Interactions between the chronic sequelae of stroke and Alzheimer's disease

中风慢性后遗症与阿尔茨海默病之间的相互作用

• 批准号: 10621332
• 负责人: Kristian Paul Doyle
• 金额: $ 37.67万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621332
• 关键词: Acceleration; Acute; Address; Alteplase; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Area; Attenuated; Automobile Driving; Autopsy; Axon; Behavioral; Biochemical; Blood brain barrier dysfunction; C57BL/6 Mouse; Characteristics; Chronic; Clinical Treatment; Clinical Trials; Cognitive; Complex; Data; Degenerative Disorder; Dementia; Development; Diagnosis; Disease; Economic Burden; Elderly; Exhibits; FDA approved; Generations; Goals; Homeostasis; Human; Impaired cognition; Impairment; Individual; Infarction; Inflammation; Inflammatory Response; Ipsilateral; Ischemia; Ischemic Stroke; Ligands; Light; Modeling; Morphology; Motor; Mus; Myelin; NGFR Protein; NRG1 gene; Nerve Degeneration; Neuregulin 1; Neurons; Oligodendroglia; Oral Administration; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmacotherapy; Phase; Phosphorylation; Procedures; Receptor Signaling; Recovery; Recovery of Function; Research; Risk; Role; Spinal cord injury; Stress; Stroke; Testing; Therapeutic; Therapeutic Effect; Time; Transgenic Mice; Transgenic Organisms; Up-Regulation; Vascular Dementia; Wild Type Mouse; abeta accumulation; aged; axonal degeneration; behavior test; beta secretase; beta-site APP cleaving enzyme 1; cerebral atrophy; cerebrovascular; cerebrovascular pathology; cholinergic; chronic stroke; clinical diagnosis; cognitive function; disease phenotype; frailty; inhibitor; innovation; mixed dementia; motor impairment; motor recovery; mouse model; neuropathology; novel; pharmacologic; post stroke; post stroke dementia; preservation; prevent; repaired; small molecule; stroke recovery; stroke therapy; tau Proteins; tau aggregation; vascular risk factor; white matter; young adult

PROJECT SUMMARY Evidence in humans suggests that vascular risk factors, such as stroke, increase the risk of, or in some cases have a synergistic effect on, the development of Alzheimer's disease (AD). Most vascular dementia (VaD) and AD mixed dementia patients exhibit more varied pathology with respect to β-amyloid (Aβ) accumulation, brain atrophy, and neurodegeneration than typical “pure” AD patients. At present, the precise number of patients presently diagnosed with a particular type of dementia that actually have mixed dementia is not known; however, post-mortem analyses suggest that the condition may be present in over half of patients clinically diagnosed with AD. Furthermore, despite the frequent co-existence of VaD and AD, little is known about how these diseases influence each other, in part due to the lack of adequate animal models. In light of this gap, the objective of Aim 1 of this proposal is to further develop two innovative new models of mixed dementia that can be used to investigate how the long-lasting pathological sequelae of ischemic stroke impact the AD phenotype. To that end, our preliminary data show in a mixed dementia model using aged wildtype (wt) mice, impaired motor recovery and accelerated onset of cognitive impairment in aged C57BL/6 mice compared to young adult mice in the months following ischemic stroke. This behavioral manifestation corresponds with increased brain atrophy and cholinergic degeneration as well as a focal increase in Aβ and tau pathology in areas of axonal degeneration and white matter tracts of the ipsilateral hemisphere. In contrast, our preliminary data show that in a mixed dementia model using aged transgenic Aβ precursor protein transgenic mice (AβPPL/S), that ischemia exacerbates behavioral deficits and that this correlates with a global increase in Aβ and tau pathology compared to AβPPL/S mice that undergo a sham procedure. Furthermore, in both models, the stroke-induced AD pathology co-localized with the presence of, or increases in, β-secretase (BACE) 1 and neuregulin (NRG) 1 type III, both of which are necessary for myelin repair. Therefore, we hypothesize that the chronic sequelae of stroke, for example, axonal degeneration, inflammation, blood brain barrier dysfunction, and impaired paravascular clearance, initiate a myelin repair pathway that leads to the abnormal genesis of AD-like pathology in aged wt mice, and exacerbates pathology in aged AβPPL/S mice. Consequently, after we have further developed these two mouse models, we will use them to determine if the BACE1-dependent myelin repair pathway is necessary for stroke recovery, but antagonistically also leads to the generation of AD-associated pathology. Finally, we will determine if the small molecule p75 neurotrophin receptor (p75NTR) ligand, LM11A-31, which is currently in Phase 2a clinical trials for the treatment of AD, and which preserves myelinated axons following spinal cord injury, slows or prevents the development of mixed dementia-related behavioral and pathological abnormalities in mice that have undergone a stroke.

项目摘要 人类的证据表明，血管危险因素，如中风，增加了风险，或在某些情况下， 对阿尔茨海默病（AD）的发展具有协同作用。大多数血管性痴呆（VaD）和 AD混合型痴呆患者在β-淀粉样蛋白（Aβ）积聚、脑内 萎缩和神经退行性变。目前，患者的准确数量 目前被诊断患有实际上具有混合性痴呆的特定类型的痴呆的人是未知的;然而， 尸检分析表明，超过一半的临床诊断为 AD.此外，尽管VaD和AD频繁共存，但对这些疾病如何影响健康知之甚少。 它们相互影响，部分原因是缺乏足够的动物模型。 鉴于这一差距，本提案目标1的目标是进一步开发两种创新的新模式， 混合性痴呆，可用于研究缺血性中风的长期病理后遗症 影响AD表型。为此，我们的初步数据显示，在使用老年野生型的混合痴呆模型中， (wt)老年C57 BL/6小鼠中运动恢复受损和认知障碍的加速发作 与缺血性中风后几个月的年轻成年小鼠相比。这种行为表现 与脑萎缩和胆碱能变性增加以及Aβ和tau蛋白的局灶性增加相对应 同侧半球轴突变性和白色物质束区域的病理学。相比之下，我们 初步数据显示，在使用老年转基因Aβ前体蛋白转基因的混合痴呆模型中， 小鼠（AβPPL/S），缺血加剧了行为缺陷，这与全球增加， Aβ和tau病理学与经历假手术的AβPPL/S小鼠相比。此外，在这两种模式中， 卒中诱导的AD病理学与β-分泌酶（BACE）1的存在或增加共定位， 神经调节蛋白（NRG）1 III型，两者都是髓鞘修复所必需的。 因此，我们假设中风的慢性后遗症，例如，轴突变性， 炎症、血脑屏障功能障碍和血管旁清除受损，启动髓鞘修复 导致老年野生型小鼠AD样病理异常发生并加剧小鼠病理的途径 老年AβPPL/S小鼠。因此，在我们进一步开发了这两种小鼠模型后， 以确定BACE 1依赖性髓鞘修复途径是否是中风恢复所必需的， 拮抗性地也导致AD相关病理的产生。最后，我们将确定，如果小 分子p75神经营养因子受体（p75 NTR）配体，LM 11 A-31，目前正在进行2a期临床试验， AD的治疗在脊髓损伤后保留了有髓鞘的轴突， 在经历了痴呆的小鼠中， 中风