G Protein-coupled Receptors Regulate Amyloid-β Production

Accumulation of amyloid-β(Aβ) has been considered as an invariant hallmark and primary cause of Alzheimer's disease (AD), which can be sporadic or familial in origin. Most of AD cases are sporadic and result from heterogeneous causes, including genetic and environmental factors. To date, lots of studies in AD research focus on the effect of genetic factors on AD pathogenesis, and growing evidence reveals that mutation can affect the activity ofγ-secretase, a pivotal enzyme for Aβproduction, and therefore associate with most of the familial AD cases. However, it is largely unknown whether and howγ-secretase activity and Aβproduction a?re regulated by environmental or physiological signals. The G protein-coupled receptor (GPCR) is the largest superfamily of cell-surface receptors, which mediate numerous physiological effects and the response to environmental stimuli. Latest researches have further revealed many new functions of GPCRs.Here we find that stimulation ofβ2-adrenergic receptors orδ-opioid receptors, two well-studied GPCRs, increase Aβproduction as well as Aβsecretion. This increase is contributed by GPCR activation-enhancedγ-secretase activity, which requires agonist-induced endocytosis of receptors. Furthermore, the time course of enhancedγ-secretase activity correlates quite well with that of promoted enrichment of this secretase in late endosomes and lysosomes (LEL). Consistently, receptor activation particularly and markedly elevatesγ-secretase activity and Aβproduction in LEL. Acute in vivo experiments in rats show that intracerebroventricular injection of norepinephrine, endogenous ligand for adrenergic receptors, also lead to enhancedγ- secretase activity and consequently increased Aβproduction in the hippocampus. Moreover, chronic experiments in Alzheimer's mouse model demonstrate that chronic administration ofβ2AR agonists isoproterenol and clenbuterol increase cerebral amyloid plaques while chronic administration ofβ2AR antagonists ICI 118,551 reduced plaques formation. Thus, our findings provide the direct evidence that physiological signals can regulate Aβproduction and that Aβlevels in brain can be changed by alteration of physiological or environmental signals.