REV-ERBs as regulators of circadian rhythm, neuroinflammation, and glial lipid homeostasis in Alzheimer's disease. A narrative review.

Abstract

Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid-β and tau aggregation, and chronic neuroinflammation, processes that are tightly coupled to circadian and metabolic dysfunction. REV-ERBα (NR1D1) and REV-ERBβ (NR1D2) are ligand-dependent nuclear receptors that function as transcriptional repressors within the core clock and coordinate programs governing lipid metabolism, innate immunity, and redox homeostasis in the brain. In microglia, REV-ERBα restrains NF-κB signaling, complement and inflammasome activation, and lipid droplet accumulation, thereby limiting synaptic engulfment and tauopathy progression, whereas its loss drives a hyper-reactive, neurotoxic state. Astrocytic REV-ERBα exerts context-dependent effects, simultaneously constraining cytokine and nitric oxide production while tuning NAD⁺ metabolism through an NFIL3-CD38 axis with implications for tau-induced neurodegeneration. Preclinical studies demonstrate that synthetic pan-REV-ERB agonists reduce glial activation, restore NCoR/HDAC3-mediated repression, improve cognitive performance, and partially realign disrupted circadian rhythms in AD models, although current compounds are limited by suboptimal pharmacokinetics and off-target actions. In this narrative review, REV-ERBs are presented as nodal integrators of circadian, metabolic, and neuroimmune pathways in AD and as promising, yet complex, therapeutic targets, highlighting opportunities for brain-penetrant ligands, rational combinations, and chronotherapeutic dosing paradigms.