Loss of TDP-43 disrupts the prefrontal neural activity and circuitry: relevance for TDP-43 linked ADRD

TDP-43 的缺失会破坏前额叶神经活动和回路：与 TDP-43 相关的 ADRD 的相关性

• 批准号: 10563569
• 负责人: YUN LI
• 金额: $ 225.54万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563569
• 关键词: Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Amyotrophic Lateral Sclerosis; Animals; Attenuated; Biology; Brain; Calcium; Calcium Channel; Calcium Signaling; Clinical; Cognitive; Custom; DNA-Binding Proteins; Dementia; Disease; Disease Progression; Disease stratification; Elderly; Encephalopathies; Event; Exhibits; Family; Frontotemporal Lobar Degenerations; Goals; Hyperactivity; Impaired cognition; Individual; Interneurons; Knowledge; Link; Modeling; Molecular; Monitor; Mus; Neurodegenerative Disorders; Neurons; Parvalbumins; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Play; Prefrontal Cortex; RNA Splicing; Repression; Response Elements; Role; System; Tamoxifen; Testing; Time; Transactivation; Transcript; Work; age related; awake; base; brain tissue; cerebral atrophy; design; excitatory neuron; graph theory; hippocampal pyramidal neuron; human pluripotent stem cell; in vivo; in vivo calcium imaging; induced pluripotent stem cell; inhibitory neuron; interdisciplinary approach; loss of function; mouse genetics; mouse model; mutant; neural circuit; neural network; neuron loss; neuropathology; new therapeutic target; novel; programs; protein TDP-43; relating to nervous system; targeted treatment; therapeutically effective; transcriptome sequencing; treatment strategy; voltage

The overarching goal of this proposal is to determine the pathogenic mechanism by which loss of TAR DNA-binding protein 43 kDa (TDP-43) contributes to the earliest neural activity and network changes that precede neuron loss in disorders associated with TDP-43 pathology. Alzheimer's Disease (AD) and Alzheimer's Disease Related Dementias (ADRD) are the most common forms of dementia currently without disease modifying therapy. ADRD shares many cognitive and pathological features with AD and can be clinically difficult to distinguish from AD. One of the most common non-canonical pathologic hallmarks of AD is TDP-43 proteinopathy, which occurs in ~30-57% of AD brains (AD-TDP). TDP-43 proteinopathy, first shown to be a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and in a major subtype of frontotemporal lobar degeneration (FTLD-TDP), is also found in other neurodegenerative diseases. Since cognitive decline and brain atrophy are exacerbated in AD TDP relative to AD, understanding the pathogenic role of TDP-43 in AD-TDP and FTLD-TDP that contributes to the earliest neural circuit abnormalities could facilitate identification of novel therapeutic targets and treatment strategies. Based on our preliminary studies, we hypothesize that TDP-43 plays essential roles in maintaining normal neural activity and circuitry through regulating RNA splicing of specific calcium channels. To test this hypothesis, we will take a multidisciplinary approach capitalizing on our team’s expertise in TDP-43 biology, mouse genetic and neuropathology, in vivo calcium imaging and circuit analysis in mouse models, and TDP-43 depleted cortical neurons derived from hPSC and patient-specific iPSC models. We have the following three specific aims. In Aim #1, we will perform repetitive in vivo calcium imaging to monitor calcium activity changes from the same pyramidal neurons in awake behaving mice, to determine the impact of pyramidal TDP-43 loss to the cortical network. In Aim #2, we will perform repetitive in vivo calcium imaging to determine the consequence of TDP-43 depletion specifically in inhibitory interneurons or sparsely in both excitatory and inhibitory neurons of the PFC. In Aim #3, we will use mouse models, hPSC derived cortical neurons, and patient brain tissues of AD-TDP and FTLD-TDP to determine the molecular mechanisms whereby TDP-43 loss leads to early aberrant neural activity in the PFC. We believe that our work will not only clarify early pathogenic mechanisms of TDP-43 loss but also identify novel therapeutic targets and design of effective therapeutic strategy to attenuate these devastating disorders of the elderly

该提案的总体目标是确定致病机制，通过这种机制，焦油DNA结合蛋白43 kDa（TDP-43）的丧失有助于最早的神经元活性和与TDP-43病理相关的疾病中神经元丧失之前的网络变化。阿尔茨海默氏病（AD）和阿尔茨海默氏病有关的痴呆症（ADRD）是目前没有疾病疗法的最常见痴呆形式。 ADRD与AD共享许多认知和病理特征，并且在临床上很难与AD区分开。 AD最常见的非经典病理标志之一是TDP-43蛋白质病，它发生在约30-57％的AD大脑（AD-TDP）中。 TDP-43蛋白质病（首先证明是肌萎缩性侧索硬化症（ALS）的主要病理标志（ALS），以及在其他神经退行性疾病中也建立的。由于与AD相对于AD的认知能力下降和脑萎缩在AD TDP中加剧，因此了解TDP-43在AD-TDP和FTLD-TDP中的致病作用，从而有助于最早的神经元电路异常，从而促进了新型治疗靶标和治疗策略的鉴定。根据我们的初步研究，我们假设TDP-43通过调节特定钙通道的RNA剪接来维持正常的神经元活性和电路起着至关重要的作用。为了检验这一假设，我们将采用多学科方法来利用团队在TDP-43生物学，小鼠遗传学和神经病理学，小鼠模型中的体内钙成像和电路分析中的专业知识，以及TDP-43加深的皮质神经元衍生自HPSC和患者特异性IPSC模型。我们有以下三个具体目标。在AIM＃1中，我们将执行重复的体内钙成像，以监测醒目的行为行为小鼠中相同金字塔神经元的钙活性变化，以确定金字塔TDP-43损失对皮质网络的影响。在AIM＃2中，我们将执行重复的体内钙成像，以确定在抑制性中间神经元中特异性耗竭或在PFC的兴奋性和抑制性神经元中稀疏的TDP-43耗竭的结果。在AIM＃3中，我们将使用小鼠模型，HPSC衍生的皮质神经元以及AD-TDP和FTLD-TDP的患者脑组织来确定TDP-43损失导致PFC中TDP-43损失导致早期异常神经元活性的分子机制。我们认为，我们的工作不仅会阐明TDP-43损失的早期致病机制，而且还可以确定新的治疗靶标和有效治疗策略的设计，以减轻较早的灾难性疾病