RESUMO
In Alzheimer's disease (AD) pathophysiology, plaque and tangle accumulation trigger an inflammatory response that mounts positive feed-back loops between inflammation and protein aggregation, aggravating neurite damage and neuronal death. One of the earliest brain regions to undergo neurodegeneration is the locus coeruleus (LC), the predominant site of norepinephrine (NE) production in the central nervous system (CNS). In animal models of AD, dampening the impact of noradrenergic signaling pathways, either through administration of beta blockers or pharmacological ablation of the LC, heightened neuroinflammation through increased levels of pro-inflammatory mediators. Since microglia are the resident immune cells of the CNS, it is reasonable to postulate that they are responsible for translating the loss of NE tone into exacerbated disease pathology. Recent findings from our lab demonstrated that noradrenergic signaling inhibits microglia dynamics via ß2 adrenergic receptors (ß2ARs), suggesting a potential anti-inflammatory role for microglial ß2AR signaling. Thus, we hypothesize that microglial ß2 adrenergic signaling is progressively impaired during AD progression, which leads to the chronic immune vigilant state of microglia that worsens disease pathology. First, we characterized changes in microglial ß2AR signaling as a function of amyloid pathology. We found that LC neurons and their projections degenerate early and progressively in the 5xFAD mouse model of AD; accompanied by mild decrease in the levels of norepinephrine and its metabolite normetanephrine. Interestingly, while 5xFAD microglia, especially plaque-associated microglia, significant downregulated ß2AR gene expression early in amyloid pathology, they did not lose their responsiveness to ß2AR stimulation. Most importantly, we demonstrated that specific microglial ß2AR deletion worsened disease pathology while chronic ß2AR stimulation resulted in attenuation of amyloid pathology and associated neuritic damage, suggesting microglial ß2AR might be used as potential therapeutic target to modify AD pathology.