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

Abstract

Dysregulation of β-site APP-cleaving enzyme (BACE) and/or γ-secretase leads to anomalous production of amyloid-β peptide (Aβ) and contributes to the etiology of Alzheimer's disease (AD). Since these secretases mediate proteolytic processing of numerous proteins, little success has been achieved to treat AD by secretase inhibitors because of inevitable undesired side effects. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. Here, we show that δ-opioid receptor (DOR) promotes the processing of Aβ precursor protein (APP) by BACE1 and γ-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and γ-secretase, and activation of DOR mediates the co-endocytic sorting of the secretases/ receptor complex for APP endoproteolysis. Dysfunction of the receptor retards the endocytosis of BACE1 and γ-secretase and thus the production of Aβ. Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Aβ pathology and Aβ-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice. Our study not only uncovers a molecular mechanism for the formation of a DOR/secretase complex that regulates the specificity of secretase for Aβ production but also suggests that intervention of either formation or trafficking of the GPCR/secretase complex could lead to a new strategy against AD, potentially with fewer side effects.

Cysteine 27 Variant of the δ-Opioid Receptor Affects Amyloid Precursor Protein Processing through Altered Endocytic Trafficking

“…To facilitate the design of novel intervention approaches for AD, it is important to identify and functionally characterize genetic alterations which play a role in AD pathogenesis. A plausible candidate in this context is the OPRD1 gene, encoding the ␦-opioid receptor (␦OR), which was recently shown to form a complex with ␤-and ␥-secretases (28,40). Following agonist-induced activation, ␦OR mediates coendocytic sorting of this complex to late endosomes and lysosomes (LEL) (28,40), in which compartments A␤ production primarily takes place.…”

“…A plausible candidate in this context is the OPRD1 gene, encoding the ␦-opioid receptor (␦OR), which was recently shown to form a complex with ␤-and ␥-secretases (28, 40). Following agonist-induced activation, ␦OR mediates coendocytic sorting of this complex to late endosomes and lysosomes (LEL) (28,40), in which compartments A␤ production primarily takes place. Conversely, ␤-and ␥-secretase activities as well as A␤ levels were found to be significantly reduced in transgenic APP/PS1⌬E9 mice (overexpressing human APP with the Swedish mutation together with human presenilin-1 harboring the exon 9 deletion) treated with a selective nonpeptide antagonist for ␦OR (40).…”

Sanofi-Cell Research outstanding paper award of 2010

“…The paper by Pei and Zhao [2] reports that δ-opioid receptor (DOR) promotes the processing of APP by BACE1 and γ-secretase, through complex formation between DOR and the secretases. They further show that knockdown or antagonization of DOR reduces secretase activities and ameliorates Aβ pathology and Aβ-dependent behavioral deficits, but does not affect the processing of other secretase substrates such as Notch, Ncadherin or APLP in AD model mice.…”

“…The winners for the 2010 Sanofi-Cell Research Outstanding Research Article Award are Drs Gang Pei and Jian Zhao, for their paper entitled "A GPCR/ secretase complex regulates β-and γ-secretase specificity for Aβ production and contributes to AD pathogenesis" [2]; and Drs Charlie Degui Chen and Naihe Jing, for their paper entitled "Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4" [3]. The award consists of a prize of € 3 000 for the Outstanding Review Article Award and € 5 000 for the Outstanding Research Article Award provided by Sanofi.…”

Regulation of β cleavage of amyloid precursor protein

“…Activation of DOR facilitates endocytosis of this complex, and therefore enhances the activities of BACE1 and -secretase, resulting in A generation. Chronic treatment of AD mice with DOR antagonist or knocking down of DOR can reduce the activities of BACE1 and -secretase, alleviate A pathology and improve deficits in spatial learning and memory [74] . have been found to be within lipid rafts, and  cleavage preferentially occurs in lipid rafts where they are close to each other [75] .…”