ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease

Macé, Sandrine; Cousin, Emmanuelle; Ricard, Sylvain; Génin, Emmanuelle; Spanakis, Emmanuel; Lafargue-Soubigou, Carole; Génin, Bérengère; Fournel, Raphaël; Roche, Sandrine; Haussy, Gilles; Massey, Florence; Soubigou, Stéphane; Bréfort, Georges; Benoit, Patrick; Brice, Alexis; Campion, Dominique; Hollis, Michael; Pradier, Laurent; Bénavidès, J.; Deleuze, Jean‐François

doi:10.1016/j.nbd.2004.09.011

Cited by 112 publications

(74 citation statements)

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“…We examined cholesterol levels in Abca2 KO mice due to the close homology of ABCA2 with the HDL-forming ABCA1 transporter and the fact that both A1 and A2 and elevated plasma cholesterol are associated with AD (26,44). Plasma HDL and free cholesterol levels were similar in KO and WT mice, implying that circulating cholesterol levels are independent of ABCA2.…”

Section: Discussionmentioning

confidence: 99%

“…AD predisposition is associated, albeit controversially, with circulating and cerebrospinal fluid (CSF) cholesterol levels and linkage to cholesterol homeostasis genes, including the APOE e4, CYP46A1, and ABCA1 genes (40). Recently, a single-nucleotide polymorphism within exon 14 of Abca2 (rs908832) was linked to earlyonset AD (26,43). This mutation produces elevated cholesterol levels in CSF, a risk factor for AD (43).…”

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confidence: 99%

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“Skittish” Abca2 Knockout Mice Display Tremor, Hyperactivity, and Abnormal Myelin Ultrastructure in the Central Nervous System

Mack

Beljanski

Soulika

et al. 2007

Molecular and Cellular Biology

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The ATP-binding cassette transporter 2 (ABCA2) is an endolysosomal protein most highly expressed in the central and peripheral nervous system tissues and macrophages. Previous studies indicated its role in cholesterol/steroid (estramustine, estradiol, and progesterone) trafficking/sequestration, oxidative stress response, and Alzheimer's disease. Developmental studies have shown its expression during macrophage and oligodendrocyte differentiation, processes requiring membrane growth. To determine the in vivo function(s) of this transporter, we generated a knockout mouse from a gene-targeted disruption of the murine ABCA2 gene. Knockout males and females are viable and fertile. However, a non-Mendelian inheritance pattern was shown among male progeny of heterozygous crosses. Compared to wild-type and heterozygous littermates, knockout mice displayed a tremor without ataxia, hyperactivity, and reduced body weight; the latter two phenotypes were more marked in females than in males. This sexual disparity suggests a role for ABCA2 in hormone-dependent neurological and/or developmental pathways. Myelin sheath thickness in the spinal cords of knockout mice was greatly increased compared to that in wild-type mice, while a significant reduction in myelin membrane periodicity (compaction) was observed in both spinal cords and cerebra of knockout mice. Loss of ABCA2 function in vivo resulted in abnormal myelin compaction in spinal cord and cerebrum, an ultrastructural defect that we propose to be the cause of the phenotypic tremor.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

“Skittish” Abca2 Knockout Mice Display Tremor, Hyperactivity, and Abnormal Myelin Ultrastructure in the Central Nervous System

Mack

Beljanski

Soulika

et al. 2007

Molecular and Cellular Biology

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“…The APOE4 allele, with a prevalence of 10-15% in most populations, remains the major genetic susceptibility allele for AD. The discovery that SNPs in genes involved in cholesterol metabolism such as Abca1, Abca2, and Cyp46 are associated with increased risk for AD further strengthens this notion (25)(26)(27). Several groups have examined effects of LXR on APP processing (14,28,29), which is sensitive to cellular sterol levels (23).…”

mentioning

confidence: 99%

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Zelcer

Khanlou

Clare

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

303

224

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Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathology. Genetic loss of either Lxr␣ or Lxr␤ in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid ␤ peptide (fA␤) in a receptordependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fA␤-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.T he liver x receptors ␣ and ␤ (LXR␣/NR1H3 and LXR␤/ NR1H2, respectively) are oxysterol-activated nuclear receptors that play an important role in the control of cellular and whole-body cholesterol homeostasis (1-4). LXRs are also potent inhibitors of inflammatory responses in macrophages, pointing to an additional function for LXR signaling in immune regulation (5-11). The function of LXRs in the brain is not well understood. Ligand activation of LXRs promotes cholesterol efflux from glia (12, 13) and primary neurons (14), whereas mice deficient in expression of Lxr␣ and Lxr␤ develop marked accumulation of neutral lipids in the brain (15). Functionally, loss of LXR␤ leads to adult-onset motor neuron degeneration by the age of 7 months (16). The role of LXRs in human neurodegenerative diseases, however, remains largely unknown.Alzheimer's disease (AD) is an age-dependent neurodegenerative disease typified by progressive neuronal loss and cognitive impairment. AD is characterized by extraneuronal deposits of ␤-amyloid (A␤) fibrils (fA␤) (17) and intraneuronal tangles of hyperphosphorylated (18). The identification of rare mutations in the amyloid precursor protein (APP) and in presenilin genes (PS) in human AD is consistent with a central role for A␤ in AD pathogenesis (19). AD is a multifactorial disease, and inflammatory processes and cholesterol metabolism are among several factors that have been linked to its etiology.The AD brain exhibits prominent activation of innate immune responses. For example, elevated levels of inflammatory mediators can be measured in AD brains, and these are postulated to contribute to neuronal loss. The local inflammatory response is mediated by activated microglia and reactive astrocytes that surround the senile plaques (20,21). Interaction of microglia with fA␤ leads to their activation and the release of an arra...

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“…A previous study (10) evaluated the temporal and frontal cortex in normal and AD brains, and showed that ABCA2-transfected cells were more resistant to a free radical initiator, which indicated the involvement of ABCA2 in protection against reactive oxygen species and suggested an association with AD. Macé et al (11) found a significant association between a C-T single-nucleotide polymorphism (SNP) in exon 14 of the ABCA2 gene (rs908832) and AD in a large case-control study involving 440 AD patients, suggesting a strong association between ABCA2 and EOAD (11).…”

Section: Atp Binding Cassette Subfamily a Member 2 (Abca2)mentioning

confidence: 99%

Unraveling the genes implicated in Alzheimer's disease

Giri¹,

Shah²,

Upreti³

et al. 2017

Biomedical Reports

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Abstract. Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and it is the most common form of dementia in the elderly. Early onset AD is caused by mutations in three genes: Amyloid-β precursor protein, presenilin 1 (PSEN1) and PSEN2. Late onset AD (LOAD) is complex and apolipoprotein E is the only unanimously accepted genetic risk factor for its development. Various genes implicated in AD have been identified using advanced genetic technologies, however, there are many additional genes that remain unidentified. The present review highlights the genetics of early and LOAD and summarizes the genes involved in different signaling pathways. This may provide insight into neurodegenerative disease research and will facilitate the development of effective strategies to combat AD.

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ABCA2 is a strong genetic risk factor for early-onset Alzheimer's disease

Cited by 112 publications

References 32 publications

“Skittish” Abca2 Knockout Mice Display Tremor, Hyperactivity, and Abnormal Myelin Ultrastructure in the Central Nervous System

“Skittish” Abca2 Knockout Mice Display Tremor, Hyperactivity, and Abnormal Myelin Ultrastructure in the Central Nervous System

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Unraveling the genes implicated in Alzheimer's disease

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