Shotgun brain proteomics reveals early molecular signature in presymptomatic mouse model of Alzheimer's disease

J Alzheimers Dis. 2013;37(2):297-308. doi: 10.3233/JAD-130476.


AβpE3-42 (N-terminal truncated amyloid-β peptide starting with pyroglutamate at the third position) is abundant in Alzheimer's disease (AD) brain and has high aggregation propensity and cellular toxicity. Transgenic TBA42 mice expressing AβpE3-42 exhibit a neurological phenotype evident at the age of 12 months. As AD has a long presymptomatic period, early detection of imminent neurodegeneration is highly desirable. In the present work we used four-month-old presymptomatic TBA42 mice and performed a whole-brain proteome analysis in order to elucidate early AD-related pathological changes and the molecular networks involved. At least three proteins were found to be moderately (by 17% to 28%) but statistically significantly upregulated, including: nectin-like molecule 1 involved in cell-cell adhesion; Homer proteins involved in scaffolding, organizing proteins at synapse and regulating intracellular calcium within neurons; and inositol-trisphosphate 3-kinase A, which is important for InsP3 induced calcium signaling in the brain. Analysis of key nodes (regulatory molecules found on pathway intersections) identified Rho-kinase (ROCK), a serine/threonine kinase and one of the major downstream effectors of the small GTPase Rho, as well as three key nodes of the mTOR/p70S6K signaling pathway previously implicated in multiple fundamental biological processes including synaptic plasticity, and upregulated in AD. These data confirm that AD-typical molecular pathways can be detected by whole-brain shotgun proteomics in young presymptomatic mice long before the onset of behavioral changes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism*
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptide Fragments / metabolism
  • Principal Component Analysis
  • Protein Interaction Mapping
  • Proteomics / methods*
  • Signal Transduction
  • Tandem Mass Spectrometry
  • Thyrotropin-Releasing Hormone / genetics
  • rho-Associated Kinases / metabolism


  • Amyloid beta-Peptides
  • Cell Adhesion Molecules, Neuronal
  • Peptide Fragments
  • amyloid beta-protein (3-42), pyroglutamyl(3)-
  • Thyrotropin-Releasing Hormone
  • Inositol 1,4,5-Trisphosphate
  • Rock1 protein, mouse
  • rho-Associated Kinases