Noncanonical Metabotropic Glutamate Receptor 5 Signaling in Alzheimer's Disease

• Published in: Annual review of pharmacology and toxicology 2022-01, Vol.62 (1), p.235-254
• Main Authors: Abd-Elrahman, Khaled S, Ferguson, Stephen S.G
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; amyloid beta; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - therapeutic use; Brain - metabolism; Female; Humans; Male; mGluR5; Receptor, Metabotropic Glutamate 5 - metabolism; Receptor, Metabotropic Glutamate 5 - therapeutic use; sex differences; Signal Transduction; synaptic plasticity; tau
• ISSN: 0362-1642; 1545-4304
• DOI: 10.1146/annurev-pharmtox-021821-091747

Metabotropic glutamate receptor 5 (mGluR5) is ubiquitously expressed in brain regions responsible for memory and learning. It plays a key role in modulating rapid changes in synaptic transmission and plasticity. mGluR5 supports long-term changes in synaptic strength by regulating the transcription and translation of essential synaptic proteins. β-Amyloid 42 (Aβ42) oligomers interact with a mGluR5 cellular prion protein (PrP C ) complex to disrupt physiological mGluR5 signal transduction. Aberrant mGluR5 signaling and associated synaptic failure are considered an emerging pathophysiological mechanism of Alzheimer's disease (AD). Therefore, mGluR5 represents an attractive therapeutic target for AD, and recent studies continue to validate the efficacy of various mGluR5 allosteric modulators in improving memory deficits and mitigating disease pathology. However, sex-specific differences in the pharmacology of mGluR5 and activation of noncanonical signaling downstream of the receptor suggest that its utility as a therapeutic target in female AD patients needs to be reconsidered.