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TonEBP increases TRIM37

ABSTRACT: Aging-related microglial activation is associated with dendritic regression and spine loss in the aged brain. However, the microglia-mediated reductions of spine densities by Tonicity-responsive enhancer-binding protein (TonEBP) in the aged brain is yet unknown. We began to address this question by examining the effect of age on microglial activation and the TonEBP expression in mice. by using molecular and morphologic approaches, the roles of TonEBP in microglial activation and dendritic spines were examined in 12-month-old mice and Alzheimer's diseases (AD) mouse models. Here, we found the increased TonEBP in the hippocampus of aged mice and frontal cortex of AD patients. TonEBP haploinsufficiency reduced microglial activation and dendritic spine regression in 12-month aged mice compared to wild-type (WT) mice. We performed electron microscopy to supply interactions with microglial and synapses. We analyzed microglial processes and extracellular space in areas contacting spines and axon terminal, synaptic cleft, among the hippocampus CA1 of 12-month-old TonEBP haploinsufficient mice versus wild-type littermates. Furthermore, in amyloid-ꞵ oligomer (AꞵO)-injected AD mouse model, TonEBP haploinsufficiency inhibited the dendritic spine loss and improved memory deficits in AβO-treated mice compared to WT mice. These findings indicate that TonEBP may play an important role in aging-induced microglial activation and memory deficits.

ORGANISM(S): Mus musculus

PROVIDER: GSE216976 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4

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TonEBP increases TRIM37

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