Mechanism of the Effect of Melatonin on Amyloid β: A Focus on Rho-associated Protein Kinase 1 (ROCK1)

Principal Investigator
Eman Al Efishat
Department
Pharmacology
Focus Area
Healthcare
Mechanism of the Effect of Melatonin on Amyloid β: A Focus on Rho-associated Protein Kinase 1 (ROCK1)

Melatonin (N-acetyl-5-methoxytryptamine) is an important endogenous neurohormone produced by the pineal gland that possess both circuannual and circadian rhythms. Melatonin promotes sleep by acting as SCN to attenuate the wake‐promoting signal of the circadian clock and improves disruptions in circadian rhythm. Circadian disruptions have been reported to be associated with increased susceptibility to several metabolic diseases with inflammatory component such as type 2 diabetes, neurodegenerative diseases, and cancer and their complications. Some of these studies reported a 50–100% higher incidence of cancer among shift workers.

One of the consequences of advancing age is the decline in circulating levels of melatonin and circadian disruption. A number of studies suggested that in patients with low melatonin levels, melatonin replacement can be beneficial to treat patients with mild cognitive impairment, diabetic nephropathy, and sleep disorders. Several mechanisms have been suggested for the role of melatonin; endothelial to mesenchymal transition that leads to diabetic nephropathy have been reported to be inhibited by melatonin in the glomeruli of diabetic rats, this beneficial effect of exogenous melatonin was shown to be mediated via elevating miR-497 and suppressing Rho-associated protein kinase (ROCK) 1 and ROCK 2 activity. It has been concluded that melatonin has a neuroprotective effect via reducing the levels of amyloid β (Aβ), the neurotoxic compound that plays a central role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD).  The exact mechanism through which melatonin affect Aβ levels is not confirmed. Recently, using in vivo and in vitro models, ROCK 1 have been found to be elevated in AD, ROCK 1 depletion reduced Aβ levels in the brain. No studies have investigated the effect of melatonin on ROCK.

The aim of this project is to investigate whether the previously reported effect of melatonin on the Aβ levels is mediated through the ROCK. Primary cortical neurons and HEK293 cells will be used to study the effect of melatonin treatment on the Aβ levels, this will be investigated two states: baseline and post-treatment with melatonin on control cells those where ROCK1 activity has been significantly reduced or eliminated. We will use Western Blot analysis to determine protein expression levels for these cellular studies.

Mechanism of the Effect of Melatonin on Amyloid β: A Focus on Rho-associated Protein Kinase 1 (ROCK1)