Presenilins, Alzheimer’s disease and neurogenesis
Autosomal dominant mutations in presenilin genes (PSEN) are causative for familial Alzheimer’s disease (FAD). Presenilins are the catalytic component of the γ-secretase complex, cleaving amyloid precursor protein (APP) and Notch. Presenilin (PS), Notch and APP are important in neural cell fate decisions during development and in adult neurogenesis. Neurogenesis is aberrant in AD, however it is debated whether neurogenesis is increased or decreased. It is conceivable that decreased PS activity in (F)AD affects the neural stem cell/neural progenitor cell (NSC/NPC) compartment via altered Notch signaling.
Modeling presenilin in zebrafish
In our research we aim to reveal the effects loss-of Psen1 and of FAD mutations in PS1 on the NSC/NPC compartment during embryogenesis and in adult brain in relation to Notch and APP signaling pathways. To study this, we use Psen1 loss-of-function zebrafish mutants. The zebrafish Psen1-null mutant is the first vertebrate model with targeted gene knockout of Psen1 during life, making this model highly relevant for human disease. Also we employ newly generated human PS1(-FAD) transgenic zebrafish lines, expressing FAD mutant PS1 under the presenilin1 promoter. Zebrafish has a typical vertebrate brain allowing studies of developmental and adult phenotypes in the context of sophisticated genetics.
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Paula van Tijn, PhD
Postdoctoral researcher, Astrocyte Biology & Neurodegeneration Group