Niche factors compromise the metabolism of Aß plaque-associated microglia
Institute of Biomedicine of Seville (IBIS)
Microglia are key contributors to Alzheimer's disease pathology as they constitute the first defensive line against Aß plaques. Hypoxia and hypoperfusion are typically found both in peripheral inflammatory foci and the AD brain. Here, we investigate if Aß plaque niches behave as immune foci and the possible synergy between local and systemic hypoperfusion over AD progression. We describe that Aß plaque-associated microglia (AßAM) and the human AD brain are under oxygen stress, characterized by the expression of HIF1-regulated genes. Hypoxia-mediated gene expression is a salient characteristic of AßAM versus other disease associated microglia, suggesting special niche characteristics. AßAM reprogram their metabolism to cope with their defensive tasks. Disruption of this metabolic status by further genetic (VHL deficient microglia) or systemic (chronic hypoxia) stabilization of HIF reduces microglial clustering and spreads Aß neuropathology both in mouse models and in the human brain. In summary, we describe that modifiable (hypoperfusion and/or hypoxia) risk factors converge with previously described age, sex, and genetic factors to induce microglial dysfunction and aggravation of AD neuropathology.
Host: Amanda Sierra