The Impact of REM Sleep Deprivation on ER Stress and Alzheimer-Like Pathology: Therapeutic Potential of Melatonin.

REM sleep deprivation (REMSD) contributes to neurodegenerative diseases like Alzheimer’s Disease (AD). This study examined REMSD’s effects on cognition, ER stress, and AD-like pathology in rats, alongside melatonin’s therapeutic potential. REMSD was induced for six days using the modified multiple platform method (MMPM). Cognitive function was tested via the Morris Water Maze (MWM). Rats received melatonin (20 mg/kg), 4-PBA (as a positive control, 100 mg/kg), or vehicle during deprivation/recovery periods. Western blotting and ELISA assessed ER stress markers (BiP, pIRE1, pPERK, peIF2-α, CHOP and GRP94, GADD34), Alzheimer related molecules (Aβ40/42, Tau, APP, GSK3β) and apoptosis-related proteins (Caspase 2, Caspase 12, BAX/Bcl-2). In addition, the mRNA expression levels of ATF4 and ATF6 were determined by PCR. Recovery sleep restored cognition, but melatonin/4-PBA enhanced it further. REMSD was associated with increased ER stress and AD-like pathology, whereas melatonin and 4-PBA appeared to attenuate these alterations, possibly by influencing the unfolded protein response (UPR) and reducing protein misfolding. Melatonin shows promise in countering SD-associated neurodegeneration, highlighting sleep’s role in proteostasis and its potential clinical use in AD and protein-misfolding disorders.