Authors: Lisa Steinbrecher, Ann‐Christin Wendeln, Desirée Brösamle, Ping Liu, Katleen Wild, Lisa M. Haesler, Rawaa Al‐Shaana, Jonas J. Neher
Published: 2020-12-07
DOI: 10.1002/alz.042904
Source: Full article
AbstractBackgroundMicroglial cells play an important role in the pathogenesis of Alzheimer’s disease. We have previously shown that microglia activate the Hypoxia inducible factor‐1α (HIF‐1α) signalling pathway in response to cerebral β‐amyloidosis in a mouse model of Alzheimer’s pathology (Wendeln et al., Nature, 2018). Importantly, we also found that activation of microglial HIF‐1α signalling correlated with disease severity and that HIF‐1α levels were particularly elevated in plaque‐associated microglia.MethodIn the experiments presented here, we analyzed the role of microglial HIF‐1α in promoting cerebral β‐amyloidosis by characterizing pathological hallmarks and microglial activation states in two APP transgenic mouse models with an induced HIF‐1α knockout (KO) in microglia cells.ResultOur results indicate that the lack of HIF‐1α in microglia increases their clustering around amyloid‐β plaques and alters the microglial phenotype and brain inflammatory state. While plaque load was indistinguishable in mice with/out microglial HIF‐1α, our data indicate that the increase in plaque‐associated microglia limits plaque‐induced neuronal damage.ConclusionOur data indicate that HIF‐1α inhibition alters the microglial phenotype, leading to an increased number of microglia around amyloid‐β plaques, thereby protecting neurons.