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

本研究的总体目标是确定TAR dna结合蛋白43 kDa （TDP-43）的缺失导致与TDP-43病理相关的疾病中神经元丢失之前的最早神经活动和网络变化的致病机制。阿尔茨海默病（AD）和阿尔茨海默病相关痴呆（ADRD）是目前没有疾病修饰治疗的最常见的痴呆形式。ADRD与AD具有许多认知和病理特征，在临床上很难与AD区分。AD最常见的非典型病理标志之一是TDP-43蛋白病变，约30-57%的AD脑（AD- tdp）发生这种病变。TDP-43蛋白病变首次被证明是肌萎缩性侧索硬化症（ALS）的主要病理标志，也是额颞叶变性（FTLD-TDP）的主要亚型，在其他神经退行性疾病中也有发现。由于认知能力下降和脑萎缩在AD-TDP中比AD加重，了解TDP-43在AD-TDP和FTLD-TDP中的致病作用，有助于确定新的治疗靶点和治疗策略。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剪接在维持正常的神经活动和电路中发挥重要作用。为了验证这一假设，我们将采用多学科方法，利用我们团队在TDP-43生物学、小鼠遗传和神经病理学、小鼠模型中的体内钙成像和电路分析以及来自hPSC和患者特异性iPSC模型的TDP-43耗尽皮层神经元方面的专业知识。我们有以下三个具体目标。在目的1中，我们将进行重复的体内钙成像，以监测清醒行为小鼠同一锥体神经元的钙活性变化，以确定锥体TDP-43丢失对皮质网络的影响。在Aim #2中，我们将进行重复的体内钙成像，以确定TDP-43耗竭的后果，特别是在抑制性中间神经元或在pfc的兴奋性和抑制性神经元中。在Aim #3中，我们将使用小鼠模型，hPSC衍生的皮质神经元，在AD-TDP和FTLD-TDP患者脑组织中，确定TDP-43缺失导致pfc早期异常神经活动的分子机制。我们相信，我们的工作不仅将阐明TDP-43缺失的早期致病机制，还将确定新的治疗靶点和设计有效的治疗策略，以减轻老年人的这些破坏性疾病

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