Dissecting Alzheimer’s Disease-associated protein dyshomeostasis in non neuronal cells for identification of novel pharmacological targets

Neurodegenerative diseases (NDD), including Alzheimer’s disease (AD), represent a tremendous scientific challenge which requires a focus on pathogenic mechanisms occurring at early disease stages and preceding neuronal loss/dysfunction. Non-neuronal cells, overlooked for decades, emerge as key determinants of NDD pathogenesis and promising targets for therapeutic intervention. Neural Stem/Progenitor Cells (NSPC) represent a non-neuronal cell type giving origin to neurons, astrocytes, oligodendrocytes but also providing immunomodulatory functions in adult CNS. Deregulated neuro(glio)genesis is found in several NDD, including AD, earlier than neuronal dysfunction and onset of symptoms. However, the mechanisms of NSPC dysfunction in AD remain poorly understood. Based on published and unpublished data we hypothesise that in AD inter-organellar and more specifically mitochondria-ER communication, may be disrupted early in NSPC. These alterations may cause ERstress/UPR, impaired protein synthesis, degradation, secretion. NSPC dysproteostasis may compromise their neurogenic and non neurogenic functions, result in reduced homeostasis and increase neuronal vulnerability to aging and noxae. Coherently with MNESIS Spoke 6 themes, this proposal aims at investigating mechanisms linking protein dyshomeostasis with dysfunction of mitochondrial-ER contacts (MERCS) in NSPC from WT and 3xTG AD mice. In these cellular models we will exploit state-of-the-art technologies in order to: 1) perform multiomic analysis and cell type-specific RNA-sequencing of NPSC and their progeny; 2) comprehensively investigate pathophysiological mechanisms associated with MERCS alterations, including protein synthesis and degradation, ER-mitochondrial communication, Ca2+ signalling and mitochondrial bioenergetics; 3) to identify novel target molecules related to protein dyshomeostasis whose modulation, by pharmacological and genetic approaches, may rescue functional properties of NSPC and their progeny.