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Abstract
Alzheimer’s disease (AD), particularly its sporadic or late-onset form (SAD/LOAD), is the most prevalent (96–98% of cases) neurodegenerative dementia in aged people. AD’s neuropathology hallmarks are intrabrain accumulation of amyloid-β peptides (Aβs) and of hyperphosphorylated Tau (p-Tau) proteins, diffuse neuroinflammation, and progressive death of neurons and oligodendrocytes. Mounting evidences suggest that family C G-protein-coupled receptors (GPCRs), which include γ-aminobutyric acid B receptors (GABABRs), metabotropic glutamate receptors (mGluR1-8), and the calcium-sensing receptor (CaSR), are involved in many neurotransmitter systems that dysfunction in AD. This review updates the available knowledge about the roles of GPCRs, particularly but not exclusively those expressed by brain astrocytes, in SAD/LOAD onset and progression, taking stock of their respective mechanisms of action and of their potential as anti-AD therapeutic targets. In particular, GABABRs prevent Aβs synthesis and neuronal hyperexcitability and group I mGluRs play important pathogenetic roles in transgenic AD-model animals. Moreover, the specific binding of Aβs to the CaSRs of human cortical astrocytes and neurons cultured in vitro engenders a pathological signaling that crucially promotes the surplus synthesis and release of Aβs and hyperphosphorylated Tau proteins, and also of nitric oxide, vascular endothelial growth factor-A, and proinflammatory agents. Concurrently, Aβs•CaSR signaling hinders the release of soluble (s)APP-α peptide, a neurotrophic agent and GABABR1a agonist. Altogether these effects progressively kill human cortical neurons in vitro and likely also in vivo. Several CaSR’s negative allosteric modulators suppress all the noxious effects elicited by Aβs•CaSR signaling in human cortical astrocytes and neurons thus safeguarding neurons’ viability in vitro and raising hopes about their potential therapeutic benefits in AD patients. Further basic and clinical investigations on these hot topics are needed taking always heed that activation of the several brain family C GPCRs may elicit divergent upshots according to the models studied.
Highlights
Alzheimer’s disease (AD), its sporadic or late-onset form (SAD/LOAD), is by far the most prevalent cause of senile dementia in humans (Alzheimer’s Association, 2018)
Multiple neurotoxic factors accumulate in the AD brain, such as soluble amyloid-β oligomers and insoluble amyloid-β peptides (Aβs) fibrils, the latter aggregating into senile plaques (Gouras et al, 2015); hyperphosphorylated soluble Tau oligomers (p-Tau-os) that collect into insoluble neurofibrillary tangles (NFTs) (Bloom, 2014); overproduced reactive oxygen species (ROS) (Butterfield and Boyd-Kimball, 2018); nitric oxide (NO); vascular endothelial growth factor-A (VEGF-A), and proinflammatory agents (Dal Prà et al, 2014a; Chiarini et al, 2016)
On the potentially beneficial therapeutic effects calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs) could exert in LOAD/SAD patients
Summary
Alzheimer’s disease (AD), its sporadic or late-onset form (SAD/LOAD), is by far the most prevalent cause of senile dementia in humans (Alzheimer’s Association, 2018). The experimental exploitation of the latter cells has revealed that exogenous Aβs bind the calciumsensing receptor (CaSR) (Dal Prà et al, 2014a; Dal Prà et al, 2014b; Dal Prà et al, 2015b), a member of family C G-protein coupled receptors (GPCR), and activate a pathological signaling that could drive human LOAD/SAD onset and progression and worsen EOFAD’s course These findings have clearly pointed out to a class of therapeutic agents, the CaSR negative allosteric modulators (NAMs), which effectively block all such AD’s pathogenetic mechanisms in untransformed cortical human neurons and astrocytes in vitro and could stop the progression of AD neuropathology in the patients (Armato et al, 2013; Chiarini et al, 2017a; Chiarini et al, 2017b). C GPCRs share a common general structure characterized by a huge bilobed N-terminal extracellular domain (ECD) or TABLE 1 | G-Protein-coupled receptors (GPCRs) Families
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