Aβ profiles generated by Alzheimer’s disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset

Abstract

Familial Alzheimer’s disease (FAD), caused by mutations in Presenilin (PSEN1/2) and Amyloid Precursor Protein (APP) genes, is associated with an early age at onset (AAO) of symptoms. AAO is relatively consistent within families and between carriers of the same mutations, but differs markedly between individuals carrying different mutations. Gaining a mechanistic understanding of why certain mutations manifest several decades earlier than others is extremely important in elucidating the foundations of pathogenesis and AAO. Pathogenic mutations affect the protease (PSEN/γ-secretase) and the substrate (APP) that generate amyloid β (Aβ) peptides. Altered Aβ metabolism has long been associated with AD pathogenesis, with absolute or relative increases in Aβ42 levels most commonly implicated in the disease development. However, analyses addressing the relationships between these Aβ42 increments and AAO are inconsistent. Here, we investigated this central aspect of AD pathophysiology via comprehensive analysis of 25 FAD-linked Aβ profiles. Hypothesis- and data-driven approaches demonstrate linear correlations between mutation-driven alterations in Aβ profiles and AAO. In addition, our studies show that the Aβ (37 + 38 + 40) / (42 + 43) ratio offers predictive value in the assessment of ‘unclear’ PSEN1 variants. Of note, the analysis of PSEN1 variants presenting additionally with spastic paraparesis, indicates that a different mechanism underlies the aetiology of this distinct clinical phenotype. This study thus delivers valuable assays for fundamental, clinical and genetic research as well as supports therapeutic interventions aimed at shifting Aβ profiles towards shorter Aβ peptides.

Enzyme–substrate interface targeting by imidazole‐based γ‐secretase modulators activates γ‐secretase and stabilizes its interaction withAPP

“…Pathogenic variants causing early‐onset, autosomal dominant AD shift Aβ production toward the generation of longer and aggregation‐prone peptides (Chávez‐Gutiérrez et al , 2012; Fernandez et al , 2014; Kretner et al , 2016; Veugelen et al , 2016; Liu et al , 2022), and the mutation‐driven increments in these longer Aβ forms (≥ 42 aa) show a linear correlation with clinical onset (Petit et al , 2022). This observation strongly supports the therapeutic value of strategies aimed at lowering the levels of longer Aβ peptides.…”

“…Notably, the more the mutation undermines E‐S interactions, the earlier the disease manifests. In fact, the molecular composition of FAD‐linked Aβ profiles not only informs about pathogenicity, but also enables the estimation of age at disease onset (Petit et al , 2022). These findings strongly support the notion that the stabilization of GSEC‐APP/Aβ n interactions, and consequent shift in Aβ production toward shorter and soluble Aβ peptides, may serve as a therapeutic strategy to tackle early, Aβ‐driven pathogenic cascades in FAD, and broadly in the most common, late‐onset SAD.…”

Clinical relevance of biomarkers, new therapeutic approaches, and role of post-translational modifications in the pathogenesis of Alzheimer’s disease

“…Recent studies that investigated potential relationships between the molecular composition of FAD-linked Aβ profiles and disease severity by analyzing Aβ profiles generated by 25 mutant PSEN1/GSECs that span a wide range of AAOs, revealed that full spectrum of Aβ profiles (including Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43) better reflects mutation pathogenicity. Furthermore, this study suggested Aβ(37 + 38 + 40)/Aβ(42 + 43) ratio better at predicting the age at disease onset (Petit et al, 2022). Presently, PSEN1 gene is considered as the most common cause of familial Alzheimer's disease (FAD).…”

Aβ43 levels determine the onset of pathological amyloid deposition

“…To quantify γ-secretase processivity, Chávez-Gutiérrez's lab has introduced a ratio between the sum of the products of the 4th catalytic turnover divided by the sum of the products of the 3rd catalytic step, which are the substrates of the 4th catalytic turnover [9]. Ultimately, this ratio provides an overall measure of γsecretase processivity along both product lines.…”

“…Ultimately, this ratio provides an overall measure of γsecretase processivity along both product lines. Applying this method to an in vitro analysis of Aβ pro les of 25 FAD-linked PSEN1 mutants, the authors found a linear correlation between mutation-driven alterations in Aβ pro les and age at onset of AD in humans [9]. Hence, to assess γ-secretase processivity in our 9 rat lines we calculated the Aβ (38 + 40)/(42 + 43) ratios.…”