Alzheimer's disease (AD) is a
neurodegenerative disease displaying extracellular plaques formed by the neurotoxic
amyloid β-
peptide (Aβ), and intracellular neurofibrillary tangles consisting of
protein tau. However, how these pathologies relate to the massive neuronal death that occurs in AD brains remain elusive.
Neprilysin is the major Aβ-degrading
enzyme and a lack thereof increases Aβ levels in the brain twofold. To identify altered
protein expression levels induced by increased Aβ levels, we performed a proteomic analysis of the brain of the AD mouse model APPsw and compared it to that of APPsw mice lacking
neprilysin. To this end we established an LC-MS/MS method to analyze brain homogenate, using an (18) O-labeled internal standard to accurately quantify the
protein levels. To distinguish between alterations in
protein levels caused by increased Aβ levels and those induced by
neprilysin deficiency independently of Aβ, the brain
proteome of
neprilysin deficient APPsw mice was also compared to that of
neprilysin deficient mice. By this approach we identified approximately 600
proteins and the levels of 300 of these were quantified. Pathway analysis showed that many of the
proteins with altered expression were involved in
neurological disorders, and that tau,
presenilin and APP were key regulators in the identified networks. The data have been deposited to the ProteomeXchange Consortium with identifiers PXD000968 and PXD001786 (http://proteomecentral.proteomexchange.org/dataset/PXD000968 and (http://proteomecentral.proteomexchange.org/dataset/PXD001786). Interestingly, the levels of several
proteins, including some not previously reported to be linked to AD, were associated with increased Aβ levels.