Understanding the degeneration of axon and nerve terminals in Alzheimer's disease and related dementia brain

了解阿尔茨海默病和相关痴呆大脑中轴突和神经末梢的变性

• 批准号: 10661457
• 负责人: Xuelin Lou
• 金额: $ 39万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661457
• 关键词: Abeta synthesis; Acceleration; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Animals; Axon; Behavior; Behavioral; Biochemical; Biochemistry; Biological Assay; Biology; Brain; Clinical Trials; Cognitive; Data; Degenerative Disorder; Dementia; Development; Disease; Disease Progression; Electrophysiology (science); Failure; Feedback; Genetic; Grant; Hydrolase; Image; Imaging Device; Impaired cognition; Interleukin-1 Receptors; Intervention; Knock-out; Knowledge; Learning; Light; Mediating; Memory; Memory Loss; Metabolism; Molecular; Monitor; Mus; Nerve; Nerve Degeneration; Neuroimmune; Neurologic; Neurologic Deficit; Neurons; Onset of illness; Outcome; Pathogenesis; Pathologic; Pathway interactions; Play; Presynaptic Terminals; Process; Proteins; Recycling; Research; Research Personnel; Resolution; Retrieval; Role; Scheme; Senile Plaques; Signal Pathway; Signal Transduction; Specific qualifier value; Sterility; Stress; Symptoms; Synapses; Testing; Vesicle; Work; abeta accumulation; axonal degeneration; beta amyloid pathology; cognitive function; cognitive performance; experimental study; high resolution imaging; improved; in vivo; insight; interest; knockout gene; loss of function; mouse genetics; mouse model; neural circuit; neuroinflammation; neuron loss; neuronal cell body; new therapeutic target; novel; novel strategies; superresolution imaging; tool; translational approach

PROJECT SUMMARY A remarkable brain attribute is a lifelong ability to store and retrieve information for learning and memory. Alzheimer's disease (AD) destroys this function and generates enormous personal, familial, and societal impacts. This situation is further compounded by the lack of disease-modifying therapies and continuous failures of the related clinical trials. An incomplete understanding of the disease has severely limited the development of new treatments, calling for mechanistic research in AD. Synapse loss has been a hallmark of AD and shows the most robust correlation with the disease symptoms. This process occurs long before massive neuron death and AD diagnosis, indicating its central role in disease pathogenesis. However, molecular mechanisms underlying synapse degeneration remain incompletely understood. Our proposal aims to study this process by investigating a novel paradigm in which a sarm1-dependent mechanism contributes to AD synapse loss. Sarm1 is a newly identified NAD+ hydrolase enriched in axonal terminals, but its role in synapse degeneration in AD is entirely unknown. We hypothesize that sarm1 plays a crucial role in AD onset and progression by inducing axon and synapse degeneration. This hypothesis is formulated based on our preliminary data showing that sarm1 gene knockout significantly alleviates AD mice's synaptic disruptions and cognitive dysfunction. We will evaluate this hypothesis using new mouse models, cognitive assays, biochemistry, electrophysiology, and super-resolution imaging. To this end, we have assembled an outstanding, interactive team of investigators with substantial expertise in synapse biology, neurocircuitry, mouse genetics, and AD pathology. We propose three specific aims: 1) define the role of sarm1 in memory disruption and disease progression in AD mice; 2) evaluate sarm1 function in axon and synapse degeneration in AD brains; 3) illustrate molecular mechanisms of sarm1 action in the context of AD pathology and its impact on β-amyloid pathology. Through the proposed work, we will test a fundamentally new concept essential to a long-standing question of AD—synapse loss—and investigate sarm1-dependent signaling mechanisms in AD-associated neurodegeneration. The results will advance the current knowledge on AD pathogenesis and provide critical insights into its novel treatments by targeting the sarm1 signaling pathway. This proposal is submitted in accordance with the Grant Notice to Specify Interest (NOT-AG-21-041 of PAR-22-093).

项目总结