Abstract Body: Background
Alzheimer’s disease (AD) patients often display not only cognitive impairment but also cardiac malfunction, but the underlying factors remain elusive. Phosphorylation of Ser14 of RPN6 (p-S14-RPN6) is required for cAMP/protein kinase A (PKA) to activate 26S proteasomes. Proteasome priming is implicated in the protection by cAMP-PKA augmentation against AD, but this remains to be established. Hence, we conducted this study to address these critical gaps.

Methods
The Rpn6^S14A knock-in mice recently created for genetic blockade of p-S14-Rpn6 were crossbred with the PS19 tauopathy model (Jackson Lab Stock # 008169). Littermate wild type (WT), PS19, and PS19::S14A mice were compared. Cardiac function was evaluated with echocardiography (Echo). Hippocampal and myocardial tissues were used for western blot analyses (WB) and histopathology.

Results
Increases in hippocampal insoluble tau proteins and in total and K48-linked ubiquitin conjugates were markedly greater in PS19::S14A mice than PS19 and WT mice. WBs for PSD95, synaptotagmin, Neu N, GFAP, and IBA1 revealed exacerbated synaptic loss, neuronal loss, gliosis, and microglial activation in the hippocampus of PS19::S14A mice in comparison to PS19 and WT mice. A more significant decline in cognitive function indicated by object recognition index was found in PS19::S14A mice vs. PS19 mice at 6 months. More interestingly, as compared to PS19 and WT littermates, PS19::S14A mice showed greater increases in myocardial tau proteins, ubiquitin conjugates, and cleaved caspase 3 and displayed more cardiac fibrosis, as reflected by increased mRNA expression of collagen 1 and picrosirius red staining. Echo revealed that PS19::S14A had significantly reduced fractional shortening, ejection fraction, stroke volume, and cardiac output at 9 months.

Conclusions
The findings of this study demonstrate that genetic blockade of p-S14-RPN6 exacerbates tauopathy pathology in both the brain and heart. This is the first to have established the role of p-S14-RPN6 and, by extension, the significance of PKA-mediated proteasome activation in AD/tauopathy. Proteasome activation via augmentation of cAMP/PKA signaling should be explored for the alleviation of AD-associated brain and cardiac pathologies.