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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE159866 | GEO | 2021/11/04

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

The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques (KW)

Project description:Microglia are involved in Alzheimer’s disease (AD) by adopting activated phenotypes. How ageing in the absence or presence of β-amyloid (Aβ) deposition in different brain areas affects this response and whether sex and AD risk genes are involved, remains however largely unknown. Here we analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from cortex and hippocampus of male and female AppNL-G-F at 4 different stages of Aβ deposition and in age-matched control mice. We demonstrate that microglia adopt two major activated states during normal aging and after exposure to amyloid plaques. One of the responses (activated response microglia, ARM) is enhanced in particular by amyloid plaques and is strongly enriched with AD risk genes. The ARM response is not homogeneous, as subgroups of microglia overexpressing MHC type II and tissue repair genes (Dkk2, Gpnmb, Spp1) are induced upon prolonged Aβ exposure. Microglia in female mice advance faster in the activation trajectories. Similar activated states were also found in a second AD model and in human brain. We demonstrate that abolishing the expression of Apoe, the major genetic risk factor for AD, impairs the establishment of ARMs, while the second microglia response type, enriched for interferon response genes, remains unaffected. Our data indicate that ARMs are the converging point of multiple AD risk factors.

2019-04-23 | GSE127892 | GEO

The major risk factors for Alzheimer’s disease: Age, Sex and Genes, modulate the microglia response to Aβ plaques (CDEP)

2019-04-23 | GSE127884 | GEO

Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related Aβ pathology

Project description:Microglia are central players in Alzheimer’s Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild type controls. Xenografted human microglia adopt a disease-associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine CRM response to oligomeric Aβo. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other AD risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in response to AD-related pathology, which should be taken into account in translational studies.

2024-02-29 | GSE216999 | GEO

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

Project description: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.

2022-12-13 | GSE212299 | GEO

Distinct amyloid-b and tau associated microglia profiles in Alzheimer's disease

Project description:Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-b and intraneuronal hyperphosphorylated, tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-b and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-b plaques or both amyloid-b plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-b load and localized to amyloid-b plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with over tau pathology. This full characterization of human disease associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.

2021-02-20 | GSE148822 | GEO

Transcriptional signature in microglia associated with Aβ plaque phagocytosis

Project description:The role of microglia cells in Alzheimer’s disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here we isolated amyloid plaque-containing (using labelling with methoxy–XO4, XO4+) and non-containing (XO4-) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4+ microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4+ microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4- microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4+ microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.

2021-04-12 | PXD024731 | Pride

Transcriptional signature in microglia associated with Aβ plaque phagocytosis

2021-01-31 | GSE165306 | GEO

Absence of microglia promotes diverse pathologies andearly lethality in Alzheimer's disease mice

Project description:Microglia are strongly implicated in the development and progression of Alzheimer’s disease (AD), yet the precise mechanisms underlying their effects on neuropathology remain unclear. To further define the influence of microglia on AD neuropathology, we generated a novel mouse model of AD that genetically lack microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA) that is further accompanied by transcriptional changes within multiple cell types, a dramatic induction of brain calcification and cerebral hemorrhages, and premature lethality. Importantly, adult microglia replacement fully rescues these comorbidities, supporting novel roles for microglia in maintaining vascular function and preventing brain calcification. We further examined the clinical implications of these findings in human tissue and hiPSC-derived microglia, finding evidence that calcification is inversely related to plaque pathology and that microglial interactions with calcifications are altered by genetic AD risk factors.

2021-11-24 | GSE189033 | GEO

Beneficial effect of ACI-24 vaccination on microglial phenotypes in an amyloidosis mouse model

Project description:Amyloid-beta (Aβ) deposition is an initiating factor in Alzheimer´s disease (AD). Microglia are the brain immune cells that surround and phagocytose Aβ, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating phagocytic function. Immunotherapies are currently pursued as therapeutic strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aβ targeting ACI-24 vaccine in preventing the AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aβ plaque load, amyloid plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, plaque-associated microglia had the tendency to be more activated post vaccination. The lower Aβ plaque load triggered by vaccination with ACI-24 was in concordance with the bulk transcriptomic analysis that revealed a reduction in the expression of several disease-associated microglial signatures. Accordingly, plaque-distant microglia displayed a more ramified morphology, supporting beneficial effects of the vaccination on bulk microglial phenotypes. Our study demonstrates that administration of the Aβ targeting vaccine, ACI-24, triggers protective microglial responses that translate into a reduction of AD pathology suggesting its use as a safe and cost effective AD therapeutic intervention.

2023-01-09 | PXD038665 | Pride

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