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ALZHEIMER-CAUSING <EM >PSEN1</EM> MUTATIONS INTERFERE WITH EARLY NEURONAL DIFFERENTIATION IN A HUMAN IPSC-DERIVED MODEL FOR NEURODEVELOPMENT
Kevin Marinusand 5 co-authors
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research (CNCR), VU University Amsterdam, de Boelelaan 1100, 1081 HZ Amsterdam, The Netherlands
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-174
Presentation
Date TBA
Board: PS05-09AM-174
Event Information
Poster Board
PS05-09AM-174
Poster
View posterAbstract
PSEN1 mutations are the most common cause of familial Alzheimer’s disease (AD) and affect the enzymatic core of the gamma-secretase complex, which cleaves ~150 substrates including APP and NOTCH. Although PSEN1 mutations generally increase amyloid-beta 42/40 ratios, their effects on other substrates, and their implications for AD, remain incompletely understood. We used proteomics and cellomics to characterize induced pluripotent stem cell (iPSC)-derived neuroepithelial stem cells from PSEN1 mutation carriers and controls and their conversion to neuronal cells. We demonstrate that induced neurons with PSEN1 mutations have a significantly higher proportion of cells that remain positive for immaturity markers, while neuroepithelial stem cells show few changes. Additionally, these cells show an altered morphology, resembling neuronal progenitors rather than mature neurons. Proteomics analysis revealed that lower-abundant proteins in PSEN1 lines vs. controls are enriched for GO-terms related to neuronal development, confirming an immature state of these lines. Preliminary data further suggest that NOTCH signaling is affected. Interestingly, APOE was one of the few upregulated proteins in PSEN1 cultures at all stages (i.e., iPSC-derived neuroepithelial stem cells and neuronal cells), confirming an AD-like state already during early neuronal development. Altogether, our data show that PSEN1 mutations interfere with neuronal differentiation and express typical AD markers at early stages of neurodevelopment.
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