Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate α-secretase activity

Kim, Minji; Suh, Jaehong; Romano, Donna M.; Truong, Mimy H.; Mullin, Kristina; Hooli, Basavaraj; Norton, D. P.; Tesco, Giuseppina; Elliott, Kathryn; Wagner, Steven L.; Moir, Robert D.; Becker, Kurt; Tanzi, Rudolph E.

doi:10.1093/hmg/ddp323

Cited by 210 publications

(183 citation statements)

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“…3 The role of ADAM10, the physiological α-secretase in neurons, in the regulation of lateonset AD has been suggested by the discovery of nonsynonymous mutations in the ADAM10 pro-domain in seven late-onset AD families. 37 In line with these findings, activation of ADAM10 expression by vitamin A derivatives 4 or the transcription factor SIRT1 6 decreases Aβ peptide production and amyloid plaque formation in APP/PSEN1 transgenic mice. In addition, SIRT1-induced ADAM10 expression increases Notch processing and the release of Notch/intracellular domain (NICD), which activates genes involved in neuronal repair in adult brain.…”

mentioning

confidence: 67%

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

Cochet

Donneger

Cassier

et al. 2012

ACS Chem. Neurosci.

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In addition to the amyloidogenic pathway, amyloid precursor protein (APP) can be cleaved by α-secretases, producing soluble and neuroprotective APP alpha (sAPPα) (nonamyloidogenic pathway) and thus preventing the generation of pathogenic amyloid-β. However, the mechanisms regulating APP cleavage by α-secretases remain poorly understood. Here, we showed that expression of serotonin type 4 receptors (5-HT 4 Rs) constitutively (without agonist stimulation) induced APP cleavage by the α-secretase ADAM10 and the release of neuroprotective sAPPα in HEK-293 cells and cortical neurons. This effect was independent of cAMP production. Interestingly, we demonstrated that 5-HT 4 receptors physically interacted with the mature form of ADAM10. Stimulation of 5-HT 4 receptors by an agonist further increased sAPPα secretion, and this effect was mediated by cAMP/Epac signaling. These findings describe a new mechanism whereby a GPCR constitutively stimulates the cleavage of APP by α-secretase and promotes the nonamyloidogenic pathway of APP processing. KEYWORDS: Alpha-secretase, Alzheimer's disease, sAPP alpha, serotonin A ccording to the amyloid hypothesis, alteration in synaptic transmission and neuronal loss observed in Alzheimer's disease (AD) mainly result from the formation of toxic amyloid-β (Aβ) oligomers followed by the extracellular accumulation of Aβ aggregates. Aβ is produced by the successive cleavage of a transmembrane amyloid precursor protein (APP) by β-secretase and γ-secretase. 1 In addition to this amyloidogenic pathway, APP can be cleaved by α-secretases, a set of membrane-bound proteases of the ADAM (A disintegrin and metalloprotease) family, generating the soluble APP ectodomain (sAPPα) and a membrane-bound carboxy-terminal fragment (nonamyloidogenic pathway). As α-secretases cleave APP within the Aβ sequence, APP shedding by α-secretases prevents the generation of the pathogenic Aβ peptide. 2,3 Therefore, enhancing α-secretase expression or activity has been considered as a valuable strategy for inhibiting Aβ formation. For instance, it has recently been shown that activation of the transcription of the gene encoding the α-secretase ADAM10, by retinoic acid and sirtuin 1 (SIRT1), reduces Aβ production. 4−6 Previous reports have shown that G protein-coupled receptors (GPCRs) can differentially affect Aβ peptide production by either modulating the cellular trafficking of APP or by influencing the activity and trafficking of α-, β-and γ-secretases. Moreover, both the expression and the stimulation of GPCRs can affect APP metabolism. 7 GPCRs that enhance sAPPα production by stimulating α-secretase activities include the muscarinic M 1 -M 3 receptors, mGlu2 metabotropic glutamate receptor, serotonin 2A (5-HT 2A ) and 5-HT 2C receptors, corticotropin-releasing factor (CRF) receptor 1, purinergic receptor P2X 7 and pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 (PAC 1 ) receptor. 7 These GPCRs are supposed to have a beneficial effect, because sAPPα exerts neuroprotective and neurotro...

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confidence: 67%

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

Cochet

Donneger

Cassier

et al. 2012

ACS Chem. Neurosci.

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“…Furthermore, GWAS misses rare variants with a minor allele frequency of \0.01, which might have relatively large effects for developing complex diseases [71]. To illustrate this point in particular, Kim et al [72] discovered rare variants in ADAM10 to be highly pathogenic in 7 of 1,000 LOAD pedigrees, which challenges the idea that LOAD is only associated with common variants like APOEe4. This is a good example of the contributions of rare variants to common diseases like LOAD, which have not been revealed readily by GWAS.…”

Section: Perspective Of Gwass In Admentioning

confidence: 99%

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

Shen

Jia

2016

Neurosci. Bull.

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Genome-wide association studies (GWASs) have revealed a plethora of putative susceptibility genes for Alzheimer's disease (AD). With the sole exception of the APOE gene, these AD susceptibility genes have not been unequivocally validated in independent studies. No single novel functional risk genetic variant has been identified. In this review, we evaluate recent GWASs of AD, and discuss their significance, limitations, and challenges in the investigation of the genetic spectrum of AD.

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“…Also, rare coding sequence variants in ADAM10 ,13 TREM2 ,12, 14 and PLD3 15 have been found in patients with LOAD. Because the majority of loci detected by SNP‐based GWAS of LOAD have not been investigated for rare coding sequence variants, we conducted targeted sequencing of the top 8 genetic loci frequently associated with LOAD,7, 8, 16, 17, 18 with the exception of the CD33 locus, which was not well replicated in subsequent large meta‐GWAS 18…”

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confidence: 99%

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Vardarajan

Ghani

Kahn

et al. 2015

Annals of Neurology

133

117

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ObjectiveTo detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD).MethodsWe conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies.ResultsOverall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.InterpretationTargeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498

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Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate α-secretase activity

Cited by 210 publications

References 47 publications

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

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Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate α-secretase activity

Cited by 210 publications

References 47 publications

5-HT4 Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

5-HT4 Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

An Overview of Genome-Wide Association Studies in Alzheimer’s Disease

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

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Product

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5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10