提供了机会，并在我的赞助商和指导委员会的指导下进行了智力发展。特别是我将学习：小鼠中的磁共振成像，使用转基因小鼠，评估TAU和血管病理学以及如何通过新型模型的发展来满足需求。这些目标旨在支持我逐渐发展自主权的进步，并将为独立研究提供基础。