Fig. 2: Melatonin modulation of amyloid beta production and clearance in Alzheimer’s disease.

In the pro-amyloidogenic pathway, membrane-bound amyloid precursor protein (APP) undergoes proteolytic cleavages orchestrated by β-secretase (BACE) and γ-secretase, leading to increased intraneuronal and brain interstitial fluid amyloid-beta (Aβ) concentrations. If enzymatically cleaved first by alpha (ADAM) and then γ-secretase, no Aβ is produced. If cleaved concertedly by β- and α-secretases, short 14-16 amino acid-long Aβ fragments form but they are highly hydrophilic and not part of any amyloidogenic cascade. Through self-assembly, soluble Aβ oligomers (Aβos) are formed, known to disrupt neuronal signaling through excitotoxicity and induce oxidative stress (e.g., through microglial activation), thereby exacerbating the process of neurodegeneration. Aβos can further assemble to build fibrils, which represent a major component of Aβ plaques [254, 255]. As reviewed in Section Unlocking Melatonin’s Anti-Amyloidogenic Potential and Section Melatonin’s Neuroprotective Mechanisms against Aβ toxicity, melatonin redirects APP toward the non-amyloidogenic pathway, potentially achieved by suppressing glycogen synthase kinase-3β (GSK3β) activity. This is achieved through various mechanisms, e.g., the activation of the membrane-bound melatonin receptor 1. GSK3β is a kinase known to promote the pro-amyloidogenic pathway. Consequently, melatonin reduces Aβ burden in the brain. Melatonin may also increase the clearance of Aβ. For example, treatment with melatonin has been shown to upregulate transporters such as the low-density lipoprotein receptor-related protein 1 (LRP1), which plays a decisive role in the uptake of soluble Aβ proteins from the brain interstitial fluid into astrocytes. In animal models that overexpress apolipoprotein E (ApoE), a variant recognized for competing with Aβ for astrocytic uptake, melatonin has been shown to alleviate Aβ burden, most likely achieved through the upregulation of LRP1. Melatonin has also been demonstrated to mitigate processes involved in Aβos’ adverse effects on brain cells, such as excitotoxicity and oxidative stress.