Defining the Role of Glial D-serine in Alzheimer's Disease

阿尔茨海默病(AD)是迟发性痴呆的最常见原因，影响着500多万人 美国人。AD的特征是淀粉样β蛋白(Ab)聚集体沉积，形成斑块和 神经原纤维缠结堆积。流行的假说是抗体纤维损伤神经元，导致 与tau相关的神经原纤维缠结积累，最终导致神经变性。因此，占主导地位的 开发阿尔茨海默病治疗策略的重点是减少淀粉样蛋白负荷的靶点。 大脑。不幸的是，使用这种方法的药物都不能改善大-中老年人的认知和功能结果。 规模临床试验，即使在轻中度AD患者中也是如此，这表明一旦临床AD症状 出现疾病的进展变得独立于抗体的产生。除了斑块和缠结， 激活的胶质细胞，包括星形胶质细胞和小胶质细胞，是阿尔茨海默病的神经病理特征。尽管 最近的发现表明，反应性胶质细胞参与AD病理生理的确切机制(S)尚不清楚 激活的小胶质细胞通过不明原因诱导型A1型反应性星形胶质细胞产生神经毒性 机械装置。我们已经证明，N-甲基-D-天冬氨酸受体(NMDAR)的共同激动剂D-丝氨酸是 在小鼠创伤性脑损伤(TBI)后由反应性星形胶质细胞产生，是造成这种损害的原因 颅脑损伤对突触可塑性和记忆的影响。此外，谷氨酸的兴奋性毒性也被认为与 AD病理生理学，通过使用美金刚(一种非竞争性NMDAR部分拮抗剂)来支持 治疗晚期AD患者。因此，我们建议检验胶质细胞释放的D-丝氨酸导致 谷氨酸通过与突触外NMDAR结合而诱导AD的兴奋性毒性。AIM 1将使用双重抗原 年龄匹配的非痴呆对照组(Braak I/II期)和 被诊断为AD的受试者(Braak III-VI期)为了定量丝氨酸消旋酶(SR)的表达， 在反应性星形胶质细胞和小胶质细胞中产生D-丝氨酸的酶。这一目标还将决定SR是否 由A1型反应性星形胶质细胞表达。AIM 2将使用RNA-seq对对照组的SR mRNA转录本进行分析 和AD患者，以及野生型(WT)和TgF344转基因AD大鼠的组织中。AIM 3将使用 在星形胶质细胞或小胶质细胞中缺乏SR的转基因小鼠以确定D-丝氨酸是否由 海马区注射可溶的b-淀粉样寡聚体后的反应性胶质细胞具有神经毒性。这笔赠款 将有助于确定与SR和D-丝氨酸相关的新途径，这些途径可能会导致改进治疗 轻度至晚期阿尔茨海默病患者抗淀粉样蛋白治疗似乎无效。我们的发现将会有 不仅对AD有重要意义，而且对与SR表达反应性相关的其他疾病也有重要意义 星形胶质细胞，并强调这一途径是一个潜在的治疗目标，以防止神经元变性。

Alzheimer’s disease (AD) is the most common cause of late-onset dementia, affecting more than 5 million Americans. AD is characterized by the deposition of amyloid beta (Ab) aggregates that form plaques and accumulation of neurofibrillary tangles. The prevailing hypothesis is that Ab fibrils damage neurons causing the accumulation of tau-related neurofibrillary tangles and ultimately neurodegeneration. As such, the predominant strategy for developing treatments for AD has focused on targets that could reduce amyloid burden in the brain. Unfortunately, no drug using this approach has improved cognitive and functional outcomes in large- scale clinical trials, even in patients with mild-to-moderate AD, suggesting that once clinical AD symptoms emerge disease progression becomes independent of Ab production. In addition to plaques and tangles, activated glial cells, including astrocytes and microglia, are neuropathological hallmarks of AD. Although the precise mechanism(s) by which reactive glia contribute to AD pathophysiology is unclear, recent findings show that activated microglia induce type A1 reactive astrocytes that are neurotoxic through unidentified mechanisms. We have shown that the N-methyl-D-aspartate receptor (NMDAR) co-agonist, D-serine, which is produced by reactive astrocytes following traumatic brain injury (TBI) in mice, is responsible for the damaging effects of TBI on synaptic plasticity and memory. Furthermore, glutamate excitotoxicity has been implicated in AD pathophysiology, as supported by the use of memantine, an uncompetitive NMDAR partial antagonist, to treat late-stage AD patients. Thus, we propose to test the novel hypothesis that glial released D-serine causes glutamate-induced excitotoxicity in AD by binding to extrasynaptic NMDARs. Aim 1 will use dual-antigen immunofluorescence on human brain tissue from age-matched, non-demented controls (Braak stages I/II) and subjects with an AD diagnosis (Braak stages III-VI) to quantify the expression of serine racemase (SR), the enzyme that produces D-serine, in reactive astrocytes and microglia. This aim will also determine if SR is expressed by A1 type reactive astrocytes. Aim 2 will use RNA-seq to profile SR mRNA transcripts in controls and subjects with AD, as well as in tissue from wild-type (WT) and TgF344 transgenic AD rats. Aim 3 will use transgenic mice lacking SR either in astrocytes or microglia to determine whether the D-serine produced by reactive glia following the intrahippocampal injection of soluble b-amyloid oligomers is neurotoxic. This grant will help to identify novel pathways related to SR and D-serine that could lead to improved therapies for patients with mild to advanced AD when anti-amyloid strategies appear to be ineffective. Our findings will have important implications not only for AD, but for other diseases associated with SR-expressing reactive astrocytes, and highlight this pathway as a potential therapeutic target to prevent neuronal degeneration.