Defining the Effects of Astrocytic TDP-43 Dysregulation on Hippocampal Function

定义星形胶质细胞 TDP-43 失调对海马功能的影响

• 批准号: 10057082
• 负责人: ANNA GOLDSHMIDT ORR
• 金额: $ 218.63万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057082
• 关键词: Ablation; Address; Affect; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Astrocytes; Behavior; Behavioral; Brain; Brain region; CXC chemokine receptor 3; CXCL10 gene; CXCL9 gene; CXCR3 gene; Cell Culture Techniques; Cells; Coculture Techniques; Complex; Cytoplasm; DNA-Binding Proteins; Data; Dementia; Disease; Electrophysiology (science); Experimental Models; Functional disorder; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Glutamates; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Interferons; Investigation; Knock-out; Link; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Normal Range; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Play; Population; Premature Mortality; Prevention; Process; Research; Role; Signal Transduction; Testing; Transact; Transgenic Mice; Work; behavior measurement; brain tissue; cell type; chemokine; chemokine receptor; cognitive function; frontotemporal lobar dementia-amyotrophic lateral sclerosis; hippocampal sclerosis; inducible gene expression; knock-down; mortality; motor deficit; mouse model; mutant; nervous system disorder; neurotransmission; novel; novel therapeutics; older patient; prevent; response; selective expression; transcriptome sequencing; transgene expression; transmission process

Cognitive impairments, including memory loss, are prevalent in the elderly and patients with neurodegenerative disease. However, the exact causes of aging-related cognitive impairments are uncertain, and effective prevention and treatment options are limited. Increasing evidence implicates astrocytic-neuronal interactions in a wide range of normal and pathophysiological processes, including memory loss and neurodegeneration. However, the exact mechanisms by which astrocytes may contribute to disease-related cognitive impairments are not known. Transactive response DNA-binding protein 43 kDa (TDP-43) is associated with diverse aging- related neurodegenerative disorders and its dysfunction correlates with cognitive decline in humans. Recent studies suggest that glial TDP-43 plays important roles in the brain and its dysfunction might contribute to disease pathogenesis. In support, mutant TDP-43 can cause cell-autonomous impairments in isolated astrocytes and its astrocytic expression in animal models causes behavioral deficits and premature mortality, suggesting that astrocytic TDP-43 is essential for brain function and its dysregulation can cause disease. Despite these intriguing findings, the roles of astrocytic TDP-43 in cognitive decline and astrocytic-neuronal interactions are not known. Our preliminary studies suggest that astrocytic TDP-43 dysregulation occurs in human cases with Alzheimer’s disease and causes memory loss in transgenic mouse models. In addition, our results implicate astrocytic TDP- 43 in regulating glial and neuronal gene expression, astrocytic-neuronal interactions, and neuronal plasticity. However, these effects and causal links between astrocytic TDP-43 dysregulation and neuronal activities linked to memory require further investigation. Here, we will investigate how astrocytic TDP-43 dysfunction affects the brain in common dementias by defining its roles in hippocampus-dependent memory (Aim 1), gene expression, neuronal activities (Aim 2), and astrocytic-neuronal signaling mechanisms (Aim 3). In these studies, we will test novel hypotheses that astrocytic TDP-43 dysregulation alters astrocytic-neuronal chemokine signaling and specific aspects of glutamatergic transmission and neural plasticity. We will use a combination of advanced molecular and cellular approaches in transgenic mice and cell cultures to target and probe specific cell populations and brain regions. These studies are poised to reveal novel TDP-43-linked mechanistic cascades, advance our understanding of how astrocytic-neuronal interactions contribute to cognitive decline, and identify novel therapeutic strategies that reduce TDP-43-linked deficits in diverse disorders.

认知障碍（包括记忆丧失）在古老的和神经退行性的患者中普遍存在 疾病。但是，与衰老相关的认知障碍的确切原因尚不确定，并且有效 预防和治疗方案有限。越来越多的证据暗示星形胶质细胞神经元相互作用 广泛的正常和病理生理过程，包括记忆丧失和神经变性。 但是，星形胶质细胞可能导致与疾病相关的认知障碍的确切机制 交易反应DNA结合蛋白43 kDa（TDP-43）与发散 - 相关的神经退行性疾病及其功能障碍与人类的认知下降相关。最近的 研究表明，神经胶质TDP-43在大脑中起重要作用，其功能障碍可能导致疾病 发病。为了支持，突变体TDP-43会导致孤立星形胶质细胞及其的细胞自主障碍 动物模型中的星形胶质性表达会导致行为定义和过早死亡，这表明 星形胶质细胞TDP-43对于脑功能至关重要，其功能障碍可能引起疾病。尽管这些有趣 发现，星形胶质细胞TDP-43在认知下降和星形细胞神经元相互作用中的作用尚不清楚。 我们的初步研究表明，星形胶质细胞TDP-43失调发生在人类的情况下，阿尔茨海默氏病发生 疾病并导致转基因小鼠模型的记忆力丧失。此外，我们的结果暗示星形细胞TDP- 43在调节神经胶质和神经元基因表达中，星形细胞 - 神经元相互作用以及神经元可塑性。 但是，星形胶质细胞TDP-43失调与神经元活动之间的这些作用和因果关系 要记忆需要进一步的投资。在这里，我们将研究星形胶质细胞TDP-43功能障碍如何影响 通过定义其在海马依赖性记忆中的作用（AIM 1），基因表达， 神经元活性（AIM 2）和星形胶质神经元信号传导机制（AIM 3）。在这些研究中，我们将测试 新颖的假设是星形细胞TDP-43失调会改变星形细胞神经元趋化因子信号传导和 谷氨酸能传播和神经可塑性的特定方面。我们将结合高级 转基因小鼠和细胞培养物中的分子和细胞方法靶向和探测特异性细胞 人群和大脑区域。这些研究被毒死，以揭示新型的TDP-43连接机械级联反应， 促进我们对星形胶质细胞神经元相互作用如何促进认知下降的理解，并确定 减少TDP-43链接的新型治疗策略定义了潜水员疾病。

项目成果

Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.

• DOI: 10.1186/s13024-022-00547-7
• 发表时间: 2022-06-11
• 期刊: MOLECULAR NEURODEGENERATION
• 影响因子: 15.1
• 作者: Xia, Dan;Lianoglou, Steve;Sandmann, Thomas;Calvert, Meredith;Suh, Jung H.;Thomsen, Elliot;Dugas, Jason;Pizzo, Michelle E.;DeVos, Sarah L.;Earr, Timothy K.;Lin, Chia-Ching;Davis, Sonnet;Ha, Connie;Leung, Amy Wing-Sze;Hoang Nguyen;Chau, Roni;Yulyaningsih, Ernie;Lopez, Isabel;Solanoy, Hilda;Masoud, Shababa T.;Liang, Chun-chi;Lin, Karin;Astarita, Giuseppe;Khoury, Nathalie;Zuchero, Joy Yu;Thorne, Robert G.;Shen, Kevin;Miller, Stephanie;Palop, Jorge J.;Garceau, Dylan;Sasner, Michael;Whitesell, Jennifer D.;Harris, Julie A.;Hummel, Selina;Gnorich, Johannes;Wind, Karin;Kunze, Lea;Zatcepin, Artem;Brendel, Matthias;Willem, Michael;Haass, Christian;Barnett, Daniel;Zimmer, Till S.;Orr, Anna G.;Scearce-Levie, Kimberly;Lewcock, Joseph W.;Di Paolo, Gilbert;Sanchez, Pascal E.
• 通讯作者: Sanchez, Pascal E.

Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines.

• DOI: 10.1126/sciadv.ade1282
• 发表时间: 2023-04-21
• 期刊: Science advances
• 影响因子: 13.6