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Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease

ABSTRACT: Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease

PROVIDER: PRJNA1231531 | ENA |

REPOSITORIES: ENA

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			Action	DRS
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	SRR32570301_1.fastq.gz	Fastqsanger.gz
	SRR32570301_2.fastq.gz	Fastqsanger.gz
	SRR32570302_1.fastq.gz	Fastqsanger.gz
	SRR32570302_2.fastq.gz	Fastqsanger.gz

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Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease [II]

Project description:Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease [II]

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Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease [5xFAD_snRNAseq]

Project description:Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease [5xFAD_snRNAseq]

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Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease

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

Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease [5xFAD_snRNAseq]

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Neuronal ABCA7 deficiency aggravates mitochondrial dysfunction and neurodegeneration in Alzheimer’s disease [II]

2025-04-02 | GSE291092 | GEO

ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism

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

ABCA7 haplodeficiency disrupts microglial inflammatory responses and membrane trafficking

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.

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ABCA7 transporter functional role on Alzheimer’s disease onset and progess

Project description:Identification of new drug targets and biomarkers with a true clinical potential to treat or at least modify the disease course of Alzheimer’s disease (AD) has become a major challenge. Despite newly identified, GWAS-derived risk factors for AD, this type of genetic information only represents the surface layer of a deep multidimensional network impacting ND pathogenesis. GWAS studies have recently highlight ABCA7 transporter as a risk marker for AD. We will assess existing and newly generated large-scale targeted proteomics data from animal cohorts to unravel the interplay and interactions of metabolites, lipids and proteins contributing to ABCA7-related disease pathogenesis. We want to understand the complex and multi-factorial mechanisms taking place at the metabolism level – including regulatory and signaling aspects – that contribute to AD onset and progression. By doing so, we will enable the identification of more drugable targets that are linked to this risk factor activity and open up novel starting points for pharmacological interventions and possibly prevention. Our work will also allow for a better disease understanding and the identification of novel metabolic biomarkers, which may help in disease monitoring and patient stratification for clinical

2025-05-07 | PXD053250 | Pride

Alzheimer's disease risk ABCA7 p.A696S variant disturbs the microglial response to amyloid pathology in mice

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

Z-RNA drives Tau-mediated neurodegeneration of Alzheimer’s disease [lncRNA-Seq]

Project description:Tau aggregates lead to progressive neurodegeneration in Alzheimer’s disease (AD) (ref). Neuron death is one of the hallmarks of neurodegeneration (ref). However, the pathological influence of neuronal death is undetermined, and the connection between Tau aggregates and neuronal death remains elusive. Here we demonstrated the essential role of neuron death in Tau-related neurodegeneration. Tau-neurons died in necroptosis, dependent on ZBP1 sensitized by Z-RNAs (an unusual left-handed conformation). Those endogenous Z-RNAs were transcripts of reactivated transposable elements (TEs) originally silenced in heterochromatin.

2023-11-22 | GSE248068 | GEO

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