Dysregulation of the de novo proteome accompanies pathology progression in the APP/PS1 mouse model of Alzheimer's disease

Abstract

Alzheimers disease (AD) is an age-related neurodegenerative disorder, but neuropathological changes in AD begin years before memory impairment. Investigation of the early molecular abnormalities in AD might offer innovative opportunities to target memory impairment prior to its onset. Decreased protein synthesis plays a fundamental role in AD, yet the consequences for cellular function remain unknown. We hypothesize that alterations in the de novo proteome drive early metabolic changes in the hippocampus that persist throughout AD progression. Using a combinatorial amino acid tagging approach to selectively label newly synthesized proteins, we found that the de novo proteome is disturbed in APP/PS1 mice prior to pathology development, affecting the synthesis of multiple components of synaptic, lysosomal and mitochondrial pathways. Furthermore, the synthesis of large clusters of ribosomal subunits were affected throughout neuropathology development in these mice. Our data suggest that large-scale changes in protein synthesis could underlie cellular dysfunction in AD.