Unveiling human astrocyte states, functions and their contribution to Alzheimer´s disease

The pathogenesis of Alzheimer´s disease (AD) is not fully understood and no cure is available so far. Current therapeutic targets are insufficient and there is an urgent need for finding new pathways and mechanisms and novel targets to treat this terrible disease. Due to critical species-specific differences and the limitations of rodent models of AD, humanized models are necessary to capture the complexity of the disease process. My lab has pioneered the use of humanized chimeric mice to study human astrocytes (h-astrocytes), integral components of the brain and understudied in AD. I propose here to investigate with a multidisciplinary approach their contribution to AD development and progression. We have already showed the potential of chimeric mice to identify novel and unexpected contributions of h-astrocytes to AD pathology. hASTROCURE will take advantage of our unique model to drive breakthrough discoveries in our understanding of h-astrocytes and their role in AD. We will investigate in humanized chimeras what is the impact of the genetic make-up (risk vs protective variants in AD risk genes) on h-astrocytes molecular states and functions as disease evolves and how they contribute to pathological features and AD progression. The overarching aim is to dissect central pathways leading to h-astrocyte activation towards detrimental states and target those pathways, which can provide the necessary knowledge to enable the development of novel astrocyte-specific therapeutic strategies.This pioneering project involves a set of innovative approaches as an essential platform for studying human genetics in h-astrocytes, in an AD relevant context. My experience and the work that my lab has developed these last years support the conceptual basis of the proposal and demonstrate its feasibility. hASTROCURE will go beyond the state-of-the-art providing groundbreaking information about h-astrocytes and their contribution to AD, and will help to define new strategies for AD.