Defining the Role of Glial D-serine in Alzheimer's Disease

确定神经胶质 D-丝氨酸在阿尔茨海默病中的作用

• 批准号: 10017812
• 负责人: DARRICK T BALU
• 金额: $ 16.4万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017812
• 关键词: AD transgenic mice; Abeta synthesis; Acute; Adult; Affect; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; American; Amyloid; Amyloid beta-Protein; Antigens; Apoptotic; Astrocytes; Binding; Brain; Calcium Binding; Calcium ion; Cell Death; Clinical; Clinical Trials; Cognitive; Data; Dementia; Disease; Disease Progression; Drug usage; Enzymes; Foundations; Functional disorder; Glial Fibrillary Acidic Protein; Glutamate Receptor; Glutamates; Grant; Hippocampus (Brain); Human; Immunofluorescence Immunologic; In Situ Hybridization; Injections; Late Onset Alzheimer Disease; Lead; Memantine; Memory; Messenger RNA; Microglia; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neuronal Dysfunction; Neurons; Pathway interactions; Patients; Physiological; Production; Proteins; RNA Splicing; Rattus; Research; Resources; Risk; Rodent; Role; Serine; Signal Pathway; Spinal Muscular Atrophy; Sum; Symptoms; Synaptic plasticity; TREM2 gene; Testing; Tissues; Transcript; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; Up-Regulation; Variant; Wild Type Mouse; abeta deposition; abeta oligomer; brain tissue; entorhinal cortex; excitotoxicity; functional outcomes; genome wide association study; improved; neurotoxic; non-demented; novel; prevent; risk variant; serine racemase; tau aggregation; therapeutic target; transcriptome sequencing; β-amyloid burden

Alzheimer’s disease (AD) is the most common cause of late-onset dementia, affecting more than 5 million Americans. AD is characterized by the deposition of amyloid beta (Ab) aggregates that form plaques and accumulation of neurofibrillary tangles. The prevailing hypothesis is that Ab fibrils damage neurons causing the accumulation of tau-related neurofibrillary tangles and ultimately neurodegeneration. As such, the predominant strategy for developing treatments for AD has focused on targets that could reduce amyloid burden in the brain. Unfortunately, no drug using this approach has improved cognitive and functional outcomes in large- scale clinical trials, even in patients with mild-to-moderate AD, suggesting that once clinical AD symptoms emerge disease progression becomes independent of Ab production. In addition to plaques and tangles, activated glial cells, including astrocytes and microglia, are neuropathological hallmarks of AD. Although the precise mechanism(s) by which reactive glia contribute to AD pathophysiology is unclear, recent findings show that activated microglia induce type A1 reactive astrocytes that are neurotoxic through unidentified mechanisms. We have shown that the N-methyl-D-aspartate receptor (NMDAR) co-agonist, D-serine, which is produced by reactive astrocytes following traumatic brain injury (TBI) in mice, is responsible for the damaging effects of TBI on synaptic plasticity and memory. Furthermore, glutamate excitotoxicity has been implicated in AD pathophysiology, as supported by the use of memantine, an uncompetitive NMDAR partial antagonist, to treat late-stage AD patients. Thus, we propose to test the novel hypothesis that glial released D-serine causes glutamate-induced excitotoxicity in AD by binding to extrasynaptic NMDARs. Aim 1 will use dual-antigen immunofluorescence on human brain tissue from age-matched, non-demented controls (Braak stages I/II) and subjects with an AD diagnosis (Braak stages III-VI) to quantify the expression of serine racemase (SR), the enzyme that produces D-serine, in reactive astrocytes and microglia. This aim will also determine if SR is expressed by A1 type reactive astrocytes. Aim 2 will use RNA-seq to profile SR mRNA transcripts in controls and subjects with AD, as well as in tissue from wild-type (WT) and TgF344 transgenic AD rats. Aim 3 will use transgenic mice lacking SR either in astrocytes or microglia to determine whether the D-serine produced by reactive glia following the intrahippocampal injection of soluble b-amyloid oligomers is neurotoxic. This grant will help to identify novel pathways related to SR and D-serine that could lead to improved therapies for patients with mild to advanced AD when anti-amyloid strategies appear to be ineffective. Our findings will have important implications not only for AD, but for other diseases associated with SR-expressing reactive astrocytes, and highlight this pathway as a potential therapeutic target to prevent neuronal degeneration.

阿尔茨海默病（AD）是迟发性痴呆的最常见原因，影响超过500万人