Regulation of Neuronal Clearance Pathways via Nuclear Calcium Signaling in Alzheimer's Disease

摘要 自溶酶体系统的抑制最近被描述为阿尔茨海默氏症最早的变化之一 阿尔茨海默病(AD)的大脑，并可能导致AD的病理特征：淀粉样斑块和 神经纤维性Tau缠结导致神经变性。自溶酶体系统受损和 随之而来的分子清除中断与神经元易损性增加和 神经退行性变。我们最近发表的研究表明，转录因子EB的核活性 (TFEB)和许多细胞清除机制在早老素(PS)缺乏时显著减弱，这是 早发性家族性AD(FAD)的主要原因。在我们的初步研究中，我们发现原子核的减少 钙水平及cAMP反应元件结合蛋白(CREB)介导的ITS表达 与自溶酶体途径相关的靶基因是导致分子衰减的潜在机制 PS和Tau突变体的清除和神经保护降低。CREB靶基因Sestrin的表达 人AD神经元中的2(Esn2)促进自噬清除和应激条件下神经元存活。 我们假设PS1和Tau突变体损害了Ryanodine受体(RyR)介导的核控制 钙，这有助于清除积聚在AD大脑中的神经毒性蛋白。如果我们的假设是 正确，这些研究将确定一种新的途径，驱动相关病理特征的形成 使用AD。诱导多能干细胞(IPSC)来源的人前脑神经元和果蝇 将用于评估核钙耗竭和分子中pCREB信号减少的影响 AD发病和进展过程中的清除。我们试图在尸检中评估我们的发现的相关性 早、中、晚期AD患者的人脑组织。互补性模型系统的使用 使我们能够评估因果关系：在表达与疾病相关的生理水平的人类神经元中， 容易聚集的蛋白质，以及在果蝇中，一种复杂性较低和 比可以通过基因操作和生理老化的人类基因组更具冗余性。整体而言 这项建议的目的是1)了解导致AD分子清除抑制的机制 2)确定衰老和AD神经元清除功能衰竭的后果 促进加强神经元清除和防止神经变性的干预措施的未来发展。

Abstract Inhibition of the autolysosomal system has recently been described among the earliest changes in Alzheimer’s disease (AD) brains and likely contributes to the pathological hallmarks of AD: amyloid plaques and neurofibrillary Tau tangles that drive neurodegeneration. Impairment of the autolysosomal system and consequent disruption of molecular clearance are causally linked to increased neuronal vulnerability and neurodegeneration. Our recently published studies show that nuclear activity of the transcription factor EB (TFEB) and many cellular clearance mechanisms, are greatly attenuated in Presenilin (PS) deficiency, which is the leading cause for early onset familial AD (FAD). In our preliminary studies, we find that a decrease of nuclear calcium levels and consequently cAMP response element-binding protein (CREB)-mediated expression of its target genes associated with the autolysosomal pathway is the underlying mechanism for attenuated molecular clearance and decreased neuroprotection in PS and Tau mutants. Expression of the CREB-target gene sestrin 2 (sesn2) in human AD neurons promotes autophagic clearance and neuronal survival under stress conditions. We hypothesize that PS1 and Tau mutants impair Ryanodine Receptor (RyR)-mediated control of nuclear calcium, which promotes clearance of neurotoxic proteins that accumulate in the AD brain. If our hypothesis is correct, these studies will identify a novel pathway that drives formation of the pathological hallmarks associated with AD. Induced pluripotent stem cell (iPSC)-derived human forebrain neurons and Drosophila melanogaster will be used to assess the impact of nuclear calcium depletion and reduced pCREB signaling in molecular clearance during AD onset and progression. We seek to assess the relevance of our findings in postmortem human brain tissues from patients with early, mid and advanced AD. The use of complementary model systems allows us to assess causality: in human neurons that express physiological levels of disease-associated, aggregation-prone proteins, and in Drosophila melanogaster, a model organism with less complexity and redundancy than the human genome that can be genetically manipulated and physiologically aged. The overall goal of this proposal is 1) to understand the mechanisms leading to inhibition of molecular clearance in AD brains, and 2) to identify consequences of functional failure of neuronal clearance in aging and AD neurons to facilitate future development of interventions enhancing neuronal clearance and prevent neurodegeneration.