G Protein-Coupled Receptors (GPCRs) in Alzheimer's Disease: A Focus on BACE1 Related GPCRs.

Juan Zhao,Hong Qing,Zhaotan Jiang,Yulin Deng

doi:10.3389/fnagi.2016.00058

Juan Zhao, Hong Qing + Show 2 more

Open Access

https://doi.org/10.3389/fnagi.2016.00058

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Abstract

The G protein coupled receptors (GPCRs) have been considered as one of the largest families of validated drug targets, which involve in almost overall physiological functions and pathological processes. Meanwhile, Alzheimer’s disease (AD), the most common type of dementia, affects thinking, learning, memory and behavior of elderly people, that has become the hotspot nowadays for its increasing risks and incurability. The above fields have been intensively studied, and the link between the two has been demonstrated, whereas the way how GPCRs perturb AD progress are yet to be further explored given their complexities. In this review, we summarized recent progress regarding the GPCRs interacted with β-site APP cleaving enzyme 1 (BACE1), a key secretase in AD pathogenesis. Then we discussed the current findings on the regulatory roles of GPCRs on BACE1, and the possibility for pharmaceutical treatment of AD patients by the allosteric modulators and biased ligands of GPCRs. We hope this review can provide new insights into the understanding of mechanistic link between GPCRs and BACE1, and highlight the potential of GPCRs as therapeutic target for AD.

Highlights

Gprotein coupled receptors (GPCRs) are integral membrane proteins that are used by cells to convert extracellular signals into intracellular responses, including responses to hormones, neurotransmitters, as well as responses to vision, olfaction and taste signals
The available documents provide us insights to the role of G protein coupled receptors (GPCRs) in mediating beta secretase (BACE1) by mechanisms that fall into the following categories: (i) GPCRs activation stimulates G protein-dependent signaling pathway, which alters the expression level of BACE1; (ii) GPCRs activation mediates the degradation of BACE1; and (iii) GPCRs activation regulates the trafficking of BACE1
It is clear that several GPCRs and GPCR related proteins are involved in the regulation of BACE1 and the pathogenesis of Alzheimer’s disease (AD) (Table 2)

Summary

Introduction

Gprotein coupled receptors (GPCRs) are integral membrane proteins that are used by cells to convert extracellular signals into intracellular responses, including responses to hormones, neurotransmitters, as well as responses to vision, olfaction and taste signals These receptors form a superfamily of membrane proteins comprising of five distinct families on the basis of their sequences and structural similarities: rhodopsin (family A), secretin (family B), glutamate (family C), adhesion and Frizzled/Taste (Fredriksson et al, 2003; Rosenbaum et al, 2009). The muscarinic acetylcholine receptors are members of the family A GPCRs that are synthesized by cholinergic cells They are widely expressed in the central nervous system where they control a variety of neuronal functions (Langmead et al, 2008). Opioid receptors and opioid peptides, vulnerable to AD, are widely expressed in the central nervous system, including hippocampus and cortex, the brain regions crucial for cognition They play important roles in synaptic activation, learning and memory. A2A receptors have low expression in healthy brain but this pattern of expression and functionality can be changed in pathological conditions

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