Abstract
Several cellular pathways contribute to neurodegenerative tauopathy-related disorders. Microglial activation, a major component of neuroinflammation, is an early pathological hallmark that correlates with cognitive decline, while the unfolded protein response (UPR) contributes to synaptic pathology. Sleep disturbances are prevalent in tauopathies and may also contribute to disease progression. Few studies have investigated whether manipulations of sleep influence cellular pathological and behavioural features of tauopathy. We investigated whether trazodone, a licensed antidepressant with hypnotic efficacy in dementia, can reduce disease-related cellular pathways and improve memory and sleep in male rTg4510 mice with a tauopathy-like phenotype. In a 9-week dosing regimen, trazodone decreased microglial NLRP3 inflammasome expression and phosphorylated p38mitogen-activated protein kinase levels which correlated with the NLRP3 inflammasome, the UPR effector ATF4, and total tau levels. Trazodone reduced theta oscillations during REM sleep and enhanced rapid eye movement (REM) sleep duration. Olfactory memory transiently improved, and memory performance correlated with REM sleep duration and theta oscillations. These findings on the effects of trazodone on the NLRP3 inflammasome, the unfolded protein response and behavioural hallmarks of dementia warrant further studies on the therapeutic value of sleep-modulating compounds for tauopathies.