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

Abstract

Amyloid plaque is the hallmark and primary cause of Alzheimer disease. Mutations of presenilin-1, the gamma-secretase catalytic subunit, can affect amyloid-beta (Abeta) production and Alzheimer disease pathogenesis. However, it is largely unknown whether and how gamma-secretase activity and amyloid plaque formation are regulated by environmental factors such as stress, which is mediated by receptors including beta(2)-adrenergic receptor (beta(2)-AR). Here we report that activation of beta(2)-AR enhanced gamma-secretase activity and thus Abeta production. This enhancement involved the association of beta(2)-AR with presenilin-1 and required agonist-induced endocytosis of beta(2)-AR and subsequent trafficking of gamma-secretase to late endosomes and lysosomes, where Abeta production was elevated. Similar effects were observed after activation of delta-opioid receptor. Furthermore, chronic treatment with beta(2)-AR agonists increased cerebral amyloid plaques in an Alzheimer disease mouse model. Thus, beta(2)-AR activation can stimulate gamma-secretase activity and amyloid plaque formation, which suggests that abnormal activation of beta(2)-AR might contribute to Abeta accumulation in Alzheimer disease pathogenesis.

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

“…Remarkably, we found in our recent study that β2-adrenoceptor signaling, which mediates the stress response in animals, regulates γ-secretase activity and senile plaque formation in vivo [67]. Our present study shows that extracellular signals, at least those mediated by RTKs, could increase Aβ production by enhancing BACE activity.…”

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

“…We have previously reported that β 2 -AR associates with PS1 and that agonist-induced endocytosis of β 2 -AR enhances trafficking of γ-secretase to late endosomes and increases Aβ production [23]. We hypothesized that a similar interaction-based mechanism might also apply here.…”

“…We have previously reported that activation of DOR enhances γ-secretase activity in vitro [23]. Here, we first investigated whether activation of DOR specifically affects secretase activities for Aβ production.…”

“…Nevertheless, in view of the multiple substrates of these secretases, designing drugs for specific inhibition of APP β-and γ-cleavage appears challenging. Previous reports have shown that altered cell signaling, especially G protein-coupled receptor (GPCR) signaling, is related to abnormal Aβ production and AD pathogenesis [19][20][21][22][23]. We have previously reported that activation of β2-adrenergic receptor (β 2 -AR) or δ-opioid receptor (DOR) directly enhances γ-secretase activity and accelerates Aβ production [23].…”

“…Previous reports have shown that altered cell signaling, especially G protein-coupled receptor (GPCR) signaling, is related to abnormal Aβ production and AD pathogenesis [19][20][21][22][23]. We have previously reported that activation of β2-adrenergic receptor (β 2 -AR) or δ-opioid receptor (DOR) directly enhances γ-secretase activity and accelerates Aβ production [23]. More recently, Thathiah et al [24] have reported that expression of GPR3 led to increased formation and cell-surface localization of the mature γ-secretase complex in the absence of an effect on Notch processing.…”