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），都与错误折叠蛋白质聚集体的积累有关。大脑缺乏淋巴引流系统，外周组织依赖淋巴引流系统清除宏观废物;然而，我们最近发现了一个全脑系统，可以发挥这一作用。我们将其命名为“胶质淋巴”通路，因为它依赖于水通道蛋白4（AQP 4）水通道，该通道在血管周围的星形胶质细胞过程中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 β蛋白从间质空间沿着胶质淋巴通路清除，并且在小鼠AD模型[表达突变型人淀粉样前体蛋白（APPsw）和早老素1（PS E9）]中清除率急剧降低。拟议的研究将利用第一个啮齿动物AD模型-转基因APPsw/PS E9大鼠-复制人类AD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）APPsw/PS E9大鼠血管淀粉样蛋白沉积与氧化应激和AQP 4定位失调引起的青年、中年和老年大鼠胶质淋巴系统功能障碍有关。(2)在活体啮齿类动物中，通过微创腰椎注射造影剂，使用临床相关的磁共振成像（MRI）可对全脑范围内的淋巴转运进行定量。(3)年轻（6个月）和中年（16个月）APPsw/PS E9大鼠，通过MRI成像被鉴定为表现出胶质淋巴清除率最严重下降的那些大鼠，当它们达到老年（26个月）时，具有更高的发展AD病理学的风险，检测为认知下降、氧化应激和淀粉样变性。目标1：使用CSF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胶质淋巴细胞下降与氧化应激的严重程度、星形小胶质细胞增生、极化血管周围AQP 4的丧失、淀粉样蛋白负荷和神经元丧失（作为年龄的函数）联系起来。目标二：建立一个临床相关的啮齿动物成像平台，使用临床相关的磁共振成像（MRI）结合经腰椎鞘内空间的顺磁造影剂微创给药，使用微创技术评价胶质淋巴通路功能。目标3：使用目标2中开发的胶质淋巴诊断MRI测试，我们将检验以下假设：6和16月龄APPsw/PS E9大鼠中的胶质淋巴通路功能障碍预测了相同大鼠在26月龄时认知下降和淀粉样蛋白负荷的严重程度。这些研究将利用APPsw/PS E9大鼠中疾病进展的已知动物间变异性来确定胶质淋巴功能衰竭是否有助于AD病理学。 这些研究首次尝试应用MRI成像来跟踪正常衰老和AD中的胶质淋巴功能障碍。MRI成像平台的临床转化可以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.