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

项目摘要 阿尔茨海默氏病（AD）是最常见的痴呆形式，其特征在于错误折叠， 特异性蛋白质聚集，表现为病理特征，包括神经元丧失、认知能力下降 和组织病理学标志，如淀粉样蛋白斑块的积累和神经纤维缠结， 个脑袋淀粉样蛋白斑块包括淀粉样蛋白-b（Ab）聚集体的细胞外沉积物，其中Aβ寡聚体是 被认为对神经元功能具有蛋白毒性。许多研究表明，AD相关 蛋白毒性触发适应性未折叠蛋白反应（UPR）， 由于内质网（ER）中错误折叠蛋白的积累而导致的功能障碍。UPR信号是 通过PERK/eIF 2a、IRE 1/XBP 1和ATF 6传感器途径介导;这些信号传导的相对贡献 神经变性的臂是复杂的，因为它们在介导细胞存活和细胞死亡中具有双重作用。 PERK/磷酸化eIF 2a、XBP 1 mRNA剪接的升高以及ER分子伴侣水平的增加， 因为人AD脑中的BiP/GRP 78、GRP 94和PDI强烈地表明ER应激的慢性激活是明显的 在人类AD病理学中。此外，先前与双相情感障碍相关的XBP 1启动子内的多态性 中国人群中AD风险增加。虽然普遍定期审议已经确定， 虽然UPR通路在AD等疾病中被激活，但尚不清楚UPR通路是否赋予神经保护作用， 影响，或者它们的激活是否有助于发病机制。 在神经退行性变中，ATF 6通路的潜在神经保护作用仍然特别重要。 难以捉摸。ATF 6作为ER应激传感器和转录因子发挥作用，其促进基因的表达， 通过增加ER分子伴侣的产生和增加蛋白质的降解来增强正确的蛋白质折叠。 错误折叠的蛋白质我们提出了新的证据表明，ATF 6是至关重要的突触功能，因为Atf 6-/-小鼠显示， 与突触棘密度降低相关的认知和行为缺陷。此外，外源表达 活性ATF 6形式抑制了AD小鼠模型中淀粉样纤维的积累。这些结果 提供了强有力的证据表明，ATF 6激活可能在突触活动和认知功能中具有生理作用。 行为，急性ATF 6激活可以赋予AD相关蛋白毒性的神经保护作用。在 我们的工作将集中在阐明ATF 6对神经元的潜在神经保护作用。 和突触功能，并区分ATF 6在神经元和小胶质细胞中的潜在作用。考虑到 ATF 6在减弱Aβ斑块形成方面的作用，我们将描述特别易受ATF 6影响的蛋白质。 AD中的蛋白抑制功能障碍。我们还将描述在细胞中鉴定的ATF 6突变变体的影响。 人类色盲患者神经元功能的影响，并确定是否有药物激活ATF 6 在AD中具有保护性。这些结果的总和将暗示ATF 6在神经元/突触功能中的新作用， 并提供了通过增强UPR功能来逆转突触损伤的潜在策略的见解。

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.