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

阿尔茨海默病中通过核钙信号传导调节神经元清除途径

• 批准号: 10624820
• 负责人: WILMA J FRIEDMAN
• 金额: $ 44.08万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624820
• 关键词: ATF6 gene; Abeta clearance; Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein Precursor; Attenuated; Automobile Driving; Autopsy; Axon; Biological Models; Brain; Calcium; Calcium Signaling; Cells; Characteristics; Cyclic AMP-Responsive DNA-Binding Protein; Data; Deposition; Development; Disease; Disease Progression; Drosophila genus; Drosophila melanogaster; Early Onset Familial Alzheimer' s Disease; Endosomes; Enzymes; Etiology; FOXO3A gene; Failure; Functional disorder; Future; Gene Expression; Genes; Goals; Histone Acetylation; Histones; Homeostasis; Human; Human Amyloid Precursor Protein; Human Genome; Impairment; Link; Mediating; Mediator; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Onset of illness; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Physiological; Play; Prosencephalon; Proteins; Publishing; Regulation; Reporting; Role; Ryanodine Receptor Calcium Release Channel; Senile Plaques; Signal Transduction; Site; Stress; Swelling; System; Tauopathies; Testing; Time; Work; aged; amyloid precursor protein processing; brain tissue; effective therapy; familial Alzheimer disease; flexibility; fly; functional decline; genetic manipulation; human disease; in vivo; induced pluripotent stem cell; model organism; mouse model; mutant; neuron loss; neuronal survival; neuroprotection; neurotoxic; novel; novel strategies; overexpression; pharmacologic; presenilin; prevent; protein transport; tau Proteins; tau aggregation; tau mutation; therapy development; trafficking; transcription factor

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.

摘要

项目成果

The role of nuclear Ca2+ in maintaining neuronal homeostasis and brain health.

• DOI: 10.1242/jcs.254904
• 发表时间: 2021-04
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: P. Mozolewski;Maciej Jeziorek;C. Schuster;H. Bading;Bess Frost;Radek Dobrowolski