α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease

Abstract

Background The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive. Methods Clinical-genetic and biomarker study of a first family with early- and late-onset AD associated with a nonsense ADAM10 mutation (p.Tyr167*). CSF analysis included AD core biomarkers, as well as Western blot of ADAM10 species and sAPPα and sAPPβ peptides. We evaluate variant’s pathogenicity, pattern of segregation, and further screened for the p.Tyr167* mutation in 197 familial AD cases from the same cohort, 200 controls from the same background, and 274 AD cases from an independent Spanish cohort. Results The mutation was absent from public databases and segregated with the disease. CSF Aβ42, total tau, and phosphorylated tau of affected siblings were consistent with AD. The predicted haploinsufficiency effect of the nonsense mutation was supported by (a) ADAM10 isoforms in CSF decreased around 50% and (b) 70% reduction of CSF sAPPα peptide, both compared to controls, while sAPPβ levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPα and sAPPβ levels resembled those of controls. Therefore, a decreased sAPPα/sAPPβ ratio was an exclusive feature of mutant ADAM10 siblings. The p.Tyr167* mutation was not found in any of the other AD cases or controls screened. Conclusions This family illustrates the role of ADAM10 in the amyloidogenic process and the clinical development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model for sporadic late-onset AD due to age-related downregulation of α-secretase. This report encourages future research on ADAM10 enhancers.

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

“…The α-secretase ADAM10 plays a major role in non-amyloidogenic APP metabolism 13 . Evidence for the AD association of rare variants in ADAM10 has remained suggestive until now: two rare missense variants in ADAM10 were reported before to incompletely segregate with LOAD in a few families 14 (these variants did not associate with AD in our study; Supplementary Data ) and a nonsense variant in the ADAM10 gene segregated with AD but in a small pedigree 15 . RIN3 has been associated with endosomal dysfunction and APP trafficking/metabolism 16 , 17 .…”

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

“…The α-secretase ADAM10 plays a major role in non-amyloidogenic APP metabolism 8 . Thus far, evidence for the association of ADAM10 with AD remained suggestive: two rare missense variants in ADAM10 were reported with incomplete penetrance for LOAD 9 (these variants did not associate with AD in our study, Table SG6) and a nonsense mutation in the ADAM10 gene was found to segregate with AD but in a very small pedigree 10 . SRC is a non-receptor protein tyrosine kinase that binds and activates Pyk2, an AD genetic risk factor 11 .…”

“…The α-secretase ADAM10 plays a major role in non-amyloidogenic APP metabolism 13 . Evidence for the AD-association of rare variants in ADAM10 has remained suggestive until now: two rare missense variants in ADAM10 were reported before to incompletely segregate with LOAD in a few families 14 (these variants did not associate with AD in our study, Table SG6) and a nonsense variant in the ADAM10 gene was found to segregate with AD but in a small pedigree 15 . Error!…”

APPsα rescues CDK5 and GSK3β dysregulation and restores normal spine density in Tau transgenic mice

“…With regard to AD it is interesting that Aβ was shown to activate CDK5 ( Lee et al, 2000 ; Shukla et al, 2012 ) whereas this study indicates that APPsα rescues p25 hyperactivation, suggesting that an imbalance in non-amyloidogenic α-secretase processing versus β-/γ-secretase processing may lead to CDK5 dysregulation and contribute to pathological signaling cascades [see also review by Mockett et al (2019) ]. Indeed, α-secretase attenuating mutations within the prodomain of ADAM10, the major α-secretase that generates secreted APPsα, were identified in families with late onset AD ( Suh et al, 2013 ; Agüero et al, 2020 ) and more recently, ADAM10 was also linked to sporadic AD through genome-wide association studies ( Kunkle et al, 2019 ). Similarly, preclinical studies indicated that blocking the transport of ADAM10 to the cell surface and thereby inhibiting APPsα secretion, enhanced Tau phosphorylation in wild type mice ( Epis et al, 2010 ).…”