Glymphatic function in a transgenic rat model of Alzheimer's disease

描述（由申请人提供）：所有神经退行性疾病，包括阿尔茨海默病（AD）都与错误折叠蛋白聚集体的积累有关。大脑缺乏外周组织所依赖的淋巴排水系统来进行宏观废物清除；然而，我们最近发现了一个全脑系统，支持这一角色。我们将其命名为“glymphatic”通路，因为它依赖于水通道蛋白4 （AQP4）水通道，该通道在血管周围星形胶质突起上以高度极化的模式表达。与年龄匹配的野生型小鼠相比，多达60%的可溶性A¿蛋白沿着淋巴通路从间质间隙被清除，而在小鼠AD模型中[表达突变的人淀粉样蛋白前体蛋白（APPsw）和早老素1(PS E9)]，清除率急剧降低。拟议的研究将利用第一个啮齿动物阿尔茨海默病模型-转基因APPsw/PS E9大鼠-复制人类阿尔茨海默病的所有特征，包括淀粉样变性，反应性星形胶质细胞和小胶质细胞增生，以及进行性神经元丢失。假设：(1)氧化应激和AQP4错位导致的青壮年和老年大鼠淋巴系统功能障碍是APPsw/PS E9大鼠血管淀粉样蛋白沉积的原因之一。(2)在活体啮齿动物中，通过微创腰椎注射造影剂，利用临床相关磁共振成像（MRI）可以量化脑内淋巴转运。(3)年轻（6个月）和中年（16个月）的APPsw/PS E9大鼠，通过MRI成像被认为是淋巴清除率下降最严重的，当它们进入老年（26个月）时，发生AD病理的风险更高，检测为认知能力下降、氧化应激和淀粉样变性。目的1：利用脑脊液示踪剂和光学成像，我们将在APPsw/PS E9和野生型大鼠中，将局部淋巴功能下降与氧化应激的严重程度、星形胶质细胞和小胶质细胞增生、极化血管周围AQP4的丧失、淀粉样蛋白负担和神经元丧失作为年龄的函数联系起来。目的2：建立一个临床相关的啮齿动物成像平台，利用临床相关的磁共振成像（MRI）结合经腰椎鞘内腔微创给药的顺磁造影剂，利用微创技术评估淋巴通路功能。目的3：利用目的2中开发的类淋巴诊断MRI测试，我们将验证6和16个月大的APPsw/PS E9大鼠的类淋巴通路功能障碍预测26个月大鼠认知能力下降和淀粉样蛋白负担的严重程度的假设。这些研究将利用APPsw/PS E9大鼠疾病进展的已知动物间变异性来确定淋巴功能衰竭是否与AD病理有关。这些研究首次尝试应用MRI成像来追踪正常衰老和AD患者的淋巴功能障碍。MRI成像平台的临床翻译可能允许在人类中提出类似的问题，并允许跟踪旨在减缓AD进展的介入性治疗方法。

DESCRIPTION (provided by applicant): All neurodegenerative diseases, including Alzheimer's disease (AD) are associated with the accumulation of misfolded protein aggregates. The brain lacks the lymphatic drainage system that peripheral tissues rely on for macroscopic waste removal; however we recently discovered a brain-wide system that subserves this role. We named it the 'glymphatic' pathway, because it is dependent on aquaporin 4 (AQP4) water channels expressed in a highly polarized pattern on astroglial processes surrounding blood vessels. As much as 60% of soluble A¿ proteins are cleared from the interstitial space along the glymphatic pathway and clearance is sharply reduced in a murine AD model [expressing mutant human amyloid precursor protein (APPsw) and presenilin 1(PS E9)] when compared to age-matched wildtype mice. The proposed studies will utilize the first rodent AD model-transgenic APPsw/PS E9 rats-that replicates all the hallmarks of AD in humans, including amylodosis, reactive astro- and microgliosis, and progressive neuronal loss. HYPOTHESES: (1) Dysfunction of the glymphatic system in young, middle aged and old rats caused by oxidative stress and mislocation of AQP4 contributes to vascular amyloid deposition in APPsw/PS E9 rats. (2) Glymphatic transport can be quantified brain-wide using clinically relevant magnetic resonance imaging (MRI) in live rodents by minimally invasive lumbar administration of contrast agents. (3) Young (6 months) and middle-aged (16 months) APPsw/PS E9 rats that by MRI imaging are identified as those that exhibit the most severe decline in glymphatic clearance are at higher risk of developing AD pathology, detected as cognitive decline, and oxidative stress and amyloidosis, when they reach old age (26 months). Aim 1: Using CSF tracers and optical imaging, we will correlate glymphatic decline locally with the severity oxidative stress, astro- an microgliosis, loss of polarized perivascular AQP4, amyloid burden, and neuronal loss as a function of age in APPsw/PS E9 and wildtype rats. Aim 2: Establish a clinically relevant rodent imaging platform for evaluation of glymphatic pathway function using minimally invasive techniques using clinically relevant magnetic resonance imaging (MRI) combined with minimally invasive administration of paramagnetic contrast via lumbar intrathecal space. Aim 3: Using the glymphatic diagnostic MRI test developed in Aim 2, we will test the hypothesis that glymphatic pathway dysfunction in 6 and 16 months old APPsw/PS E9 rats predicts the severity of cognitive decline and amyloid burden in the same rats at 26 months. These studies will take advantage of the known interanimal variability of disease progression in APPsw/PS E9 rats to define whether failure of glymphatic function contributes to AD pathology. These studies present the first attempt to apply MRI imaging to track glymphatic dysfunction in normal aging and in AD. Clinical translation of the MRI imaging platform may allow similar questions to be asked in humans and permit tracking of interventional therapeutic approaches intended to slow AD progression.