Abstract
BackgroundThe 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.MethodsClinical-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.ResultsThe 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.ConclusionsThis 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.
Highlights
Since mutations in the PSEN1, PSEN2, and APP genes were reported as causes of autosomal dominant earlyonset familial Alzheimer’s disease (EOAD), no otherAgüero et al Alzheimer's Research & Therapy (2020) 12:139All known genetic causes of EOAD are related to the same pathogenic process, that is, abnormal processing of the amyloid precursor protein (APP) and subsequent pathological accumulation of Aβ peptides in the brain [3]
ADAM10 is a transmembrane and secreted protein of 748 amino acids in length that plays a role in cell adhesion and proteolytic processing of the ectodomains of more than 40 substrates, several of which are crucial for normal brain development and function [7,8,9]
Clinical assessment The family members have been evaluated over the past year (Table 1 and Fig. 1). Their ages at onset ranged from 58 to 68 years, though the late-onset AD (LOAD) presented by the maternal aunt, starting in her late seventies, could be related to a p.Tyr167* mutation carrier status
Summary
Since mutations in the PSEN1, PSEN2, and APP genes were reported as causes of autosomal dominant earlyonset familial Alzheimer’s disease (EOAD), no otherAgüero et al Alzheimer's Research & Therapy (2020) 12:139All known genetic causes of EOAD are related to the same pathogenic process, that is, abnormal processing of the amyloid precursor protein (APP) and subsequent pathological accumulation of Aβ peptides in the brain [3]. In the non-amyloidogenic processing of APP, the protein is proteolyzed through the α-secretase pathway, resulting in soluble fragments (sAPPα) formation [4]. Several enzymes in the disintegrin and metalloprotease (ADAM) family have α-secretase activity in vitro. ADAM10 is a transmembrane and secreted protein of 748 amino acids in length that plays a role in cell adhesion and proteolytic processing of the ectodomains of more than 40 substrates, several of which are crucial for normal brain development and function [7,8,9]. The role of ADAM10 in the non-amyloidogenic processing of APP, shown in vitro and in animal models [7–. The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the nonamyloidogenic 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
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