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: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.
| S-EPMC11884743 | biostudies-literature
Project description:Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7+/- knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7-/- suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.
2024-07-19 | GSE244550 | 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.
2025-04-02 | GSE291674 | 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 | GSE291092 | GEO
Project description:Carrying premature termination codons in one allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute or chronic conditions. When the acute inflammation was induced through peripheral lipopolysaccharide (LPS) injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished pro-inflammatory responses by impairing CD14 expression in the brain.
2019-10-31 | GSE139592 | GEO
Project description:Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer's disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to App NL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.
| S-EPMC6876254 | biostudies-literature
Project description:ABCA7 loss-of-function variants are associated with increased risk of Alzheimer’s disease (AD). Using ABCA7 knockout human iPSC models generated with CRISPR/Cas9, we investigated the impacts of ABCA7 deficiency on neuronal metabolism and function. Lipidomics revealed that mitochondria-related phospholipids, such as phosphatidylglycerol and cardiolipin were reduced in the ABCA7-deficient iPSC-derived cortical organoids. Consistently, ABCA7 deficiency induced alterations of mitochondrial morphology accompanied by reduced ATP synthase activity and exacerbated oxidative damage in the organoids.
2024-01-17 | GSE247360 | GEO
Project description:Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting memory and cognition. The disease is accompanied by an abnormal deposition of ß-amyloid plaques in the brain that contributes to neurodegeneration and is known to induce glial inflammation. Studies in the APP/PS1 mouse model of ß-amyloid-induced neuropathology have suggested a role for inflammasome activation in ß-amyloid-induced neuroinflammation and neuropathology. Here, we evaluated the in vivo role of microglia-selective and full body inflammasome signalling in several mouse models of ß-amyloid-induced AD neuropathology. Unexpectedly, microglia-specific deletion of the inflammasome regulator A20 and inflammasome effector protease caspase-1 in the AppNL-G-F and APP/PS1 models failed to identify a prominent role for microglial inflammasome signalling in ß-amyloid-induced neuropathology. Moreover, global inflammasome inactivation through respectively full body deletion of caspases 1 and 11 in AppNL-G-F mice and Nlrp3 deletion in APP/PS1 mice, also failed to modulate amyloid pathology and disease progression. In agreement, single-cell RNA sequencing did not reveal an important role for Nlrp3 signalling in driving microglial activation and the transition into disease-associated states, both during homeostasis and upon amyloid pathology. Collectively, these results question a generalizable role for inflammasome activation in pre-clinical amyloid-only models of neuroinflammation.
2024-01-17 | GSE249611 | GEO