Build-up of beta-amyloid in the brain in Parkinson's disease

帕金森病患者大脑中β-淀粉样蛋白的积累

• 批准号: 10328282
• 负责人: MIKHAIL INYUSHIN
• 金额: $ 10.48万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328282
• 关键词: Abeta synthesis; Affect; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Amyloidosis; Antiplatelet Drugs; Apolipoproteins; Area; Autoimmunity; Biochemistry; Biology; Blood; Blood Platelets; Blood Vessels; Brain; Brain Neoplasms; Cells; Cerebral Amyloid Angiopathy; Cerebral Thrombosis; Cerebrum; Chemicals; Coagulation Process; Collaborations; Corpus striatum structure; Data; Dementia; Development; Direct Costs; Disasters; Disease; Disease model; Dopamine; Encephalitis; Facilities and Administrative Costs; Goals; Hour; Immunofluorescence Immunologic; Impaired cognition; Income; Infectious Agent; Inflammation; Injury; Lead; Lesion; Membrane; Midbrain structure; Mus; Natural Immunity; Neurofibrillary Tangles; Neurons; Oxidopamine; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Patients; Peptides; Physiology; Plasma; Platelet Activation; Platelet Count measurement; Prealbumin; Process; Production; Public Health; Publishing; Research; Role; Senile Plaques; Site; Skin; Slice; Social Security; Source; Specialist; Substantia nigra structure; Testing; Therapeutic; Thrombosis; Time; Tissues; United States; abeta accumulation; abeta oligomer; antimicrobial; antimicrobial drug; artery occlusion; base; brain cell; brain tissue; density; disabling symptom; dopaminergic neuron; experience; experimental study; frontal lobe; immunocytochemistry; innovation; motor impairment; mouse model; natural antimicrobial; neuropathology; novel strategies; novel therapeutics; payment; synucleinopathy; tau aggregation; thrombotic

PROJECT SUMMARY/ABSTRACT: Amyloid beta (Aβ) is the hallmark of Alzheimer’s disease (AD) but also affects Parkinson’s disease (PD) patients, especially in later stages when PD dementia (PDD) starts to develop. When PDD advances, about 50% of PDD patients develop extensive neuropathology similar to AD. This includes misfolded Aβ plaques and tau neurofibrillary tangles, while the source and scale of Aβ-produced damage and its effects on PDD development are unknown. In 53% of PD patients there is also an accumulation of insoluble Aβ amyloid around blood vessels, known as cerebral amyloid angiopathy (CAA). We previously found that systemic Aβ peptide, generated by blood platelets during cerebral thrombosis, is highly visible on and around the blood vessels within the brain. In addition, in a murine model of PD, when chemicals are injected into the brain to kill dopaminergic neurons, Aβ appears on and around blood vessel walls. We hypothesized that tissue accumulation of Aβ and CAA in PD may be the result of continual platelet activation due to local brain inflammation, with high quantities of Aβ transported through blood vessel walls to brain tissue, causing injury. The objectives of this proposal are to find the platelet-related mechanisms involved in late- PD pathogenesis. Our specific aims will test whether the direct reduction of platelet count, platelet activation/degranulation, or blood plasma Aβ carriers are important in the development of Aβ accumulation. Our proposed innovative research will determine whether this direct approach is effective and could thereby lead to a cure for late-stage Aβ accumulation in PD. This approach might open the way for new therapeutics to stop the development of PDD, which would be a very significant contribution to public health.

项目摘要/摘要： 淀粉样蛋白β（Aβ）是阿尔茨海默氏病（AD）的标志，但也影响帕金森氏病（PD） 患者，尤其是在PD痴呆（PDD）开始发展的后期阶段。当PDD前进时 50％的PDD患者患有类似于AD的广泛神经病理学。这包括错误折叠的Aβ斑块 和Tau神经原纤维缠结，而Aβ产生的损伤的源和尺度及其对PDD的影响 发展是未知的。在53％的PD患者中，也有不溶性Aβ淀粉样蛋白的积累 周围的血管，称为脑淀粉样血管病（CAA）。我们以前发现系统性 在脑血栓形成过程中由血小板产生的Aβ肽在脑血小板过程中高度可见 大脑中的血管。另外，在PD的鼠模型中，将化学物质注入 大脑杀死多巴胺能神经元，Aβ出现在血管壁上和周围。我们假设了这一点 Aβ和CAA在PD中的组织积累可能是由于局部引起的连续血小板激活的结果 大脑感染，大量的Aβ通过血管壁运输到脑组织， 造成伤害。该提案的目标是找到与晚期有关的血小板相关机制 PD发病机理。我们的具体目的将测试是否直接减少血小板计数，血小板 激活/脱粒或血浆Aβ载体在Aβ的发展中很重要 积累。我们提出的创新研究将确定这种直接方法是否有效 因此，可能导致治愈PD的晚期Aβ积累。这种方法可能打开道路 对于新的治疗剂制止PDD的发展，这将是非常重要的贡献 公共卫生。