Influence of thalamic IL-33 signaling in aging-associated exacerbation of cognitive impairment after brain injury via microglial dysfunction and tau pathology

摘要 创伤性脑损伤是认知障碍和痴呆症的危险因素，如阿尔茨海默病(AD) 额颞性痴呆(FTD)，特别是在老年人群中。然而，这些机制是由 其中，衰老加剧了脑损伤后的认知障碍，目前尚不完全清楚。人脑成像 研究报告了丘脑小胶质细胞激活的迹象，这与认知缺陷有关。我们的 利用小鼠局部小胶质细胞耗竭的初步研究发现，丘脑小胶质细胞激活 是脑损伤后认知缺陷所必需的。中年小鼠脑损伤后认知功能障碍 加重并伴有小胶质细胞反应紊乱和AT8阳性堆积 磷酸化tau蛋白(p-tau)。最近的研究报道，与衰老相关的分子之一 小鼠大脑的特征是少突胶质细胞中白介素33(IL-33)的表达增加。事实上，伊利诺伊- 33在丘脑少突胶质细胞中的表达增加。值得注意的是，在老化的丘脑中阻断IL-33 改善与衰老相关的认知缺陷恶化。这些发现表明，与衰老相关的 丘脑环境和小胶质细胞反应的变化有助于p-tau的积累和 加重老年小鼠皮质损伤后的认知缺陷。因此，在拟议的研究中，我们将测试我们的 衰老相关少突胶质细胞来源的IL-33加重认知功能障碍的假说 皮质损伤后通过驱动丘脑中的小胶质细胞功能障碍和tau病理。在目标1中，我们 将进一步评估与衰老相关的丘脑病理变化和皮质后认知障碍 丘脑小胶质细胞耗竭和神经元tau缺失对急性加重期脑损伤的影响 认知障碍。在目标2中，我们将调查对少突胶质细胞-小胶质细胞IL-33的需求 衰老相关的小胶质细胞功能障碍、p-tau蓄积和认知损害加重中的信号转导 在大脑皮层受伤后。在目标3中，我们将研究与衰老相关的IL-33信号的机制 改变皮质损伤后的小胶质细胞反应。总而言之，这项研究将确定 少突胶质细胞-小胶质细胞IL-33信号诱导小胶质细胞功能障碍、p-tau积聚和认知 与AD/ADRD相关的减损。

ABSTRACT Traumatic brain injury is a risk factor for cognitive impairment and dementia, such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), particularly in the aged populations. Nevertheless, the mechanisms by which aging exacerbates cognitive deficits after brain injury are not fully understood. Human brain imaging studies reported the signs of microglial activation in the thalamus that correlate with cognitive deficits. Our preliminary studies using a local microglia depletion in mice have discovered that thalamic microglia activation is required for cognitive deficits after brain injury. In the middle-aged mice, cognitive deficits after brain injury were exacerbated and accompanied by dysregulated responses of microglia and accumulation of AT8-positive phosphorylated tau proteins (p-tau). Recent studies have reported that one of the aging-associated molecular signatures in the mouse brain is an increased interleukin-33 (IL-33) expression in oligodendrocytes. Indeed, IL- 33 expression was increased in thalamic oligodendrocytes. Notably, blocking of IL-33 in the aging thalamus ameliorated aging-associated exacerbation of cognitive deficits. These findings suggest that aging-associated changes in the thalamic environment and microglial responses contribute to p-tau accumulation and exacerbated cognitive deficits in aged mice after cortical injuries. Thus, in the proposed study, we will test our hypothesis that aging-associated oligodendrocyte-derived IL-33 exacerbates cognitive impairment after cortical injury by driving microglial dysfunction and tau pathology in the thalamus. In Aim 1, we will further evaluate aging-associated changes in thalamic pathology and cognitive impairment after cortical injuries and determine the effects of thalamic microglial depletion and neuronal tau deletion on exacerbated cognitive impairment. In Aim 2, we will investigate the requirement of oligodendrocyte-microglial IL-33 signaling in aging-associated microglial dysfunction, p-tau accumulation, and worsening cognitive impairment after cortical injuries. In Aim 3, we will examine the mechanisms by which aging-associated IL-33 signaling alters microglial responses after cortical injuries. Together, this study will determine the mechanisms by which oligodendrocyte-microglia IL-33 signaling induces microglial dysfunction, p-tau accumulation, and cognitive impairment relevant for AD/ADRD.