Homeostatic Activation of 26S Proteasomes by Protein Kinase A Protects against Cardiac and Neurobehavior Malfunction in Alzheimer’s Disease Mice

Alzheimer’s Disease (AD) patients often show brain and cardiac malfunction. AD represents a leading cause of morbidity and mortality worldwide, but the demand for effective treatment for AD is far from being met. This is primarily because AD pathogenesis, including brain-heart interaction, is poorly understood. Proteasome functional insufficiency is implicated in AD; as such, proteasome enhancement promises a potentially new strategy to treat AD. The proteasome can be activated by protein kinase A (PKA) via selectively phosphorylating Ser14-RPN6/PSMD11 (p-S14-RPN6); however, whether p-S14-RPN6 is altered and what role p-S14-RPN6 plays in AD remain unclear. Hence, this study was conducted to address these critical gaps. We found that genetic blockade of the homeostatic p-S14-Rpn6 via germline knock-in of Rpn6 ^S14A (referred to as S14A) significantly reduced proteasome activities in the cerebral cortex but did not discernibly impair learning and memory function in 4-month-old mice or cause cardiac dysfunction before 12 months of age. Increases in Ser14-phosphorylated Rpn6 in the cerebral cortex and markedly elevated Aβ proteins in the myocardium were observed in young 5XFAD mice, a commonly used AD model. When introduced into the 5XFAD mice, S14A significantly aggravated the learning and memory deficits as revealed by the radial arm water maze tests and accelerated cardiac malfunction as measured by serial echocardiography in the same cohort of 5XFAD mice. Thus, the present study establishes for the first time that homeostatic activation of 26S proteasomes by basal p-S14-RPN6 or PKA activity protects against both the brain and heart malfunction in the 5XFAD mice.