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Deletion of the Alzheimer’s disease risk associated Abi3 gene locus in mice results in obesity and systemic metabolic disruption

ABSTRACT: A rare coding variant was identified within the human ABI3 gene that is associated with increased risk of Alzheimer’s disease (AD). Following this discovery, we recently demonstrated that deletion of Abi3 gene locus notably exacerbates AD neuropathology in the 5xFAD transgenic mouse model of amyloidosis. In the course of a related investigation into the functional impact of Abi3 deletion in mice, we made an unexpected discovery regarding the impact of Abi3 deletion on the non-transgenic littermates of those 5xFAD mice. In those mice, we found that deletion of Abi3 gene locus resulted in an obese phenotype. Therefore, we investigated this serendipitous discovery. In this report, we demonstrate that mice lacking Abi3 have dramatically increased body weight and body fat. Further, we determined that these mice without Abi3 have reduced energy expenditure. Additionally, we found that deletion of the Abi3 gene locus altered gene expression, particularly within immune pathways, within the hypothalamus. Subsequent immunohistological analysis of the central nervous system (CNS) revealed that microglia number and area were decreased specifically within the mediobasal hypothalamus of mice without Abi3. Altogether, this investigation establishes the functional importance of the Abi3 gene locus, particularly within the CNS, in the regulation of systemic metabolism and maintenance of healthy weight.

ORGANISM(S): Mus musculus

PROVIDER: GSE212299 | GEO | 2022/12/13

REPOSITORIES: GEO

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Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis

Project description:Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of late-onset Alzheimer’s disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this critical question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid-b (Ab) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knock-out (“Abi3-/-”) mice. Moreover, we identified dramatic changes in the proportion of microglia subpopulations in Abi3-/- mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Taken together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Ab accumulation and neuroinflammation.

2021-11-10 | GSE175389 | GEO

Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis

Project description:Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of late-onset Alzheimer’s disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this critical question, we determined whether loss of ABI3 function affects pathological features of AD, such as amyloid- (A) accumulation, inflammation, and synaptic dysfunction, in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases levels of soluble and insoluble A and amyloid plaques and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in Abi3 knock-out (Abi3-/-) mice. Nanostring-based transcriptomic analyses indicate that genes involved in microglial phagocytosis and immune response pathways are dysregulated in Abi3-/-mice. Moreover, we identified dramatic changes in microglia subpopulations in Abi3-/- mice using a single-cell RNA sequencing approach. Taken together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting A pathway and neuroinflammation.

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RNA sequencing of microglia sorted form tamoxifen treated Sall1CreER/fl and control Sall1fl/fl mice

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2016-10-19 | E-MTAB-5077 | biostudies-arrayexpress

HOST MICROBIOTA REGULATE SELECTIVE MYELOID SUBSETS IN THE CENTRAL NERVOUS SYSTEM DURING HOMEOSTASIS AND DISEASE

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2021-10-01 | GSE178956 | GEO

Restraint of IFN-γ expression through a distal silencer CNS–28 for tissue homeostasis

Project description:Interferon-gamma (IFN-gamma) is a key cytokine in response to viral or intracellular bacterial infection in mammals. While a number of enhancers are described to promote IFN-gamma responses, no silencers for the Ifng gene have been identified. By examining H3K4me1 histone modification in naïve CD4+ T cells within Ifng locus, we identified an unrecognized silencer (CNS–28) that is responsible for restraining Ifng expression. Mechanistic study further demonstrates that CNS–28 maintains Ifng silence by diminishing enhancer-promoter interactions within Ifng locus in a T-bet independent manner. Functionally, CNS–28 restrains Ifng transcription in Th1, Tc1, and NK cells during both innate and adaptive immune responses. Moreover, CNS–28 deficiency resulted in repressed type 2 responses due to elevated IFN-gamma expression, shifting Th1 and Th2 paradigm. Thus, CNS–28 activity ensures immune cell quiescence by cooperating with other regulatory cis elements within the Ifng gene locus to minimize autoimmunity.

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2017-12-31 | GSE106210 | GEO

scRNAseq and scATACseq of Cd45+ cells from brains of 5XFAD mice bearing distinct APOE alleles and across age

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2015-03-13 | E-GEOD-65067 | biostudies-arrayexpress

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