Importance of GPCR-Mediated Microglial Activation in Alzheimer’s Disease

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.

Taurine and its analogs in neurological disorders: Focus on therapeutic potential and molecular mechanisms

“…Currently, analysis of the pathophysiology of neurodegeneration represents a great challenge for scientist [[175], [176], [177]]. Copious scientific articles have reported neuroprotective activity of natural constituents on the various model of neurodegeneration.…”

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

“…Although very little is known about their endogenous or exogenous ligands, these so-called oGPCRS have gained considerable attention as drug targets [163]. Several findings have postulated the critical role of oGPCRs in the cognitive deficits in disorders such as AD and schizophrenia [164][165][166][167]. For example, an expression map of the mouse brain has listed 78 oGPCRs and showed that many of them are relevant to cognition, motivation, and emotional processing [168].…”

Curcumin’s Nanomedicine Formulations for Therapeutic Application in Neurological Diseases

“…The neurotoxic phenotype express iNOS and major histocompatibility complex (MHC) II, activating the NF-κB pathway to produce several pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-12 and IL-23, and generate ROS and NO, which subsequently induce immune stimulation, neuroinflammation, the block of axonal remodeling and prevent neurogenesis. However, neuro-protective phenotypes mediate neuroprotection by Aβ phagocytosis and clearance, neuronal regeneration modulation, and arginase 1 (Arg1) release for tissue remodeling, wound healing and debris clearance [80].…”