Investigating tau and ApoE4-mediated alterations in oligodendrocyte progenitor cells

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是痴呆症最常见的病因，其病理学特征是β淀粉样蛋白（amyloid beta，A β） 老年斑中的Aβ沉积和神经纤维缠结（NFT）中的tau聚集。除了 除了淀粉样变性和tau蛋白病之外，脱髓鞘也是AD的一致但经常被忽视的特征。值得注意的是， 即使在疾病的早期阶段也检测到髓鞘损失，在轻度认知障碍患者中观察到减少， 损害（MCI）。这暗示了少突胶质细胞群的失调，大脑的髓鞘- 产生细胞，可能是AD病理生理学中的关键因素。多个团体最近的几项研究 一致确定髓鞘形成网络中的转录改变是AD的关键特征，强调了 迫切需要阐明少突胶质细胞群体中疾病相关的改变，以提供新的 对AD病理生理学的深刻见解。特别相关的是，tau蛋白积累与白色的丧失相关。 在人类患者和tau蛋白病小鼠模型中的物质完整性。白色物质异常甚至 在认知正常的载脂蛋白E ε4（APOE ε4）基因型携带者中检测到， 发展AD的风险很高。考虑到ApoE 4已显示出增强tau毒性和缺血诱导的脑缺血。 小鼠中的白色物质损伤，这些发现可能表明tau负荷和ApoE 4会聚以驱动白色 AD中的物质异常。考虑到少突胶质祖细胞（OPCs）对白色物质的反应， 通过迁移到损伤部位并分化成髓鞘形成的少突胶质细胞来修复损伤， 病变，一个关键问题是为什么OPC和/或少突胶质细胞不能纠正白色物质异常， 存在异常形式的tau和/或ApoE 4。最近的一项研究发现，在死后的大脑中， AD小鼠模型显示细胞衰老的标志物， OPCs缓解小鼠的炎症和认知缺陷。这些结果提供了令人信服的证据，表明 OPC功能障碍实际上可能有助于并加剧AD的疾病进展。因此，目前 研究将调查tau病理学和APOE基因型对OPC异常的影响， 少突胶质细胞，包括髓鞘再生能力。此外，考虑到ApoE受体Lrp 1的缺失， OPCs提供了神经保护，刺激髓鞘修复，减少炎症小鼠模型， 脱髓鞘，我们将评估Lrp 1缺陷在tau蛋白病背景下OPCs中的保护作用， 以及在ApoE 4存在下在tau蛋白病恶化中的作用。总的来说，目前的项目将 确定在OPC/少突胶质细胞群体中观察到的关键功能和转录改变， 对tau蛋白病和ApoE 4的反应，并确定OPCs中Lrp 1的缺失是否减轻ApoE 4介导的 tau病理学恶化。

PROJECT SUMMARY/ABSTRACT As the most common cause of dementia, Alzheimer’s disease (AD) is pathologically defined by amyloid beta (Aβ) deposition in senile plaques and tau aggregation in neurofibrillary tangles (NFTs). In addition to amyloidosis and tauopathy, demyelination is also a consistent, yet often overlooked, feature of AD. Notably, myelin loss is detected even at early stages of disease with decreases observed in patients with mild cognitive impairment (MCI). This implicates that dysregulation of the oligodendrocyte cell population, the brain’s myelin- producing cells, may be a critical factor in AD pathophysiology. Several recent studies from multiple groups consistently identified transcriptional alterations in myelination networks as a key feature of AD, underscoring the great need to elucidate disease-related alterations in the oligodendrocyte population to provide novel insights into AD pathophysiology. Of particular relevance, tau accumulation is associated with loss of white matter integrity in both human patients and mouse models of tauopathy. White matter abnormalities have even been detected in cognitively-normal carriers of the apolipoprotein E ε4 (APOE ε4) genotype, a population at high risk of developing AD. Given that ApoE4 has been shown to potentiate tau toxicity and ischemia-induced white matter damage in mice, these findings may indicate that tau burden and ApoE4 converge to drive white matter abnormalities in AD. Considering that oligodendrocyte progenitor cells (OPCs) respond to white matter damage by migrating to the site of injury and differentiating into myelinating oligodendrocytes to repair the lesion, a key question is why OPCs and/or oligodendrocytes fail to correct white matter abnormalities in the presence of abnormal forms of tau and/or ApoE4. A recent study found that OPCs in both postmortem brain and a mouse model of AD exhibited markers of cellular senescence, with pharmacologic removal of senescent OPCs alleviating inflammation and cognitive defects in mice. These results provide compelling evidence that OPC dysfunction may actually contribute to and exacerbate disease progression in AD. As such, the current study will investigate the impact of tau pathology and APOE genotype on abnormalities in OPCs and oligodendrocytes, including remyelination ability. In addition, given that deletion of the ApoE receptor, Lrp1, from OPCs provided neuroprotection, stimulated myelin repair and reduced inflammation in mouse models of demyelination, we will evaluate the protective effect of Lrp1 deficiency in OPCs in the context of tauopathy, as well as the role in exacerbation of tauopathy in the presence of ApoE4. Collectively, the current project will identify key functional and transcriptional alterations observed in the OPC/oligodendrocyte population in response to tauopathy and ApoE4, and determine whether loss of Lrp1 in OPCs mitigates ApoE4-mediated exacerbation of tau pathology.