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IMPACT OF SRC VARIANTS ON ALZHEIMER’S DISEASE
Pauline Walleand 9 co-authors
Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-192
Presentation
Date TBA
Board: PS05-09AM-192
Event Information
Poster Board
PS05-09AM-192
Poster
View posterAbstract
Alzheimer’s disease (AD) is a complex multifactorial pathology, and understanding the genetics of common forms may improve knowledge of its underlying mechanisms. Genome-wide association studies have identified several genetic determinants, including FERMT2, which encodes KINDLIN2, a regulator of APP metabolism and Aβ production. We previously showed that KINDLIN2 directly interacts with APP and modulates synaptic plasticity. Here, we identify SRC as a novel modulator of APP metabolism through its influence on the KINDLIN2/APP complex. Exome sequencing data from 32,558 individuals were analyzed to assess the burden of predicted damaging rare variants in SRC associated with AD risk. Functional consequences of these variants were evaluated by analyzing (i) SRC/KINDLIN2 interactions using NMR, GST pull-down and Proximity Ligation Assay (PLA), and (ii) APP metabolism and Aβ production in a HEK293-APP model. The synaptic localization of the interaction was examined in primary neuronal cultures using PLA combined with synaptic markers, while neuronal activity was assessed using Microelectrode Array (MEA). In parallel, iPSCs carrying the SRC V177L variant were edited by CRISPR/Cas9 to evaluate its impact in human induced neurons. We demonstrate the existence of a SRC/KINDLIN2/APP complex in which APP stabilizes the SRC–KINDLIN2 interaction. Rare damaging SRC variants were associated with increased AD risk. The SRC V177L variant was associated with accumulation of APP-derived byproducts, including Aβ peptides, and showed reduced binding to KINDLIN2 compared with wild-type SRC. Overall, our findings identify SRC, KINDLIN2 and APP as genetic determinants of AD forming a synaptic complex whose disruption may promote synaptic dysfunction.
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