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

TitleAstrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines.
Publication TypeJournal Article
Year of Publication2023
AuthorsLicht-Murava A, Meadows SM, Palaguachi F, Song SC, Jackvony S, Bram Y, Zhou C, Schwartz RE, Froemke RC, Orr AL, Orr AG
JournalSci Adv
Volume9
Issue16
Paginationeade1282
Date Published2023 Apr 21
ISSN2375-2548
KeywordsAnimals, Antiviral Agents, Astrocytes, DNA-Binding Proteins, Interferons, Memory Disorders, Mice
Abstract

Transactivating response region DNA binding protein 43 (TDP-43) pathology is prevalent in dementia, but the cell type-specific effects of TDP-43 pathology are not clear, and therapeutic strategies to alleviate TDP-43-linked cognitive decline are lacking. We found that patients with Alzheimer's disease or frontotemporal dementia have aberrant TDP-43 accumulation in hippocampal astrocytes. In mouse models, induction of widespread or hippocampus-targeted accumulation in astrocytic TDP-43 caused progressive memory loss and localized changes in antiviral gene expression. These changes were cell-autonomous and correlated with impaired astrocytic defense against infectious viruses. Among the changes, astrocytes had elevated levels of interferon-inducible chemokines, and neurons had elevated levels of the corresponding chemokine receptor CXCR3 in presynaptic terminals. CXCR3 stimulation altered presynaptic function and promoted neuronal hyperexcitability, akin to the effects of astrocytic TDP-43 dysregulation, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented TDP-43-linked memory loss. Thus, astrocytic TDP-43 dysfunction contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions.

DOI10.1126/sciadv.ade1282
Alternate JournalSci Adv
PubMed ID37075107
PubMed Central IDPMC10115456
Grant ListF31 AG079616 / AG / NIA NIH HHS / United States
RF1 NS118569 / NS / NINDS NIH HHS / United States