Ser14-phosphorylated Rpn6 Limits Proteostasis Impairment and Pathology in Both Brain and Heart of Tauopathy Mice

Alzheimer's disease (AD) patients often display neurobehavioral and cardiac impairments, but the underlying factors remain unclear. Ser14 phosphorylation in RPN6 (p-S14-RPN6) mediates the activation of 26S proteasomes by protein kinase A (PKA). Proteasome priming is implicated in protection by cAMP-PKA against AD, but this remains to be established. Hence, this study was conducted to interrogate homeostatic p-S14-RPN6 in AD. The recently validated Rpn6 ^S14A knock-in (S14A) mice were crossbred with the PS19 tauopathy mice (RRID: IMSR_JAX:008169). The resultant wild type (WT), PS19, and PS19::S14A littermates were compared. Expedited declines in cognitive and motor functions as indicated respectively by significant decreases in object recognition and discrimination indexes and rotarod time were observed in PS19::S14A mice vs. PS19 mice, which is associated with more pronounced synaptic losses, microglial activation, and gliosis in the hippocampus. Compared with WT and PS19 mice, PS19::S14A mice showed exacerbated cardiac malfunction, cardiac hypertrophic responses and fibrosis, and greater increases of total and hyperphosphorylated tau proteins and ubiquitin conjugates in both hippocampi and hearts. These findings demonstrate that genetic blockade of p-S14-RPN6 exacerbates tauopathy in both the brain and heart, which for the first time establishes that homeostatic p-S14-RPN6 promotes proteostasis and protects against pathogenesis in AD.