A unique subpopulation of wild-type neurons recapitulating FAD phenotypes

野生型神经元的独特亚群再现了 FAD 表型

• 批准号: 10559827
• 负责人: Masato Maesako
• 金额: $ 51.87万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559827
• 关键词: Age of Onset; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid beta-Protein; Autopsy; Binding; Biological Assay; Biological Models; Biosensor; Brain; Cell Separation; Cells; Characteristics; Clinical; Cyclic AMP-Dependent Protein Kinases; Data; Data Set; Databases; Development; Disease; FDA approved; Fluorescence Resonance Energy Transfer; Genetic; Genetic Transcription; Goals; Grant; Heterogeneity; Human; Impairment; In Vitro; Individual; Knock-in; Knowledge Portal; Link; Mediating; Molecular; Molecular Conformation; Mus; Mutation; Nerve Degeneration; Neurons; PKA inhibitor; Pathologic; Pathology; Pathway interactions; Persons; Pharmacologic Substance; Phenotype; Phosphorylation; Physiological; Play; Population; Post-Translational Protein Processing; Production; Proteomics; Role; Site; Tg2576; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Vulnerable Populations; brain tissue; early onset; enzyme substrate; familial Alzheimer disease; gamma secretase; in vivo; induced pluripotent stem cell; mouse model; mutant; non-demented; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; presenilin; presenilin-1; resilience; response; sensor; tau Proteins; transcriptomics

Abstract People with late-onset sporadic Alzheimer’s disease (SAD) display overall the same clinical and pathological features as those with early-onset familial AD (FAD). However, the mechanism(s) underlying the clinicopathologic commonality between these two genetically distinct AD forms is unclear. Our overall hypothesis is that a subpopulation of wild-type neurons in the brain strikingly recapitulates the phenotypes of neurons expressing FAD mutant Presenilin (PSEN) (perhaps via post-translational modification of wild-type PSEN1), and this selective cell population plays a role in SAD neurodegeneration. Several pieces of evidence support this hypothesis. First, we showed that wild-type PSEN1 in a subset of neurons within the SAD brain displays a conformation similar to FAD mutant PSEN1 (Wahlster et al. Acta Neuropathol 2013). Second, we uncovered that PKA-mediated PSEN1 phosphorylation at Ser310 is significantly upregulated in SAD brains, and this post translational modification, together with phosphorylation of two other sites, steers wild-type PSEN1 conformation towards that of FAD mutant PSEN1 (Maesako et al. eLife 2017). Lastly, we have recently developed novel genetically encoded FRET-based biosensors that for the first time allow quantitative recording of the gamma-secretase activity over time, on a cell-by-cell basis, in live neurons (Maesako et al. iScience 2020, Houser et al. Sensors 2020, Houser et al. Biosensors 2021, Maesako et al. J Neurosci 2022). Surprisingly, these biosensors have enabled us to discover a unique subpopulation of wild-type neurons displaying diminished endogenous gamma-secretase activity. More importantly, our strong preliminary data show that this cell population recapitulates several key characteristics that have been identified in neurons expressing FAD mutant PSEN; these include impaired gamma-secretase “processivity” and thus predominant production of long Aβ, endo-lysosomal abnormalities, and vulnerability phenotypes in response to toxic insults. Therefore, this proposal will further employ multiple model systems and complementary assays to establish the molecular basis and physiological relevance that support our hypothesis. Aim 1 will elucidate the molecular mechanism(s) underlying the heterogeneity in endogenous gamma-secretase activity and its consequences in neurons. Aim 2 will further verify the cause-and-effect relationship between dysfunctional gamma-secretase, endo-lysosomal abnormalities, and neuronal vulnerability. More importantly, we will explore the therapeutic potential of the US FDA-approved compounds that could potentially function as gamma-secretase modulators (GSMs) or gamma-secretase activators (GSAs). Aim 3 will determine if the unique FAD-like neuronal population exists in “AD” mouse models endogenously expressing wild-type PSEN, as our preliminary results indicate, in iPSCs derived human neurons and post-mortem brains from SAD cases. Given that promoting neuronal resilience could be a new therapeutic strategy for AD, a better understanding of the molecular basis behind the newly discovered selectively vulnerable cell population will open a new path for developing novel therapeutic opportunities.

抽象的 患有晚期零星的阿尔茨海默氏症（SAD）的人总体上表现出与Ilial AD相同的临床和病理特征（FAD）。 IS IS IS IS不清楚显示类似于FAD突变体PSEN1的同意（Wahlster等人Acta Neuropathol 2013）。对THAD突变体PSEN1的结合（Maesako等，Elife 2017）。基础，在活神经元中（Maesako等人。令人惊讶的是，这些生物传感器已使我们能够发现野生型神经元的独特子表现出降低的内源性内源性γ-分泌酶活性。更重要的是，我们的强烈初步数据表明，该细胞种群严重程度严重程度严重程度严重程度严重程度严重程度严重程度严重程度。在表达FAD突变体PSEN的神经元中的关键特征包括受损的γ-分泌酶“杂化酶”和thedominals的产生。分子基础和生理相关性支持我们的假设。如果在“ AD”小鼠模型中存在独特的FAD样神经元种群，则gsms）或伽马分泌酶激活剂（GSAS）可观，如果我们的初步结果表明，在“ AD”小鼠模型中存在明确表达野生型PSEN的内源性，则表明，在IPSCS人类神经元中，来自SAD SADES中的sade s sad sades s brains s sad sades brains。 LD是一种新的AD治疗策略，对新发现的有选择的脆弱细胞种群的分子基础有更好的理解，将为发展新的治疗性开发率开辟新的途径。