Defining the role of age-related glymphatic pathway impairment in amyloid beta plaque deposition

摘要摘要 阿尔茨海默病(AD)是世界范围内导致痴呆的主要原因，其特征是 老年斑是由Aβ蛋白组成的细胞外聚集体，十多年来开始形成 在临床症状出现之前。衰老是阿尔茨海默病发展的最大风险因素，但 使老化的大脑容易受到β沉积影响的因素仍不清楚，目前还没有治疗方法。 可以防止或逆转大脑老化的这一过程。我们最近定义了全脑血管周围 网络，称为促进间质液体和脑脊液交换的‘淋巴’系统， 促进包括β在内的间质废物从大脑中清除。沿这些区域的流体运动 水通道水通道蛋白-4(AQP4)促进通路和通过脑间质，水通道蛋白-4是 在直接面对脑血管的星形细胞膜上以高度极化的方式表达。 AQP4基因缺失减缓β从脑中的清除并加速β斑块的沉积 转基因AD小鼠模型的建立。我们观察到AQP4在血管周围的定位在两个 衰老的小鼠和人的皮质，以及在人的皮质中，血管周围AQP4的定位丢失是 与Aβ斑块负荷恶化和AD相关。基于这些发现，我们建议损失 水通道蛋白4在衰老脑组织中的定位损害间质Aβ清除并促进Aβ斑块 队形。在这个方案中，我们将使用一个缺乏血管周围AQP4定位的转基因小鼠模型来 确定AQP4定位的丢失是否减缓了间质Aβ的清除。然后我们将使用体内病毒 用转染法检测在衰老过程中上调的AQP4-M23变异体 大脑，扰乱血管周围AQP4的定位，损害淋巴途径功能。这两种方法 然后将用于确定血管周围AQP4定位的丢失，包括AQP4-M23 上调，促进阿尔茨海默病小鼠模型中β斑块的沉积，从而自发发生β 斑块。使用基于MRI的淋巴功能成像，我们将评估受损的区域 淋巴功能促进局部A-β斑块沉积。如果得到证实，这些研究可能会提供一种 衰老大脑对β聚集易感性的机制基础，包括对 在疾病病程的早期，某些大脑区域对这一过程的脆弱性。这些发现可能会确定一个 防止大脑老化的这些过程的新的治疗方法。

Summary Abstract Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the formation of senile plaques, extracellular aggregates composed of the protein Aβ that begin forming more than a decade before the onset of clinical symptoms. Aging is the strongest risk factor for the development of AD, yet the factors that render the aging brain vulnerable to Aβ deposition remain unknown and no treatments exist that can prevent or reverse this process in the aging brain. We have recently defined a brain-wide perivascular network, termed the `glymphatic' system that facilitates the exchange of interstitial fluid and cerebrospinal fluid, facilitating the clearance of interstitial wastes including Aβ from the brain. Fluid movement along these pathways and through the brain interstitium is facilitated by the water channel aquaporin-4 (AQP4) which is expressed in a highly polarized manner in astrocyte membranes that directly face the brain vasculature. Genetic deletion of AQP4 slows Aβ clearance from the brain and accelerates Aβ plaque deposition in a transgenic mouse model of AD. We have observed that perivascular AQP4 localization is disrupted in both the aging mouse and human cortex, and that in the human cortex, loss of perivascular AQP4 localization is associated with worsening Aβ plaque burden and AD. Based on these findings, we propose that loss of perivascular AQP4 localization in the aging brain impairs interstitial Aβ clearance and promotes Aβ plaque formation. In this proposal, we will use a transgenic mouse model that lacks perivascular AQP4 localization to determine whether loss of AQP4 localization slows interstitial Aβ clearance. We will then use an in vivo viral transfection approach to test whether upregulation of the AQP4-M23 variant, which is upregulated in the aging brain, disrupts perivascular AQP4 localization and impairs glymphatic pathway function. These two approaches will then be used to determine whether loss of perivascular AQP4 localization, including by AQP4-M23 upregulation, promotes Aβ plaque deposition in a mouse model of AD that spontaneously develops Aβ plaques. Using MRI-based imaging of glymphatic function, we will evaluate whether regions of impaired glymphatic function promote local Aβ plaque deposition. If validated, then these studies may provide a mechanistic basis for the vulnerability of the aging brain to Aβ aggregation, including an explanation for the vulnerability of certain brain regions to this process early in the disease course. These findings may identify a new therapeutic approach to preventing these processes in the aging brain.