ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid-β Peptide Efflux in an in vitro Model of the Blood-Brain Barrier

Lamartinière, Yordenca; Boucau, Marie-Christine; Dehouck, Lucie; Krohn, Markus; Pahnke, Jens; Candela, Pietra; Gosselet, Fabien; Fénart, Laurence

doi:10.3233/jad-170883

Cited by 41 publications

(31 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the functions of ABCA7 (ATP Binding Cassette Subfamily A Member 7) is to clear the blood brain barrier from Aβ (30). Impaired ABCA7 protein function was also associated with a faster APP endocytosis, an increased in vitro Aβ production, and an accelerated amyloid pathology accumulation in young transgenic mice (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease

Holstege

Hulsman

Charbonnier

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

show abstract

Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease

Holstege

Hulsman

Charbonnier

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…More recently, PICALM has been described in vitro and in vivo to participate to Aβ transcytosis and clearance at the BBB through clathrin-dependent internalisation of Aβ after its binding to the LDLR-related protein-1 [157]. ABCA7 is also potentially involved in amyloid clearance at the BBB [78]. Finally, a peripheral Aβ clearance mechanism involving CR1 in human erythrocytes has been proposed to be impaired in AD cases [105].…”

Section: The Post-gwas Era and The Amyloid Cascade Hypothesismentioning

confidence: 99%

The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?

Dourlen¹,

et al. 2019

View full text Add to dashboard Cite

A strong genetic predisposition (60–80% of attributable risk) is present in Alzheimer’s disease (AD). In view of this major genetic component, identification of the genetic risk factors has been a major objective in the AD field with the ultimate aim to better understand the pathological processes. In this review, we present how the genetic risk factors are involved in APP metabolism, β-amyloid peptide production, degradation, aggregation and toxicity, innate immunity, and Tau toxicity. In addition, on the basis of the new genetic landscape, resulting from the recent high-throughput genomic approaches and emerging neurobiological information, we propose an over-arching model in which the focal adhesion pathway and the related cell signalling are key elements in AD pathogenesis. The core of the focal adhesion pathway links the physiological functions of amyloid precursor protein and Tau with the pathophysiological processes they are involved in. This model includes several entry points, fitting with the different origins for the disease, and supports the notion that dysregulation of synaptic plasticity is a central node in AD. Notably, our interpretation of the latest data from genome wide association studies complements other hypotheses already developed in the AD field, i.e., amyloid cascade, cellular phase or propagation hypotheses. Genetically driven synaptic failure hypothesis will need to be further tested experimentally within the general AD framework. Electronic supplementary material The online version of this article (10.1007/s00401-019-02004-0) contains supplementary material, which is available to authorized users.

show abstract

“…ABCA7 defects decrease APOE secretion and cholesterol exchange across the BBB [87]. Cholesterol-related genes such as APOA5 (rs662799), APOC1 (rs11568822), APOD (rs1568565), CH25H (rs13500), LDLR (rs5930), and SORL1 (rs2282649), which affect lipid metabolism and membrane trafficking, may also be pathogenic and PGx-disruptive [63,88]. Soluble low-density lipoprotein receptor-related protein-1 (sLRP1), soluble receptor of advanced glycation end products (sRAGE), and transport proteins participate in the clearance of plasma Aβ in an APOE-dependent manner [89].…”

Section: The Pharmacogenomic Machinerymentioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

View full text Add to dashboard Cite

Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

show abstract

ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid-β Peptide Efflux in an in vitro Model of the Blood-Brain Barrier

Cited by 41 publications

References 72 publications

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease

The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Contact Info

Product

Resources

About