Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity, <i>in vitro</i>

Jepsen, Wayne M.; Both, Matthew De; Siniard, Ashley L.; Ramsey, Keri; Piras, Ignazio S.; Naymik, Marcus; Henderson, Adrienne; Huentelman, Matthew J.

doi:10.1242/bio.054627

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…A single significant SNP (2L_12758562_SNP) was not annotated to any particular gene in our analysis, but falls within a noncoding region of Multidrug-Resistance like Protein 1 ( MRP ), whose mammalian ortholog is a transporter that has been shown to export Aβ from the endothelium of the blood brain barrier ( Krohn et al . 2011 ; Jepsen et al . 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Using Drosophila to identify naturally occurring genetic modifiers of amyloid beta 42- and tau-induced toxicity

Yang,

Zinkgraf,

Fitzgerald-Cook

et al. 2023

G3: Genes, Genomes, Genetics

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Alzheimer’s disease (AD) is characterized by two pathological proteins, amyloid beta 42 (Aβ42) and tau. The majority of AD cases in the population are sporadic and late-onset AD (LOAD), which exhibits high levels of heritability. While several genetic risk factors for LOAD have been identified and replicated in independent studies, including the ApoE ε4 allele, the great majority of the heritability of LOAD remains unexplained, likely due to the aggregate effects of a very large number of genes with small effect size, as well as to biases in sample collection and statistical approaches. Here, we present an unbiased forward genetic screen in Drosophila looking for naturally occurring modifiers of Aβ42- and tau-induced ommatidial degeneration. Our results identify 14 significant SNPs, which map to 12 potential genes in 8 unique genomic regions. Our hits that are significant after genome-wide correction identify genes involved in neuronal development, signal transduction and organismal development. Looking more broadly at suggestive hits (P < 10-5), we see significant enrichment in genes associated with neurogenesis, development and growth as well as significant enrichment in genes whose orthologs have been identified as significantly or suggestively associated with AD in human GWAS studies. These latter genes include ones whose orthologs are in close proximity to regions in the human genome that are associated with AD, but where a causal gene has not been identified. Together, our results illustrate the potential for complementary and convergent evidence provided through multi-trait GWAS in Drosophila to supplement and inform human studies, helping to identify the remaining heritability and novel modifiers of complex diseases.

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Section: Resultsmentioning

confidence: 99%

Using Drosophila to identify naturally occurring genetic modifiers of amyloid beta 42- and tau-induced toxicity

Yang,

Zinkgraf,

Fitzgerald-Cook

et al. 2023

G3: Genes, Genomes, Genetics

View full text Add to dashboard Cite

show abstract

“…For dataset 3, since original study 26 did not distinguish between AD1 and AD2, we could not compare their results with ours. For datasets 4 and 5, since original studies 12,27 compared treated cell lines with controls, which we did not try, we could not compare their results with ours. For dataset 6, since original studies 28 did not compare AD samples and controls directly, but in only tissue specific manner, we could not compare their results with ours.…”

Section: Comparisons With the Original Individual Studiesmentioning

confidence: 89%

A tensor decomposition-based integrated analysis applicable to multiple gene expression profiles without sample matching

Taguchi

Turki

2022

Sci Rep

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The integrated analysis of multiple gene expression profiles previously measured in distinct studies is problematic since missing both sample matches and common labels prevent their integration in fully data-driven, unsupervised training. In this study, we propose a strategy to enable the integration of multiple gene expression profiles among multiple independent studies with neither labeling nor sample matching using tensor decomposition unsupervised feature extraction. We apply this strategy to Alzheimer’s disease (AD)-related gene expression profiles that lack precise correspondence among samples, including AD single-cell RNA sequence (scRNA-seq) data. We were able to select biologically reasonable genes using the integrated analysis. Overall, integrated gene expression profiles can function analogously to prior- and/or transfer-learning strategies in other machine-learning applications. For scRNA-seq, the proposed approach significantly reduces the required computational memory.

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“…This activity is reduced in the AD brain ( Lovell et al, 1998 ; Abuznait and Kaddoumi, 2012 ). A recent report suggested that in addition to its exporting of Aβ, ABCC1 may also lower Aβ levels by increasing the ratio of α- to β-secretase cleavage of APP ( Jepsen et al, 2021 ).…”

Section: Abc Transporters Involved In Clearance Of Cerebral Aβmentioning

confidence: 99%

Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches

Loeffler

2024

Front. Aging Neurosci.

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Clearance of amyloid-beta (Aβ) from the brain is impaired in both early-onset and late-onset Alzheimer’s disease (AD). Mechanisms for clearing cerebral Aβ include proteolytic degradation, antibody-mediated clearance, blood brain barrier and blood cerebrospinal fluid barrier efflux, glymphatic drainage, and perivascular drainage. ATP-binding cassette (ABC) transporters are membrane efflux pumps driven by ATP hydrolysis. Their functions include maintenance of brain homeostasis by removing toxic peptides and compounds, and transport of bioactive molecules including cholesterol. Some ABC transporters contribute to lowering of cerebral Aβ. Mechanisms suggested for ABC transporter-mediated lowering of brain Aβ, in addition to exporting of Aβ across the blood brain and blood cerebrospinal fluid barriers, include apolipoprotein E lipidation, microglial activation, decreased amyloidogenic processing of amyloid precursor protein, and restricting the entrance of Aβ into the brain. The ABC transporter superfamily in humans includes 49 proteins, eight of which have been suggested to reduce cerebral Aβ levels. This review discusses experimental approaches for increasing the expression of these ABC transporters, clinical applications of these approaches, changes in the expression and/or activity of these transporters in AD and transgenic mouse models of AD, and findings in the few clinical trials which have examined the effects of these approaches in patients with AD or mild cognitive impairment. The possibility that therapeutic upregulation of ABC transporters which promote clearance of cerebral Aβ may slow the clinical progression of AD merits further consideration.

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Adenosine triphosphate Binding Cassette subfamily C member 1 (ABCC1) overexpression reduces APP processing and increases alpha- versus beta-secretase activity, in vitro

Cited by 7 publications

References 21 publications

Using Drosophila to identify naturally occurring genetic modifiers of amyloid beta 42- and tau-induced toxicity

Using Drosophila to identify naturally occurring genetic modifiers of amyloid beta 42- and tau-induced toxicity

A tensor decomposition-based integrated analysis applicable to multiple gene expression profiles without sample matching

Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches

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