Title | Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Licht-Murava A, Meadows SM, Palaguachi F, Song SC, Jackvony S, Bram Y, Zhou C, Schwartz RE, Froemke RC, Orr AL, Orr AG |
Journal | Sci Adv |
Volume | 9 |
Issue | 16 |
Pagination | eade1282 |
Date Published | 2023 Apr 21 |
ISSN | 2375-2548 |
Keywords | Animals, 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. |
DOI | 10.1126/sciadv.ade1282 |
Alternate Journal | Sci Adv |
PubMed ID | 37075107 |
PubMed Central ID | PMC10115456 |
Grant List | F31 AG079616 / AG / NIA NIH HHS / United States RF1 NS118569 / NS / NINDS NIH HHS / United States |