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

Abstract

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.

Cite this article

Ni, Y., Zhao, X., Bao, G. et al. Activation of β₂-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation. Nat Med 12, 1390–1396 (2006). https://doi.org/10.1038/nm1485

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