Priming the proteasome to protect against aging and Alzheimer's disease

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PROJECT SUMMARY Alzheimer’s disease (AD) is the most common cause of dementia that affects million people and poses a serious financial burden to the nation. However, to develop effective therapeutics for AD has been a challenge. To date, no effective treatment is available to either prevent the disease or halt its progression. A major hurdle for this is the lack of reliable therapeutic targets for the disease. AD is associated with accumulation of misfolded proteins including senile (Aβ) plaques and neurofibrillary tangles. It remains unclear how these protein accumulations occur and what roles they play in the pathogenesis of AD. Additionally, AD is a multifactorial disease exhibiting symptoms both in the brain and heart. However, the temporal relationship between the peripheral symptoms to AD pathogenesis remains unknown. In response to the NOT-AG-18-051 from the National Institute on Aging, we propose to study the role of a key phosphoregulation of the proteasome in aging and AD. Specifically, we will determine whether changes in proteasome functionality, through increase or decrease of Rpn6 phosphorylation at the serine-14 residue (Ser14-Rpn6 phosphorylation), alter aging process and AD pathogenesis in both the brain and heart. Two unique mouse knock-in models, phosphorylation mimicry and phosphorylation blockade at Ser14-Rpn6, will be studied at baseline and when crossed with an AD mouse model to generate the phosphorylation mimicry-AD and phosphorylation blockade- AD mice. Furthermore, the contribution of proteasome activation by PKA to the therapeutic benefits to the brain and heart of AD animals exerted by a pharmacological strategy that can augment cAMP/PKA signaling and increase Ser14-Rpn6 phosphorylation and proteasome activities in both the brain and heart will be determined. This work will lead to significant mechanistic insight into a key phosphoregulation of the proteasome in protection against aging and AD. Success of this work can also advance the mechanistic understanding of a clinically translatable therapeutic strategy for the disease.