Big data and small molecules for Alzheimer's disease

摘要 神经元丢失和认知功能障碍与含tau蛋白的神经元的病理形成有关。 神经纤维缠结（NFT）。NFT是所有tau蛋白病的标志，包括阿尔茨海默病（AD）和阿尔茨海默病（AD）。 慢性创伤性脑病（CTE）。创伤性脑损伤（TBI）可引发持续性，甚至 人类和实验室动物中的进行性tau蛋白病。TBI诱导的tau蛋白病与早发性 认知能力下降以及AD和CTE的后期发展。表达突变型人tau P301L的转基因小鼠 显示与人AD脑中类似的进行性tau蛋白病。这个多PI项目的目标是调查 美国食品药品监督管理局（FDA）批准的药物作为AD和相关疾病的潜在治疗药物 痴呆症我们将研究药物对诱导的tau蛋白相关蛋白质组学和神经病理学改变的疗效。 通过：（i）神经创伤（TBI），和（ii）致病性突变人tau转基因（P301L）的遗传过表达 转基因小鼠）。我们已经检测到并报道了p-tau蛋白和其他磷酸化蛋白的显著差异， 使用多种技术（神经病理学， 免疫印迹、ELISA、质谱分析）。通过筛选血管紧张素转换酶抑制剂 （ACEI），β受体阻滞剂（BB），二甲双胍（MET），他汀类药物（STAT）和联合治疗超过一百万的医疗 在VA-CDW的记录中，我们发现小分子药物ACEI和STAT的联合治疗 与AD发作前较长的临床前（无症状）期相关 在创伤性脑损伤事件后使用这些药物。这些结果告知我们的中心假设，tau蛋白病和相关的 神经变性疾病病理学可以在TBI-CTE和tau P301L小鼠中得到抑制， ACEI + STAT联合治疗。我们提出了三个目标来检验这一假设。目标1.搜索 联合使用三种ACEI、BB、MET或STAT或FDA批准的单一新类别药物， 在一个大型的国家医疗记录数据库（VA-CDW）中，事件TBI和AD发作之间的时间。目标二。 目的探讨磷酸化tau蛋白病（p-tau）与神经退行性变和轴突病变的关系。 影响TBI-CTE和突变型人tau过表达的经验证的小鼠模型。我们将量化脑组织 经验证的侧向冲击诱导的TBI-CTE小鼠模型中的tau和p-tau水平（与未受伤的对照组相比） 在P301L转基因小鼠模型中（与野生型，WT），我们将分析脱髓鞘和微管 神经变性的不稳定性和测量特定的靶蛋白（例如，Map1b，通过蛋白质组学鉴定 TBI小鼠脑的分析）。目标3.为了抑制TBI-CTE、P301L小鼠脑中的致病性tau蛋白病， ACEI + STAT治疗。我们将确定ACEI + STAT治疗是否会降低两组患者脑中的tau和p-tau， 模型与生理盐水（SAL）对照处理进行比较，并通过质谱法表征蛋白质组学图谱 和神经病理学。

Abstract Neuronal loss and cognitive dysfunction are associated with pathological formation of tau protein-containing neurofibrillary tangles (NFT). NFTs are hallmarks of all tauopathies, including Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Traumatic brain injury (TBI) can trigger persistent and even progressive tauopathy in humans and laboratory animals. TBI-induced tauopathy is associated with early-onset cognitive decline and later development of AD and CTE. Transgenic mice expressing mutant human tau P301L show progressive tauopathy similar to that in human AD brains. The goal of this multi-PI project is to investigate repurposed Food and Drug Administration (FDA)-approved drugs as potential therapeutics for AD and related dementias. We will investigate drug efficacy on tau-related proteomic and neuropathological alterations induced by: (i) neurotrauma (TBI), and (ii) genetic overexpression of a pathogenic mutant human tau transgene (P301L transgenic mice). We have detected and reported significant differences in p-tau and other phospho-proteins in mice exposed to various forms of neurotrauma (blast, impact) using a multitude of techniques (neuropathology, immunoblotting, ELISA, mass spectrometry profiling). By screening angiotensin converting enzyme inhibitor (ACEI), Beta Blockers (BB), Metformin (MET), Statins (STAT) and combination therapy in over a million medical records in the VA-CDW, we found that combined treatment with small molecule drugs ACEI and STAT was associated with a longer preclinical (asymptomatic) period before AD onset compared to patients not treated with these drugs after incidents of TBI. These results inform our central hypothesis that tauopathy and related neurodegenerative disease pathologies can be suppressed in TBI-CTE and tau P301L mice treated with ACEI+STAT combination therapy. We propose three Aims to test this hypothesis. Aim 1. To search for combination of three ACEI, BB, MET or STAT or single new class of FDA-approved medications that prolong the period between incident TBI and AD onset in a large national medical record data base (VA-CDW). Aim 2. To investigate the relationship of phosphorylated tauopathy (p-tau) to neurodegeneration and axonopathy in validated mouse models of impact TBI-CTE and mutant human tau overexpression. We will quantify brain tissue levels of tau and p-tau in a validated mouse model of lateral impact-induced TBI-CTE (vs. uninjured controls) and in P301L transgenic mouse model (vs wildtype, WT), and we will analyze demyelination and microtubule instability in neurodegeneration and measure specific target proteins (e.g., Map1b, identified by proteomic analysis of TBI mouse brains). Aim 3. To suppress pathogenic tauopathy in TBI-CTE, P301L mouse brains by ACEI+STAT treatment. We will determine whether ACEI+STAT treatment reduces tau and p-tau in brains in both models compared to saline (SAL) control treatment and characterize proteomic profiles by mass spectrometry and neuropathology in brains from the treated mice.