PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer’s Disease: Data from PUMCH Dementia Cohort

Abstract

Background: The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1%,Alzheimer’s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common. Objective: With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients. Methods: 702 AD participants, aged 30–85, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT/MRI, and next-generation DNA sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations. Results: Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher Aβ 42 and Aβ 42/Aβ 40 levels relative to the wild-type PSEN2. The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter Aβ 42, Aβ 40 levels, or Aβ 42/Aβ 40 ratio. 1.9%,(13/702) subjects harbored rare PSEN2 variants. 0.4%,(3/702) subjects carried pathogenic/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization. Conclusion: The PSEN2 N141S, M239T, and I368F are functionally validated mutations.

Screening and functional validations of APP, PSEN1 and PSEN2 mutations from PUMCH dementia cohort

“…The HEK293 cells transfected with PSEN2 N141S, I368F and M239T showed increased Aβ42 levels and ratio of Aβ42/Aβ40 relative to wild type PSEN2. The functional validation results of PSEN2 mutations were reported by our group previously 23 .…”

“…Among 26 detected variants were novel discovered (among some variants were reported by our group previously). 22,23 16 patients (16/1277, 1.25%) have been identi ed carrying 11 causative APP variants, including 7 variants were novel; 16 patients (16/1277, 1.25%) have been identi ed carrying 13 causative PSEN1 variants, including 9 variants were novel; 14 patients (14/1277, 1.10%) have been identi ed carrying 12 causative PSEN2 variants, including 10 variants were novel.…”

Cognitive- and memory-enhancing effects of Augmentin in Alzheimer’s rats through regulation of gene expression and neuronal cell apoptosis

“…PSEN2 is a critical component of ? -secretase, which is responsible for the proteolytic cleavage of the amyloid precursor protein (APP) and the formation of Aβ peptides and has recently been linked to AD ( Dong et al, 2022 ). Studies have found that AD-related PSEN2 dysregulation alters intracellular calcium signaling, resulting in the aggregation of Aβ to form brain plaques and cause neuronal cell death ( Pizzo et al, 2020 ).…”

The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

“…Furthermore, various APP mutations are linked to familial AD, for instance, the Swedish (K670_M671delinsNL), London (V717I), or Indiana (V717F) mutations that result in amplified production of amyloidogenic Aβ peptides or structural modifications which enhance the propensity of the peptides to aggregate (reviewed in 243 ). Additionally, variations in PSEN1 or PSEN2 , which encode for presenilin 1 (PS1) and 2 (PS2) that are part of the γ‐secretase complex, result in a dominant‐negative effect on γ‐secretase activity and alter the balance between Aβ 42 and Aβ 40 peptides 254,255 …”

“…Additionally, variations in PSEN1 or PSEN2 , which encode for presenilin 1 (PS1) and 2 (PS2) that are part of the γ‐secretase complex, result in a dominant‐negative effect on γ‐secretase activity and alter the balance between Aβ 42 and Aβ 40 peptides. 254 , 255 …”