Potential Astrocytic Receptors and Transporters in the Pathogenesis of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by the progressive loss of memory and cognition in the aging population. However, the etiology of and therapies for AD remain far from understood. Astrocytes, the most abundant neuroglia in the brain, have recently aroused substantial concern due to their involvement in synaptotoxicity, amyloidosis, neuroinflammation, and oxidative stress. In this review, we summarize the candidate molecules of astrocytes, especially receptors and transporters, that may be involved in AD pathogenesis. These molecules include excitatory amino acid transporters (EAATs), metabotropic glutamate receptor 5 (mGluR5), the adenosine 2A receptor (A2AR), the ␣7-nicotinic acetylcholine receptor (␣7-nAChR), the calcium-sensing receptor (CaSR), S100␤, and cannabinoid receptors. We describe the characteristics of these molecules and the neurological and pharmacological underpinnings of these molecules in AD. Among these molecules, EAATs, A2AR, and mGluR5 are strongly related to glutamate-mediated synaptotoxicity and are involved in glutamate transmission or the clearance of extrasynaptic glutamate in the AD brain. The ␣7-nAChR, CaSR, and mGluR5 are receptors of A␤ and can induce a plethora of toxic effects, such as the production of excess A␤, synaptotoxicity, and NO production triggered by changes in intracellular calcium signaling. Antagonists or positive allosteric modulators of these receptors can repair cognitive ability and modify neurobiological changes. Moreover, blocking S100␤ or activating cannabinoid receptors reduces neuroinflammation, oxidative stress, and reactive astrogliosis. Thus, targeting these molecules might provide alternative approaches for treating AD.

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

“…Neuronal influence on GFAP expression is due to alteration of extracellular ions and bioactive molecule levels as well as their activation of receptors and/or organic transporters on astrocyte membrane (Guidolin, Marcoli, Tortorella, Maura, & Agnati, ; Zhang et al, ). Increased neuronal activity can increase extracellular K + level which increases GFAP fiber formation, typically observed during seizures in hippocampus (Vizuete, Hennemann, Gonçalves, & de Oliveira, ).…”

“…The red lines/ arrows represent facilitatory pathways and the black lines/stops show inhibitory pathways. Abbreviations: AR, arginine residues; Ca 2+ /CAM, Ca 2 + /calmodulin; CDK5, cyclin-dependent kinase 5; CR, citrulline residues; CREB, cyclic AMP response element-binding protein; Ecrg4, esophageal cancer-related gene 4; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Glu, glutamate; gp130, glycoprotein 130; iNOS, inducible nitric oxide synthase; JAK2, Janus kinase-2; STAT3, signal transducer and activator of transcription 3; KDMs, histone lysine-specific demethylases; NMDAR, NMDA receptors; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; OSM, oncostatin M; PADs, peptidylarginine deiminases; PI3K/AKT, phosphatidylinositide 3-kinases; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PPARγ, peroxisome proliferator-activated receptor γ; TLR-4, Toll-like receptor 4; Trg, troglitazone receptors and/or organic transporters on astrocyte membrane (Guidolin, Marcoli, Tortorella, Maura, & Agnati, 2019;Zhang et al, 2019). Increased neuronal activity can increase extracellular K + level which increases GFAP fiber formation, typically observed during seizures in hippocampus (Vizuete, Hennemann, Gonçalves, & de Oliveira, 2017).…”

Royal Jelly as an Intelligent Anti-Aging Agent—A Focus on Cognitive Aging and Alzheimer’s Disease: A Review

“…As a result, the synthesis, transport, release, and uptake of neurotransmitters gets disrupted. Such interactions promote neurotoxicity, aggravate tau and Aβ deposition, and ultimately lead to more cellular lesions and sporadic neurodegeneration [ 73 , 76 , 80 ]. Finally, progressive damage and death of neurons in several areas of the brain, expressly the hippocampus—an important region for learning and memory—represent the direct cause of clinical manifestations in AD [ 16 , 23 , 28 ].…”

“…The destruction of synaptic spines in AD brains results from increased activity of free radicals, phosphorylated tau oligomers, and caspase-3, which follow excessive intercellular Ca 2+ influx. Synaptic loss triggers dysregulation of synaptic signal transduction, i.e., the synthesis, transport, release, and uptake of neurotransmitters, which accelerates neurodegeneration [ 73 , 80 , 84 ]. Evidence shows that serotonergic transmission, which plays a role in the pathogenesis of depression [ 148 ], influences processes of learning and memory.…”

“…CRE-mediated transcription is a principal signaling pathway that promotes learning and memory through long-term hippocampal potentiation. Dysregulation of this pathway influences Aβ metabolism and stimulates tau phosphorylation, which contributes to the development of cognitive impairment in neurodegenerative diseases such as AD [ 80 , 93 ]. Several lines of evidence note that RJ repairs dysregulated neurons encompassing Aβ pathology via activation of CREB signaling [ 28 , 116 ].…”