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ePoster
IDENTIFICATION OF A FUNCTIONAL VARIANT IN THE ALZHEIMER’S DISEASE GENETIC RISK FACTOR <EM>PTK2B</EM>
Nina Lannette-Weimannand 16 co-authors
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-193
Presentation
Date TBA
Board: PS05-09AM-193
Event Information
Poster Board
PS05-09AM-193
Poster
View posterAbstract
Genome-wide association studies have associated 7 variants in the PTK2B gene with Alzheimer’s disease (AD) risk. However, how PTK2B gene variability affects AD pathophysiology is not fully understood. Our aim was to characterize the functional impact of the 7 AD-associated PTK2B gene variants in silico and in vitro.
Bioinformatic analyses were performed to predict the functional effect of the 7 AD-associated PTK2B variants. In silico predictions were confirmed through luciferase assays and Electrophoretic Mobility Shift Assays (EMSAs) in SH-SY5Y cells. To investigate the impact of the rs28834970 variant on PTK2B expression and AD-related phenotypes, isogenic induced pluripotent stem cells (iPSCs) that differ only for the genotypes of this variant were obtained via CRISPR-Cas9.
Bioinformatic analyses combined with luciferase assays and EMSAs in C/EBPβ overexpressing SH-SY5Y cells suggested that the rs28834970 risk allele favors the binding of C/EBPβ in a cis-regulating element of PTK2B, which may repress gene expression. We have CRISPR-edited the KOLF2.1J reference line and obtained iPSCs that differ only for the rs28834970 genotype. Two differentiation protocols were used to generate human iPSCs-derived neurons (hiNs). First results suggested a decrease in PTK2B levels in hiNs bearing the rs28834970 risk genotype compared to hiNs carrying the common genotype. We also observed a detrimental impact of the rs28834970 genotype on AD molecular hallmarks in hiNs.
In conclusion, our work suggests a functional role for the rs28834970 variant, and identifies an original mechanism that explain, at least in part, the association between variability in the PTK2B gene and AD risk.
Bioinformatic analyses were performed to predict the functional effect of the 7 AD-associated PTK2B variants. In silico predictions were confirmed through luciferase assays and Electrophoretic Mobility Shift Assays (EMSAs) in SH-SY5Y cells. To investigate the impact of the rs28834970 variant on PTK2B expression and AD-related phenotypes, isogenic induced pluripotent stem cells (iPSCs) that differ only for the genotypes of this variant were obtained via CRISPR-Cas9.
Bioinformatic analyses combined with luciferase assays and EMSAs in C/EBPβ overexpressing SH-SY5Y cells suggested that the rs28834970 risk allele favors the binding of C/EBPβ in a cis-regulating element of PTK2B, which may repress gene expression. We have CRISPR-edited the KOLF2.1J reference line and obtained iPSCs that differ only for the rs28834970 genotype. Two differentiation protocols were used to generate human iPSCs-derived neurons (hiNs). First results suggested a decrease in PTK2B levels in hiNs bearing the rs28834970 risk genotype compared to hiNs carrying the common genotype. We also observed a detrimental impact of the rs28834970 genotype on AD molecular hallmarks in hiNs.
In conclusion, our work suggests a functional role for the rs28834970 variant, and identifies an original mechanism that explain, at least in part, the association between variability in the PTK2B gene and AD risk.
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