Investigating tau and ApoE4-mediated alterations in oligodendrocyte progenitor cells

项目摘要/摘要 作为痴呆症最常见的原因，阿尔茨海默病(AD)的病理定义是淀粉样β蛋白 (A)β在老年斑中沉积，tau在神经纤维缠结(NFT)中聚集。除了……之外 除了淀粉样变性和肌萎缩侧索硬化症，脱髓鞘也是AD的一贯特征，但往往被忽视。值得注意的是， 即使在疾病的早期阶段也可以检测到髓鞘丢失，在轻度认知障碍的患者中观察到髓鞘丢失 损害(MCI)。这意味着少突胶质细胞群体的失调，大脑的髓鞘- 细胞的产生可能是AD病理生理学中的一个关键因素。来自多个小组的几项最新研究 一致认为髓鞘网络的转录改变是阿尔茨海默病的关键特征，强调 迫切需要阐明少突胶质细胞群体中与疾病相关的变化，以提供新的 对阿尔茨海默病病理生理学的洞察。尤其重要的是，tau的积累与白蛋白的丧失有关。 在人类患者和小鼠的牵牛症模型中的物质完整性。白质异常甚至 在载脂蛋白Eε4(apoEε4)基因的认知正常携带者中检测到，一个在 阿尔茨海默病的高风险。鉴于载脂蛋白E4已被证明可增强tau的毒性和缺血诱导 在小鼠脑白质损伤中，这些发现可能表明tau负荷和ApoE4汇聚在一起驱动白质 AD中的物质异常。考虑到少突胶质前体细胞(OPC)对白质的反应 通过迁移到损伤部位并分化为髓鞘少突胶质细胞修复损伤 损伤，一个关键的问题是为什么OPC和/或少突胶质细胞未能纠正脑白质异常 存在异常形式的tau和/或apoE4。最近的一项研究发现，死后大脑中的OPC 而阿尔茨海默病的小鼠模型显示出细胞衰老的标志，药物可以消除衰老 OPC可减轻小鼠的炎症和认知缺陷。这些结果提供了令人信服的证据 OPC功能障碍实际上可能导致并加剧AD的疾病进展。因此，目前的 研究将调查tau病理和apoE基因对OPC和OPC异常的影响。 少突胶质细胞，包括重新髓鞘形成能力。此外，由于ApoE受体Lrp1缺失， OPC提供神经保护，刺激髓鞘修复，并减少炎症 脱髓鞘，我们将在紧张症的背景下评估LRP1缺乏对OPC的保护作用，AS 以及在ApoE4存在的情况下在紧张型变态反应加重中的作用。总体而言，当前项目将 确定在OPC/少突胶质细胞群体中观察到的关键功能和转录变化 对肌松和载脂蛋白E4的反应，并确定OPC中LRP1的缺失是否缓解了载脂蛋白E4的介导 肌萎缩侧索硬化病理加重。

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.