G Protein-Coupled Receptors
In addition to these markers, various families of G protein-coupled receptors (GPCRs) have been identified to have putative roles in CNS disorders as well as Alzheimer’s disease (Dal Pra, I. 2019; Alavi 2018; Xu, 2020, Zhao, J 2016). The vertebrate GPCRs are a superfamily of membrane proteins comprising five distinct families on the basis of structural similarity and sequence, including rhodopsin (family A), secretin (family B), glutamate (family C), adhesion, and Frizzled/Taste2. These families all share a structure which consists of seven transmembrane helices connected to three extracellular and three intracellular loops. Despite a common structure, they have distinct roles in signal-transduction and regulatory processes. GPCRs have been implicated in the pathogenesis of Alzheimer’s disease and have been shown to bind to BACE1 and gamma secretase, both involved in the hydrolytic processing of APP (Zhao, 2016).
GPCRs implicated in AD include well-described GPCRS such as the gamma-aminobutyric acid B receptors, muscarinic cholinergic receptors (M1-3 AChR), the metabotropic glutamate receptors mGluR1-8, histamine receptors, delta opioid receptor, chemokine receptors, and calcium-sensing receptor CaSR, as well as orphan receptors such as GPR3, GPR6, GPR17, GPR26, GPR37, GPR39, GPR40, GPR50, GPR52, GPR54, GPR55, GPR68, GPR85, GPR88, GPR103, and GPR139 (Dal Pra 2019; Alavi, 2018; Xu 2020, Table 1). Other groups of GPCRs have also been identified that appear to be primarily involved in the microglial activation response to AD (Haque 2018). The GPCRs are variously involved in neurodevelopment, cytoskeletal organization, cell migration and synapse development, synaptic plasticity, endocytosis and phagocytosis, microglial or astroglial function, or immune regulation, so it is unsurprising that a number of these genes may be involved in the pathological progression of AD (see Table 1, GPCRs Involved in AD).
LifeSpan has also generated and tested antibodies to over 350 GPCRs by IHC on brain samples from patients with Alzheimer’s disease. Positive staining of senile plaques, neurofibrillary tangles, or overexpression in astrocytes in areas of injury was observed in IHC using antibodies to 33 different GPCRs (Table 1), most of which have been associated with AD progression or as a marker in previous (non-IHC) studies, demonstrating the widespread involvement of this class of proteins in neurodegenerative disorders such as AD.