The neuropathology of mild traumatic brain injury in Alzheimer's disease

描述(由申请人提供)： 头部创伤是阿尔茨海默病(AD)和慢性创伤性脑病(CTE)的危险因素，慢性创伤性脑病(CTE)是一种进行性神经退行性疾病，由反复轻度创伤性脑损伤(MTBI)引起。CTE导致人格和行为改变、执行功能障碍和记忆丧失，其特征是磷酸化的tau蛋白在大脑中积聚。我们已经证明，CTE可以在单次爆炸伤后发生。因此，退伍军人患CTE的风险特别大。 以及AD。目前，CTE只能在尸检中诊断，还没有已知的临床生物标志物。我们提出了一种翻译方法，系统地解决了世界上最大的经神经病理证实的CTE和CTE合并AD(CTE-AD)患者在蛋白质、DNA和RNA水平上的神经退行性变，目的是识别生物标记物、遗传风险因素和可以作为药物发现靶点的机制。我们假设头部创伤通过涉及不同tau单倍型和异构体的独立机制导致AD和CTE的病理。由于头部创伤和由此导致的CTE的早期病理可能会影响到大脑的不同区域，我们将使用组织微阵列将组织学、生化和遗传指标关联起来，以展示人类大脑中受影响和未受影响的区域。我们将使用平板法对A�(1-40，1-42，寡聚体)和tau(总的和磷酸化的)水平进行定量。此外，我们还将检测受试者的载脂蛋白E(APOE)基因和tau单倍型，并与临床和病理指标相关联。我们的初步数据表明，�4等位基因和H1tau单倍型在慢性萎缩性脑病患者中表现丰富，提示tau亚型在慢性精神分裂症和阿尔茨海默病患者中的表达不同。因此，APOE和MAPT的基因组变异可能预测发生创伤诱导的神经退行性变的风险。此外，我们将招募105名患有AD、有和没有脑外伤病史的受试者以及对照组，以测定脑脊液中的tau和A�生物标志物。我们预计创伤将加剧AD的变化，导致更大的tau和更少的A�。我们的初步数据显示，脑脊液中tau和A-�水平可用于区分CTE和A-�斑块与AD或FTLD患者。总体而言，我们提出了一个双管齐下的方法：1)揭示患有重复性mTBI的受试者的AD病理进展，以及与CTE和AD转位相关的机制；2)在活体受试者中发现基于这些病理的遗传风险因素和生物标记物。对mTBI神经病理机制的基本了解将有助于合理的药物设计；开发可靠的生物标记物来检测mTBI的长期影响将使CTE和CTE-AD能够在生命中诊断和监测，并将对潜在治疗方法的疗效进行评估。

DESCRIPTION (provided by applicant): Head trauma is a risk factor for both Alzheimer disease (AD) and Chronic Traumatic Encephalopathy (CTE), a progressive neurodegenerative disease that occurs as a consequence of repetitive mild traumatic brain injury (mTBI). CTE causes personality and behavioral changes, executive dysfunction, and memory loss and is characterized by the accumulation of phosphorylated tau protein in the brain. We have shown that CTE can develop following a single explosive blast injury. Thus, veterans are at particular risk for developing CTE as well as AD. Presently, CTE can only be diagnosed at autopsy and there are no known clinical biomarkers. We propose a translational approach to systematically address neurodegeneration in the largest neuropathologically-confirmed autopsy cohort of CTE and CTE with AD (CTE-AD) patients in the world on the protein, DNA, and RNA levels, with the goal of identifying biomarkers, genetic risk factors, and mechanisms that can be targeted for drug discovery. We hypothesize that head trauma leads to the pathologies of AD and CTE through independent mechanisms involving different tau haplotypes and isoforms. Because head trauma and the resulting early pathology of CTE can affect different regions of the brain, we will correlate histological, biochemical, and genetic measures with a tissue microarray demonstrating affected and non-affected regions in human brain. We will use plate-based ELISA to quantitate levels of A� (1-40, 1-42, oligomeric) and tau (total and phosphorylated). In addition, we will determine the apolipoprotein E (APOE) genotypes and tau haplotypes of our subjects and correlate with clinical and pathological measures. Our preliminary data demonstrate that the APOE �4 allele and H1 tau haplotype are enriched in subjects with CTE and suggests that tau isoform expression differs between CTE and AD. Thus, genomic variation in APOE and MAPT may predict risk for developing trauma-induced neurodegenerations. Furthermore, we will recruit 105 subjects with AD and with and without a history of mTBI as well as controls to measure tau and A� biomarkers in the CSF. We expect that trauma will exacerbate the changes seen in AD, leading to greater tau and less A�. Our preliminary data shows that tau and A� levels in CSF can be used to discriminate subjects with CTE and A� plaques from subjects with AD or FTLD. Overall, we propose a two-pronged approach of 1) uncovering the progression of AD pathologies in subjects with repetitive mTBI and the mechanisms involved in CTE and AD tauopathy and 2) discovering genetic risk factors and biomarkers based on these pathologies in living subjects. A basic understanding of the mechanisms underlying the neuropathology of mTBI will facilitate rational drug design; and the development of reliable biomarkers to detect the long-term effects of mTBI will enable the diagnosis and monitoring of CTE and CTE-AD during life and will be crucial for assessing the efficacy of potential therapies as they are developed.