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，在老年人和神经退行性疾病患者中很普遍

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