Alzheimer's disease risk ABCA7 p.A696S variant disturbs the microglial response to amyloid pathology in mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1216322 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32145828_1.fastq.gz | Fastqsanger.gz | |||
| SRR32145828_2.fastq.gz | Fastqsanger.gz | |||
| SRR32145829_1.fastq.gz | Fastqsanger.gz | |||
| SRR32145829_2.fastq.gz | Fastqsanger.gz | |||
| SRR32145830_1.fastq.gz | Fastqsanger.gz |
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Project description:The adenosine triphosphate–binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer’s disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque–associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34–positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7.
2025-03-13 | GSE288170 | GEO
Project description:Loss-of-function variants of the ABCA7 gene are associated with the increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown. Using neuron-specific Abca7 knockout mice (nAbca7−/−) with or without 5×FAD amyloid model background and postmortem AD brains, we investigated AD-related phenotypes through comprehensive approaches including transcriptomics and lipidomics. Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; nAbca7−/− mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; nAbca7−/− mice showed diminished mitochondria respiration and reduced synaptic protein levels, which are further supported by results from human AD brains. Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology.
2025-04-02 | GSE291086 | GEO
Project description:Loss-of-function variants of the ABCA7 gene are associated with the increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown. Using neuron-specific Abca7 knockout mice (nAbca7−/−) with or without 5×FAD amyloid model background and postmortem AD brains, we investigated AD-related phenotypes through comprehensive approaches including transcriptomics and lipidomics. Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; nAbca7−/− mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; nAbca7−/− mice showed diminished mitochondria respiration and reduced synaptic protein levels, which are further supported by results from human AD brains. Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology.
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Project description:Loss-of-function variants of the ABCA7 gene are associated with the increased risk of Alzheimer's disease (AD). How neuronal ABCA7 contributes to AD pathogenesis is unknown. Using neuron-specific Abca7 knockout mice (nAbca7−/−) with or without 5×FAD amyloid model background and postmortem AD brains, we investigated AD-related phenotypes through comprehensive approaches including transcriptomics and lipidomics. Lipidomics analysis detected altered lipid profiles in the brains and synaptosomes of 5×FAD; nAbca7−/− mice compared to controls. Transcriptomics profiling revealed that neuronal ABCA7 deficiency altered the expression of genes and pathways related to mitochondrial homeostasis and apoptosis, particularly in excitatory neurons. Consistently, synaptosomes isolated from 5×FAD; nAbca7−/− mice showed diminished mitochondria respiration and reduced synaptic protein levels, which are further supported by results from human AD brains. Our findings reveal that neuronal ABCA7 plays a critical role in mitochondrial homeostasis important for neuronal function and survival in the presence of AD pathology.
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Project description:Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase Alzheimer's disease risk (odds ratio circa 2), yet the underlying pathogenic mechanisms and specific neural cell types affected remain unclear. To investigate this, we generated a single-nucleus RNA sequencing atlas of 36 human postmortem prefrontal cortex samples, including 12 carriers of ABCA7 LoF variants and 24 matched non-carriers. ABCA7 LoF variants were associated with transcriptional changes across all major neural cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed significant alterations in oxidative phosphorylation, lipid metabolism, DNA damage responses, and synaptic signaling pathways. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers) - predicted by molecular dynamics simulations to disrupt ABCA7 structure -, indicating that findings from our study may extend to large portions of the at-risk population. Human induced pluripotent stem cell (iPSC)-derived neurons carrying ABCA7 LoF variants closely recapitulated the transcriptional changes observed in human postmortem neurons. Biochemical experiments further demonstrated that ABCA7 LoF disrupts mitochondrial membrane potential via regulated uncoupling, increases oxidative stress, and alters phospholipid homeostasis in neurons, notably elevating saturated phosphatidylcholine levels. Supplementation with CDP-choline to enhance de novo phosphatidylcholine synthesis effectively reversed these transcriptional changes, restored mitochondrial uncoupling, and reduced oxidative stress. Additionally, CDP-choline normalized amyloid-beta secretion and alleviated neuronal hyperexcitability in ABCA7 LoF neurons. This study provides a detailed transcriptomic profile of ABCA7 LoF-induced changes and highlights phosphatidylcholine metabolism as a key driver in ABCA7-induced risk. Our findings suggest a promising therapeutic approach that may benefit a large proportion of individuals at increased risk for Alzheimer's disease.
2025-07-25 | GSE299277 | GEO
Project description:Clonally expanded CD8+ T cells may contribute to Alzheimer's disease (AD) pathology through interactions with brain-resident cells. However, the functional impact of AD-specific T cell receptor (TCR) clonotypes remains unclear. Here, we demonstrate that CD8+ T cells undergo clonal expansion in early-stage AD mouse models, AppNL-G-F and 5xFAD, and that their depletion reduces amyloid plaque accumulation. Expanded TCR-expressing CD8+ T cells preferentially infiltrate the brain, exacerbating plaque deposition. Moreover, brain-infiltrating CD8+ T cells impair microglial transition into disease-associated states, suppressing amyloid clearance via CCL5-CCR5 signaling. Pharmacological blockade of CCL5 attenuates amyloid deposition, whereas CCL5 administration aggravates pathology. Notably, T cell depletion at later disease stages exacerbates amyloid pathology, suggesting a temporal shift in their function. Early-stage CD8+ T cells exhibit cytotoxic and effector profiles, whereas late-stage cells acquire tissue-resident and exhausted phenotypes. This temporal switch-from pathogenic to protective roles-highlights the stage-specific contribution of CD8+ T cells to AD and their potential as therapeutic targets.
2025-09-05 | GSE287555 | GEO
Project description:The adenosine triphosphate-binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer's disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque-associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34-positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7. ONE SENTENCE SUMMARY: A rare Alzheimer's disease risk ABCA7 p.A696S variant compromises microglial response to amyloid pathology.
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