Abstract
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with memory loss, but the AD-associated neuropathological changes begin years before memory impairments. Investigation of the early molecular abnormalities in AD might offer innovative opportunities to target memory impairment prior to onset. Decreased protein synthesis plays a fundamental role in AD, yet the consequences of this dysregulation for cellular function remain unknown. We hypothesize that alterations in the de novo proteome drive early metabolic alterations in the hippocampus that persist throughout AD progression. Using a combinatorial amino acid tagging approach to selectively label and enrich newly synthesized proteins, we found that the de novo proteome is disturbed in young APP/PS1 mice prior to symptom onset, affecting the synthesis of multiple components of the synaptic, lysosomal, and mitochondrial pathways. Furthermore, the synthesis of large clusters of ribosomal subunits were affected throughout development. Our data suggest that large-scale changes in protein synthesis could underlie cellular dysfunction in AD.
Highlights
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with memory loss, but the AD-associated neuropathological changes begin years before memory impairments
Previous studies using puromycin and azidohomoalanine (AHA) incorporation to label newly synthesized proteins in mice modeling aspects of AD pathology demonstrated a reduction in de novo protein synthesis[15,21,22,30,31], and the translation efficiency of polyribosomes isolated from the mild cognitive impairment (MCI) and end-stage AD brain is reduced by >60% in affected cortical areas[17]
Translation is impaired throughout the AD process[10,11,12,13,14,15,16,17] and de novo protein synthesis is decreased in mouse lines that model various aspects of AD pathology[15,21,31]
Summary
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with memory loss, but the AD-associated neuropathological changes begin years before memory impairments. MRNA is translated to a polypeptide chain via ribosomal activity, a process that in neurons occurs both somatically and locally in projections[8] This de novo protein synthesis is a dynamic process that is necessary for basal neuronal function, responds to stimuli that induced longlasting plasticity and is required for memory consolidation[9,10]. In. AD, multiple studies have observed dysregulation of translation throughout the disease process, as indicated by changes in p70 S6 kinase 1, eukaryotic initiation factors 2 alpha (eIF2α) and 4E (eIF4E) phosphorylation[11,12,13,14,15,16], as well as decreased ribosomal function[3,17,18,19]. When monitored in APP/PS1 mutant mice, which express familial AD-
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