Abstract
BackgroundAlzheimer’s disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ1–43 is more prone to aggregation and has higher toxic properties than the long-known Aβ1–42. However, a direct effect on Aβ1–43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined.MethodsN = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ1–43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ1–42 and Aβ1–40 CSF levels.The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers.ResultsA known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ1–43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ1–43 levels positively correlated with CSF Aβ1–42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ1–43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ1–43 and Aβ1–42 levels, we could re-classify as “likely pathogenic” 3 of the unclear mutations.ConclusionThis is the first time that Aβ1–43 levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ1–43 in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ1–43 could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.
Highlights
Alzheimer’s disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides
In 0.086% (1/1151) and 0.26% (3/1151) of Late-onset Alzheimer (LOAD) patients, known pathogenic mutations were identified in APP and presenilin 1 (PSEN1), respectively
The prevalence of Apolipoprotein E (APOE) ε4 was higher in Early-onset Alzheimer (EOAD) (60%) than LOAD (55%) only on individuals without any APP or PSENs mutations, but this difference was still not significant (p = 0.15)
Summary
Alzheimer’s disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. The cleavage by βsecretase generates a large soluble extracellular secreted domain (sAPPβ) and C99 The latter undergoes additional cleavages by γ-secretase to generate a series of Aβ peptides 39–43 amino acids long, following two different pathways: Aβ1–49 > Aβ1–46 > Aβ1–43 > Aβ1–40 and Aβ1–48 > Aβ1–45 > Aβ1–42 > Aβ1–38 [8]. The most abundant Aβ peptides in the cerebrospinal fluid (CSF) resulting from APP processing are Aβ1–38, Aβ1–40 and Aβ1–42 The latter is considered the most pathological peptide in AD as it is most prone to aggregation into amyloid plaques [12]. Aβ1–43 was detected in the brain of sporadic and familial AD patients [22–
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