β-Adrenergic Receptors and G Protein-Coupled Receptor Kinase-2 in Alzheimer's Disease: A New Paradigm for Prognosis and Therapy?

Alzheimer's disease (AD) is a devastating form of dementia that imposes a severe burden on health systems and society. Although several aspects of AD pathogenesis have been elucidated over the last few decades, many questions still need to be addressed. In fact, currently available medications only provide symptomatic improvement in patients with AD without affecting disease progression. The beta-adrenergic receptor (beta-AR) system can be considered a possible target that deserves further exploration in AD. The central noradrenergic system undergoes substantial changes in the course of AD and beta-ARs have been implicated not only in amyloid formation in AD brain but also in amyloid-induced neurotoxicity. Moreover, clinical evidence suggests a protective role of beta-AR blockers on AD onset. In addition to that, post-receptor components of beta-AR signaling seem to have a role in AD pathogenesis. In particular, the G protein coupled receptor kinase 2, responsible for beta-AR desensitization and downregulation, mediates amyloid-induced beta-AR dysfunction in neurons, and its levels in circulating lymphocytes of AD patients are increased and inversely correlated with patient's cognitive status. Therefore, there is an urgent need to gain further insight on the role of the adrenergic system components in AD pathogenesis in order to translate preclinical and clinical knowledge to more efficacious prognostic and therapeutic strategies.