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

项目总结 在人类身上的证据表明，血管风险因素，如中风，增加了风险，或在某些情况下 对阿尔茨海默病(AD)的发展有协同作用。大多数血管性痴呆(VAD)和 AD混合性痴呆患者在β-淀粉样蛋白(A-β)积聚、脑内和脑内表现出更多样的病理 萎缩，和神经退行性变比典型的单纯AD患者。目前，患者的确切数量 目前被诊断为一种特定类型的痴呆症，实际上患有混合性痴呆症是未知的；然而， 尸检分析表明，超过一半的临床诊断为 广告。此外，尽管vaD和AD经常共存，但对这些疾病是如何发生的知之甚少 相互影响，部分原因是缺乏适当的动物模型。 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)小鼠、运动恢复受损和老年C57BL/6小鼠认知功能障碍的加速发病 与缺血性中风后几个月的年轻成年小鼠相比。这种行为表现形式 对应于脑萎缩和胆碱能变性的加重以及Aβ和tau的局灶性增加 同侧大脑半球轴索变性和白质束区的病理改变。相比之下，我们的 初步数据显示，在混合痴呆模型中使用老年转基因Aβ前体蛋白转基因 小鼠(AβPPL/S)，缺血加剧行为缺陷，这与全球脑缺血增加有关。 β和tau病理与βPp1/S假手术小鼠的比较。此外，在这两种模式中， 卒中诱导的AD病理与β-分泌酶1和BACE1的存在或增加共存 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WT小鼠AD样病理异常发生的途径，并加剧老年WT小鼠的病理 老龄AβPpl/S小鼠。因此，在我们进一步开发了这两个鼠标模型之后，我们将使用它们 以确定BACE1依赖的髓鞘修复途径是否对中风的康复是必要的，但 拮抗性也会导致AD相关病理的产生。最后，我们将确定小的 分子p75神经营养素受体(P75NTR)配体LM11A-31，目前正处于2a期临床试验 阿尔茨海默病的治疗，在脊髓损伤后保留有髓轴突，减缓或防止 与痴呆相关的混合性行为和病理异常的发生 中风。

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.