Fig. 1: Light-driven regulation of melatonin synthesis.

Light, particularly in the blue wavelength range (450-490 nm), a pivotal component of sunlight, activates intrinsically photosensitive retinal ganglion cells (ipRGC) situated in the retina of the eyes. These ipRGCs transform light stimuli into action potentials transmitted to the suprachiasmatic nucleus (SCN), positioned above the optic nerve crossing [243]. Individuals with Alzheimer’s disease (AD) often exhibit a significant loss of ipRGC. The SCN comprises of approximately 20,000 neurons in each hemisphere. The interplay of core clock genes, including BMAL1, CLOCK, PER, and CRY, not only governs 24-hour processes like gene transcription in SCN neurons but also orchestrates their regulatory impact on other brain regions [244, 245]. The intricate regulation of pineal melatonin synthesis and release relies on the signaling pathway originating from the SCN in the hypothalamus, extending to the pineal gland (PG) [246]. This process involves the intermediolateral cell column in the spinal cord and sympathetic input from the superior cervical ganglion (SCG), located near the base of the skull [247]. Once released into the bloodstream by the PG, melatonin exerts its influence on target cells through specific melatonin receptors, distributed in various central and peripheral tissues [248]. Notably, melatonin is released into both the blood and directly into the brain. Several factors can disrupt the body’s natural melatonin production, including nighttime light exposure, such as the use of light-emitting devices [249]. Advanced aging [250], medications (e.g., beta blockers) [251], and various medical conditions, including dementia, pain, cancer, and type 2 diabetes mellitus [252], can also impede melatonin production. Conditions that hinder the synchronization of endogenous melatonin production with the solar day, such as blindness [253], add an additional layer of complexity.