Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with impairment of cognition, memory deficits and behavioral abnormalities. Accumulation of amyloid beta (Aβ) is a characteristic hallmark of AD. Microglia express several GPCRs, which, upon activation by modulators, mediate microglial activation and polarization phenotype. This GPCR-mediated microglial activation has both protective and detrimental effects. Microglial GPCRs are involved in amyloid precursor protein (APP) cleavage and Aβ generation. In addition, microglial GPCRs are featured in the regulation of Aβ degradation and clearance through microglial phagocytosis and chemotaxis. Moreover, in response to Aβ binding on microglial Aβ receptors, they can trigger multiple inflammatory pathways. However, there is still a lack of insight into the mechanistic link between GPCR-mediated microglial activation and its pathological consequences in AD. Currently, the available drugs for the treatment of AD are mostly symptomatic and dominated by acetylcholinesterase inhibitors (AchEI). The selection of a specific microglial GPCR that is highly expressed in the AD brain and capable of modulating AD progression through Aβ generation, degradation and clearance will be a potential source of therapeutic intervention. Here, we have highlighted the expression and distribution of various GPCRs connected to microglial activation in the AD brain and their potential to serve as therapeutic targets of AD.
Highlights
Microglia or resident macrophages of the central nervous system (CNS) originate from the embryonic yolk sac and are incorporated into the CNS during the earlier stages of development (Lannes et al, 2017)
Seeing the conventional strategy for selecting a therapeutic agent is based on the characteristics of prevention, clearance and degradation of amyloid-β peptide (Aβ) peptides, these can be achieved by targeting microglial G-Protein-Coupled Receptors (GPCRs) involved in different stages from Aβ generation, degradation, and clearance in the brain
Different microglial GPCRs are linked with Aβ generation
Summary
Microglia or resident macrophages of the central nervous system (CNS) originate from the embryonic yolk sac and are incorporated into the CNS during the earlier stages of development (Lannes et al, 2017). Microglia contribute to protection and maintenance of the CNS (Datta et al, 2018) Their role in the pathophysiology of many neurodegenerative disorders has been studied over the previous decades (Gentleman, 2013; Giunti et al, 2014; Salter and Stevens, 2017; Dukhinova et al, 2018), suggesting that microglia can rapidly change their phenotype to express different receptors according to stimuli generated by CNS damage or infection. In the AD brain, accumulation of this misfolded Aβ has been demonstrated to induce neuroinflammation by binding with several microglial innate immune receptors, including G-Protein-Coupled Receptors (GPCRs), which were postulated to induce an inflammatory cascade known as the ‘‘amyloid cascade-inflammatory hypothesis of AD’’ (Hardy and Higgins, 1992; Karran et al, 2011; McGeer and McGeer, 2013) This hypothesis is one of the most influential hypotheses surrounding AD pathogenesis to date.
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