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The role of G protein-coupled receptors in the pathology of Alzheimer's disease

Key Points

  • Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by massive neuronal cell and synapse loss, senile plaques composed primarily of the amyloid-β peptide, and tau-containing neurofibrillary lesions.

  • Current AD therapies mainly target acetylcholinesterase, which broadly stimulates cholinergic neurons. However, neurodegeneration is not limited to a specific neurotransmitter system. Glutamatergic, serotonergic, adrenergic and peptidergic neurotransmitter systems are also deregulated in AD.

  • G protein-coupled receptors (GPCRs), also known as seven-transmembrane receptors (7TMRs), are the largest class of transmembrane receptors and a common therapeutic target. Several studies have presented compelling evidence implicating GPCRs in the pathogenesis of AD and in multiple stages of the proteolysis of amyloid precursor protein (APP).

  • Amyloid-β is produced from sequential proteolysis of the APP by β- and γ-secretase. By contrast, sequential cleavage by α- and γ-secretase precludes amyloid-β generation. α-, β- and γ-secretases are regulated by GPCRs, and amyloid-β itself can directly or indirectly affect GPCR function.

  • Activation of muscarinic acetycholine receptors (mAChRs), group I metabotropic glutamate receptors (mGluRs), and 5-hydroxytryptamine (5-HT; also known as serotonin) receptors have been shown to increase the non-amyloidogenic processing of APP through activation of α-secretase. For example, the M1 and M3 mAChR agonist AF267B reduces amyloid- and tau-related pathologies and rescues hippocampus-dependent learning and memory impairments in an AD mouse model.

  • The opioid receptors are involved in learning and memory and are deregulated in the AD brain. Recent studies suggest that these GPCRs and their ligand, enkephalin, are involved in modulation of the β-secretase and subsequent amyloid-β generation.

  • The β2 adrenergic receptor (β2-AR) and G protein-coupled receptor 3 (GPR3) are involved in regulation of the γ-secretase-mediated cleavage of APP. The β2-AR influences the localization of the γ-secretase complex and thereby regulates the amyloidogenic processing of APP and exacerbates the amyloid pathology in an AD mouse model. GPR3 regulates the in vitro and in vivo amyloidogenic proteolysis of APP through modulation of the localization and/or activity of the γ-secretase complex in the absence of an effect on Notch processing.

  • Although the mechanism of amyloid-β-mediated toxicity is not clearly understood, recent studies suggest that amyloid-β accumulation is involved in the oligomerization of the angiotensin type 2 receptor and sequestration of the Gαq/11 family of G proteins. Sequestration of Gαq/11 results in dysfunctional M1 mAChR–Gαq/11 coupling and signalling, and accompanies hippocampal neurodegeneration, tau phosphorylation and neuronal loss in an AD transgenic mouse model.

  • The chemokine receptors CC-chemokine receptor 2 (CCR2) and CX3C-chemokine receptor 1 (CX3CR1) have a putative role in Alzheimer's disease pathology. These receptors are expressed by microglia, which have been shown to surround amyloid plaques both in patients with AD and in AD transgenic mouse models, but whether they have beneficial or detrimental effects on plaque formation remains unclear.

  • Promoting amyloid-β clearance from the brain is a possible therapeutic strategy for inhibition of amyloid-β generation. However, stimulation of GPCRs, in particular the somatostatin receptor, could represent an interesting alternative approach, as these GPCRs induce expression of amyloid-β-degrading enzymes, such as neprilysin, in the brain. A combination of memory enhancement, neuroprotection and anti-amyloid-β activity makes this an attractive therapeutic approach for AD.

Abstract

G protein-coupled receptors (GPCRs) are involved in numerous key neurotransmitter systems in the brain that are disrupted in Alzheimer's disease (AD). GPCRs also directly influence the amyloid cascade through modulation of the α-, β- and γ-secretases, proteolysis of the amyloid precursor protein (APP), and regulation of amyloid-β degradation. Additionally, amyloid-β has been shown to perturb GPCR function. Emerging insights into the mechanistic link between GPCRs and AD highlight the potential of this class of receptors as a therapeutic target for AD.

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Figure 1: Modulation of APP processing by GPCRs.
Figure 2: GPCR signalling and the α-secretase pathway.
Figure 3: Amyloid-β toxicity and deregulation of AT2R and M1 mAChR signalling.
Figure 4: Adenosine A2A receptor and amyloid-β-mediated toxicity.

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Acknowledgements

Work in the laboratory was supported by the Flanders Institute for Biotechnology (VIB), Fonds voor Wetenschappelijk onderzoek (FWO) and Stichting Alzheimer Onderzoek-Fondation pour la recherche de la maladie d'Alzheimer (SAO-FRMA) (grant cycle 2008–2009), the Federal Office for Scientific Affairs, Belgium (IUAP P6/43/), a Methusalem grant of the Catholic University of Leuven (KUL) and the Flemish Government, and Memosad (FZ-2007-200611) of the European Union. B.D.S. is supported by an Arthur Bax and Anna Vanluffelen Chair for Alzheimer's Disease.

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Synaptoneurosome

A purified synapse, containing a presynaptic sac (synaptosome) attached to a resealed postsynaptic sac (neurosome), that is modestly enriched for synaptic proteins.

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Thathiah, A., De Strooper, B. The role of G protein-coupled receptors in the pathology of Alzheimer's disease. Nat Rev Neurosci 12, 73–87 (2011). https://doi.org/10.1038/nrn2977

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