"A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways"

项目总结 阿尔茨海默病(AD)是痴呆症最常见的形式，其特征是折叠错误和 特定蛋白质的聚集，表现为病理特征，包括神经元丢失、认知能力下降 以及组织病理学特征，如淀粉样斑块和神经原纤维缠结在 大脑。淀粉样斑块由淀粉样蛋白b(Ab)聚集体的细胞外沉积组成，其中Aβ寡聚体 被认为对神经功能有蛋白质毒性。大量研究表明，与AD相关的 蛋白毒性触发适应性未折叠蛋白反应(UPR)，试图恢复蛋白恒定 由于错误折叠的蛋白质在内质网(ER)中堆积而导致的功能障碍。UPR信令是 通过PERK/eIF2a、IRE1/XBP1和ATF6传感器通路介导；这些信号的相对贡献 手臂到神经退行性变是复杂的，因为它们在调节细胞生存和细胞死亡方面具有双重作用。 PERK/磷酸化eIF2a，XBP1 mRNA剪接的上调，以及ER伴侣蛋白水平的增加，如 人AD脑组织中Bip/GRP78、GRP94和PDI强烈提示内质网应激的慢性激活 在人类AD病理学中。此外，以前与XBP1启动子内的双相情感障碍相关的多态 该地区与中国人群中AD风险的增加有关。尽管已经确定普遍定期审议 在AD等疾病中，通路被激活，目前尚不清楚UPR通路是否具有神经保护作用 影响，或者它们的激活是否有助于发病。 ATF6通路在神经退行性变中的潜在神经保护作用仍然特别明显 难以捉摸。ATF6是一种内质网应激感受器和转录因子，可促进 通过增加内质网伴侣的产生和增加内质网的降解来增强适当的蛋白质折叠 错误折叠的蛋白质。我们提出了ATF6对突触功能至关重要的新证据，正如ATF6-/-小鼠所显示的那样 认知和行为缺陷与突触脊椎密度降低有关。此外，外源表达 活性ATF6形式抑制阿尔茨海默病小鼠模型中淀粉样纤维的积聚。这些结果 提供强有力的证据表明ATF6的激活可能在突触活动和认知中起到生理作用 行为，急性激活ATF6可以赋予AD相关蛋白毒性的神经保护作用。在 建议的研究，我们的努力将集中在阐明ATF6对神经元的潜在神经保护作用 和突触功能，并区分ATF6在神经元和小胶质细胞中的潜在作用。考虑到 ATF6关于减弱β斑块的形成，我们将描述那些特别容易感染的蛋白质 阿尔茨海默病中的蛋白抑制功能障碍。我们还将确定ATF6突变变体的影响 人类色觉障碍患者的神经功能，并确定ATF6是否具有药理激活作用 在AD中是保护性的。这些结果的总和将暗示ATF6在神经元/突触功能中的新角色， 并为通过增强UPR功能逆转突触损伤的潜在策略提供了洞察力。

PROJECT SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia, characterized by misfolding and aggregation of specific proteins which manifest in pathological features including neuronal loss, cognitive decline and histopathological hallmarks such as the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Amyloid plaques comprise extracellular deposits of amyloid-b (Ab) aggregates, where Aβ oligomers are thought to be proteotoxic to neuronal function. Numerous studies have demonstrated that AD-associated proteotoxicity triggers an adaptive unfolded protein response (UPR) which attempts to restore proteostatic dysfunction due to accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR signaling is mediated through PERK/eIF2a, IRE1/XBP1, and ATF6 sensor pathways; relative contributions of these signaling arms to neurodegeneration is complex as they have dual roles in mediating cell survival and cell death. Elevations in PERK/phosphorylated eIF2a, XBP1 mRNA splicing, and increased levels of ER chaperones such as BiP/GRP78, GRP94 and PDI in human AD brain strongly suggests chronic activation of ER stress is evident in human AD pathology. Further, a polymorphism previously linked to bipolar disorders within the XBP1 promoter region was linked to increased AD risk in Chinese populations. Although it has been established that UPR pathways are activated in disorders such as AD, it is not clear whether UPR pathways confer neuroprotective effects, or if their activation can contribute to pathogenesis. Potential neuroprotective effects of the ATF6 pathway in neurodegeneration have remained particularly elusive. ATF6 functions as an ER stress sensor and transcription factor that promotes expression of genes that enhance proper protein folding via increased production of ER chaperones and increased degradation of misfolded proteins. We present new evidence that ATF6 is essential for synaptic function, as Atf6-/- mice display cognitive and behavioral defects associated with reduced synaptic spine density. Further, exogenous expression of the active ATF6 form suppressed accumulation of amyloid fibrils in a murine model of AD. These results provide strong evidence that ATF6 activation may have a physiological role in synaptic activity and cognitive behavior, and acute ATF6 activation can confer neuroprotective effects with AD-associated proteotoxicity. In the proposed study, our efforts will be focused on elucidating potential neuroprotective effects of ATF6 on neuronal and synaptic function, and differentiate potential roles for ATF6 in neurons and microglia. Given the effects of ATF6 on attenuating Aβ plaque formation, we will characterize proteins that are particularly susceptible to proteostatic dysfunction in AD. We will also characterize the effects of ATF6 mutational variants identified in human Achromatopsia patients on neuronal function, and determine whether pharmacological activation of ATF6 is protective in AD. The sum of these results will implicate a novel role for ATF6 in neuronal/synaptic function, and provide insight into potential strategies to reverse synaptic impairment through enhancing UPR function.