These findings, together with other studies, suggest that cellular membrane receptors, especially GPCRs, might be potential targets for modulating APP processing. 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. 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. ![]() Nevertheless, in view of the multiple substrates of these secretases, designing drugs for specific inhibition of APP β- and γ- cleavage appears challenging. However, as the physiological roles of putative Aβ-degrading enzymes in Aβ clearance in vivo are still inconclusive, the β- and γ-secretases are thus regarded as key therapeutic targets so far. Dysregulation of either APP processing or Aβ clearance leads to anomalous Aβ deposition in brains, and contributes to the etiology of both familial and sporadic AD 18. All these protease activities respond elaborately to diverse genetic and biochemical mediations. Accumulated Aβ can be removed by Aβ-degrading enzymes, such as neprilysin (NEP) 14, insulin-degrading enzyme (IDE) 15, endothelin-converting enzyme 16 and angiotensin-converting enzyme 17. Conversely, cleavage of APP by α-secretase precludes the production of the toxic Aβ peptide 13. Imprecise cleavage of C99 by γ-secretase produces Aβ variants, mainly Aβ40 and Aβ42 12. γ-Secretase is an intramembranous complex composed of presenilin-1 (PS1), PEN-2, nicastrin and APH-1, with PS1 constituting the active site 11. Thus, BACE1 cleavage of APP is a prerequisite for γ-cleavage and is regarded as a rate-limiting step in the production of Aβ 10. ![]() BACE1 is the novel transmembrane aspartic protease that cleaves APP to form Aβ N-terminus and generate a C-terminal fragment, C99, as the substrate for γ-secretase 9. Aβ is derived from Aβ precursor protein (APP) after sequential β- and γ-endoproteolysis by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase complex, respectively 6, 7, 8. Reduction of Aβ could conceivably be accomplished either by inhibiting its production or aggregation or by promoting its degradation and removal 5. A large body of studies suggests that reduction of Aβ levels in the brain should be a promising therapeutic approach 3, 4. Amyloid plaque composed of amyloid-β peptide (Aβ) in AD patient brains is one of the pathological hallmarks of the disease 2. 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.Īlzheimer's disease (AD) is the most common neurodegenerative disorder causing progressive memory loss and cognitive dysfunction 1. 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. Dysfunction of the receptor retards the endocytosis of BACE1 and γ-secretase and thus the production of Aβ. ![]() 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. 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. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. 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. 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).
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