Christopher Polo

Background: Alzheimer’s disease (AD) is the leading cause of dementia globally.^1,2 In 2023, more than 6.7 million individuals 65 years of age or older living in the United States had AD, and by the year 2060, that number will more than double.³ The pathological hallmarks of AD are the accumulation of extracellular amyloid-â (Aâ) plaques and intracellular neurofibrillary tangles (NFTs) in the brain. AD patients present with sleep disturbances and display reduced levels of melatonin, an important regulator of the sleep-wake cycle.^4,5 Disease-associated protein kinase 1 (DAPK1) is a Ser/Thr protein kinase with important functions in regulating cell survival under stress.⁶ Notably, DAPK1 protein levels have been observed to be elevated in the brain and the plasma from patients with AD, which also correlated with worse scores on the Montreal Cognitive Assessment.^7,8 These observations and other studies suggest potential synergy between DAPK1 inhibitors and melatonin for treating AD.

Objective: In this narrative review, we describe evidence supporting the synergy of DAPK1 inhibitors and melatonin to halt the multimodal pathogenesis and progression of AD.

Search Methods: An online search in the PubMed database was performed to identify publications from 2019-2024 using the following keywords: “Alzheimer’s disease”, “disease-associated protein kinase 1”, and “melatonin.” Search parameters were later expanded to access less recent publications that provided further context to the developing narrative.

Results: Treating mouse primary cortical neurons with Aâ oligomers induced significant cell death compared to controls, and the neuronal loss was concomitant with increased expression of pro-apoptotic markers.⁹ DAPK1 knockout (KO) protected cells from the Aâ-induced apoptosis.⁹ Further study revealed DAPK1 mediates the Aâ-induced cell death via phosphorylation of prolyl isomerase 1 (Pin1), which negatively regulates the activity of Pin1 to modulate tau turnover, thereby linking Aâ pathology to aberrant tau phosphorylation.⁹ The specific mechanisms leading to pathogenic accumulation of Aâ remain unclear; however, synthesis of Aâ correlates with synaptic activity.¹⁰ Consequently, levels of Aâ fluctuate with the sleep-wake cycle, showing greater clearance from the interstitial fluid during sleep.¹¹ Compared to healthy individuals, AD patients experience significant sleep disturbances.⁵ Moreover, significantly reduced levels of melatonin in AD patients are inversely correlated to levels of DAPK1.⁴ Melatonin directly binds DAPK1, promoting its ubiquitination and proteasomal degradation.⁴ When transgenic mice overexpressing human tau protein received melatonin 3 times per week over 5 months, the density of NFTs and the degree of neuronal loss were significantly reduced compared to saline-treated mice.¹² Furthermore, combining melatonin and a DAPK1 inhibitor resulted in an even greater reduction in NFT density than either treatment alone.⁴ The combination therapy also synergistically promoted neurite outgrowth.⁴

Conclusions: The studies described here outline the role of DAPK1 in mediating Aâ-induced NFT formation and neuronal loss as seen in AD. Furthermore, the evidence supports melatonin deficiency and sleep disturbance as factors promoting the pathogenic accumulation of Aâ in patients with AD. Therefore, future investigation into the therapeutic potential of the synergistic activity of melatonin and a DAPK1 inhibitor to halt the multimodal pathogenesis and progression of AD should be considered.

Works Cited:

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