Alzheimer's amyloidosis induces global changes in protein homeostasis in the brains of transgenic mice

Abstract

Background: The deposition of amyloid beta peptide (Ab) is viewed as a key trigger in the early pathogenesis of Alzheimer’s Disease (AD) that precedes or is coincident with the appearance of intracellular neurofibrillary tangles (NFTs). The latter pathology could be viewed as evidence for alterations protein homeostasis. Transgenic mice that model Alzheimer-type amyloidosis do not develop NFTs, providing a means to specifically assess whether amyloid deposition impacts protein homeostasis. Methods: Using a heat-shock model of cultured cells we determined that loss of protein solubility and an accumulation of polyubiquitin chains linked via lysine 48 residues, indicating an accumulation of excess proteasome substrates, are key biomarkers of altered protein homeostasis. We then use mass spectrometry approaches to determine whether these biomarkers were present in the brains of mice that model Alzheimer amyloidosis. Results: We identified numerous cytosolic proteins that show specific losses insolubility in the brains of mice with high amyloid burden. Importantly we also detected an accumulation of lysine 48 linked polyubiquitin in these animals. Conclusions: We conclude that amyloid deposition is sufficient to trigger changes in intracellular protein homeostasis and as such could be a critical component of the amyloid cascade.