Mutant β₁-adrenergic receptor improves REM sleep and ameliorates tau accumulation in a mouse model of tauopathy.

Abstract

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, <i>DEC2-P384R</i> and <i>Npsr1-Y206H</i>, are strong genetic modifiers of tauopathy in <i>PS19</i> 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, <i>Adrb1-A187V</i>, by crossing mice with this mutation onto the <i>PS19</i> background. We found that the <i>Adrb1-A187V</i> mutation helped restore rapid eye movement (REM) sleep and alleviated tau aggregation in a sleep-wake center, the locus coeruleus (LC), in <i>PS19</i> mice. We found that ADRB1⁺ neurons in the central amygdala (CeA) sent projections to the LC, and stimulating CeA^ADRB1+ neuron activity increased REM sleep. Furthermore, the mutant <i>Adrb1</i> attenuated tau spreading from the CeA to the LC. Our findings suggest that the <i>Adrb1-A187V</i> mutation protects against tauopathy by both mitigating tau accumulation and attenuating tau spreading.