fig2

Figure 2. The core components of the circadian oscillator within the cell autonomously regulate the 24-h gene expression cycle, and a series of pathological alterations are caused by the loss of BMAL1. The 24-h rhythm of gene expression and the absence of BMAL1 are governed by the cell-autonomous core components of the circadian oscillator. Within the primary loop, as well as the core loop, the heterodimerization of CLOCK and BMAL1 drives the expression of PER and CRY genes in the morning, mediated by E-box elements. Subsequently, the PER and CRY proteins constitute a repressor complex that inhibits the transactivation of CLOCK and BMAL1. In the secondary loop, REV-ERBα, REV-ERBβ, and RORα, RORβ, RORγ subfamilies of nuclear receptors act as repressors and activators to antagonistically regulate BMAL1 and other target genes at RORE promoter elements at nighttime. The D-box, activated by PAR-bZIP proteins like DBP and repressed by E4BP4, plays a crucial role in the transcriptional regulation of circadian clock-controlled genes. Various ligands and small molecules have been identified to influence core clock components and circadian functions. Loss of BMAL1 is associated with neurodegeneration in AD and other age-related dementias. The absence of BMAL1 in the brain adversely affects astrocytes, microglia, neurons, and pericytes, resulting in increased oxidative stress and inflammation, as well as alterations in neurotransmitter signaling. These changes may contribute to astrogliosis and astrocyte activation, impaired microglial phagocytosis, and neuronal injury, which, in turn, lead to synaptic damage, alterations in Aβ dynamics, and loss of brain connectivity - key pathological features of AD and related dementias. Potential signaling pathways involved include GST-mediated protein glutathionylation, the SIRT1-BMAL1 axis, GABA signaling, NAD⁺ depletion-related cyclic GMP-AMP synthase, and interferon gene stimulating factor activation, all of which play potential roles in AD. BMAL1: Aryl hydrocarbon receptor nuclear translocator-like; CLOCK: clock circadian regulator; PER: period circadian regulators; CRY: cryptochrome circadian regulators; DBP: D-box binding PAR bZIP transcription factor; AD: Alzheimer’s disease; Aβ: amyloid-β; GST: glutathione S-transferase; GABA: gamma-aminobutyric acid; NAD⁺: nicotinamide adenine dinucleotide; GMP-AMP: guanosine monophosphate - adenosine monophosphate.