Decoding the Role of an Alzheimer's Causal Gene in Distinct Brain Cell Types

We will combine new chimeric human-mouse models with in vitro human neurons and microglia, to unravel the cell type specific contributions of the causal gene, presenilin2 in AD etiopathogenesis.

Mutations in the gene encoding presenilin2 (PSEN2) cause early onset familial Alzheimer’s disease but thus far this was mainly studied in the context of a build-up of toxic amyloid aggregates. However given its restricted localization in degradative compartments, we hypothesize that mechanisms exist leading to disease onset that may differ from its close relative PSEN1. Utilizing new PSEN2 AD mouse models and human neurons/microglia, we will employ functional assays and advanced morphological studies to unravel the cell type specific contributions of PSEN2 in AD etiopathogenesis.

We hypothesize that the mechanisms by which PSEN2 mutations contribute to etiopathogenesis may differ from PSEN1- and APP-linked mutations. This project will uniquely explore this from the brain tissue level down to the cellular level in neurons and glia. Herein, it focuses on underlying molecular defects in lysosomes, the ‘waste bins’ of cells required for neuronal survival. Experimentally, we combine functional readouts for brain circuits, with most advanced imaging technologies in vivo and in human cell models, and innovative transcriptomics to map brain changes at single cell resolution.

Research has focused on the major causal genes, PSEN1 and the amyloid precursor protein, ignoring the more rare PSEN2 mutations. As such, this project will provide a comprehensive picture with unprecedented insights in the contribution of PSEN2 in Alzheimer disease pathology; and this from a molecular and mechanistic level up to functional brain circuits particularly vulnerable in Alzheimer’s disease pathogenesis. The outlined strategies, if successful, may as well have the potential to identify novel therapeutic strategies to tackle these rare cases of PSEN2-associated Alzheimer disease.