Activation of β₂-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation

Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the γ-secretase catalytic subunit, can affect amyloid-β (Aβ) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how γ-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including β₂-adrenergic receptor (β₂-AR). Here we report that activation of β₂-AR enhanced γ-secretase activity and thus Aβ production. This enhancement involved the association of β₂-AR with presenilin-1 and required agonist-induced endocytosis of β₂-AR and subsequent trafficking of γ-secretase to late endosomes and lysosomes, where Aβ production was elevated. Similar effects were observed after activation of δ-opioid receptor. Furthermore, chronic treatment with β₂-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, β₂-AR activation can stimulate γ-secretase activity and amyloid plaque formation, which suggests that abnormal activation of β₂-AR might contribute to Aβ accumulation in Alzheimer disease pathogenesis.