Actually, no therapies are available to delay or prevent Alzheimer's disease (AD) progression. Targeting amyloid hypothesis has failed in human clinic, existing other pathogenic mechanisms unsolved. Microglia and astroglia are revealed as key candidates, however, their function in the disease continuum is unknown. This project, continuation of our current coordinated project (PI18/01556 and PI18/01557), proposes the existence of a transient microglial cell subset as the trigger from the presymptomatic (Abeta pathology) to the clinical phase of the disease by inducing and/or propagate phospho-Tau and then, neuronal dysfunction/death and symptoms onset. This “tau-driver” microglia could be the consequence of a pathological microglial activation. In non-pathological conditions (i.e. APP models, pre-clinical AD) activated microglia acquired protective (DAM/HAM) phenotype. This phenotype is ApoE-Trem2 dependent and, as we recently demonstrated (Nat Aging accepted), holds largely on a metabolic adaptation to an aerobic/oxidative metabolism. In a pathological context (vascular pathology, oxygen limitations, ApoE4, Trem2 mutations..) the oxidative metabolism is impaired and microglial cells no longer maintain their protective role. We propose that this microglial metabolic impairment produces the transition from protective to cytotoxic phenotype that could be implicated in astroglial activation and Tau phosphorylation. To probe this hypothesis, we propose: 1) decipher microglia and astroglia genotype-phenotype predictors of AD onset in human samples; 2) study microglial malfunction (APOE-Trem2-metabolic axis) as the trigger from Abeta- to tau-pathology by using novel in vivo models and human IPSC-derived cells; 3) preclinical analysis to prevent/revert AD pathology targeting microglial activation/metabolism. Multidisciplinary and complementary experimental approaches (transcriptomic, molecular, cellular, morphological) will be used by the two coordinated groups , JV and AG

Alzheimer
microglia
astroglia
neuroinflamacion Beta-amiloide
Tau

Acción Estratégica en Salud (AES)