Mutant & beta;1-adrenergic receptor improves REM sleep and ameliorates tau accumulation in a mouse model of tauopathy

Sleep is essential for our well-being, and chronic sleep deprivation has unfavorable health consequences. We recently demonstrated that two familial natural short sleep (FNSS) mutations, DEC2-P384R and Npsr1-Y206H, are strong genetic modifiers of tauopathy in PS19 mice, a model of tauopathy. To gain more insight into how FNSS variants modify the tau phenotype, we tested the effect of another FNSS gene variant, Adrb1-A187V, by crossing mice with this mutation onto the PS19 background. We found that the Adrb1-A187V mutation helped restore rapid eye movement (REM) sleep and alleviated tau aggregation in a sleep-wake center, the locus coeruleus (LC), in PS19 mice. We found that ADRB1+ neurons in the central amygdala (CeA) sent projections to the LC, and stimulating CeAADRB1+ neuron activity increased REM sleep. Furthermore, the mutant Adrb1 attenuated tau spreading from the CeA to the LC. Our findings suggest that the Adrb1-A187Vmutation protects against tauopathy by both mitigating tau accumulation and attenuating tau spreading.

Automated summary

Sleep is important for well-being, and chronic sleep deprivation has negative health consequences. Two familial natural short sleep (FNSS) mutations, DEC2-P384R and Npsr1-Y206H, modify tauopathy in PS19 mice. This study investigated the effect of another FNSS gene variant, Adrb1-A187V, on tau pathology in PS19 mice. The Adrb1-A187V mutation improved REM sleep and reduced tau aggregation in the locus coeruleus (LC) in PS19 mice. ADRB1+ neurons in the central amygdala (CeA) projected to the LC, and stimulating CeAADRB1+ neuronal activity increased REM sleep. Additionally, the Adrb1 mutation attenuated tau spreading from the CeA to the LC, suggesting that it protects against tauopathy by reducing tau accumulation and propagation.