Dysregulated Ribosomal Protein Synthesis in Amyloid and Tau Mouse Models

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Abstract It is known that protein homeostasis is impaired in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). A multitude of studies have indicated that the proteome is altered throughout the disease process, and ribosomal dysfunction occurs prior to advanced disease states. We have previously shown that de novo protein synthesis is impaired in APP/PS1 mutant mice, which express known human mutations associated with early-onset AD. Mounting evidence suggests changes in cell functioning occur decades prior to the development of symptoms in AD. In addition, the lack of success of clinical drug trials based on the amyloid hypothesis indicates greater understanding of the AD process is necessary to develop novel and effective therapies. To address these issues, we have used novel proteomic technology to label newly synthesized proteins in asymptomatic APP/PS1 mice, as well as symptomatic APP/PS1 mice that exhibit AD-like memory deficits. Our preliminary studies indicate that protein synthesis is dysregulated in these mice, and significant changes in the synthesis of protein components of the ribosome are observed even prior to symptom onset. As these findings may underlie the pathology of this proteopathy, we propose to investigate the impact of this ribosomal dysregulation and test our overall hypothesis that that age-dependent alterations observed in the synthesis of specific ribosomal proteins (RPs) in amyloid and tau model mice alter the translation of selective mRNAs that ultimately result in synaptic and memory impairments. Moreover, as RP synthesis has recently been shown to be dysregulated in the rTg4510 mouse model of AD- and FTD-like tauopathy, we hypothesize that alterations in RP synthesis in response to AD- and FTD-like tau dysregulation could impact ribosomal protein content, and similarly affect translational activity. We first will determine the RP content of functional ribosomes from asymptomatic and symptomatic APP/PS1 mice. Then, we will determine the translational activity of ribosomes from AD model mice. Finally, we will determine RP stoichiometry and translational activity of ribosomes from the K3 and PS19 mouse models of tauopathy and neurodegeneration. The results of these experiments will further our understanding of the neurodegenerative disease process, paving the way for similar investigations in AD and FTD patient cells, and subsequently identifying therapeutic targets for the treatment of AD and FTD.