Nonchimeric polytransgenic 152F7 mice encompassing four human chromosome 21 genes (DSCR3, DSCR5, TTC3, and DYRK1A) within the Down syndrome critical region present with learning and memory impairment. However, no abnormalities were shown by in vitro electrophysiological or neuroanatomical findings in hippocampus of 152F7 mice. To search for molecular changes that may be linked to cognitive impairment, we compared hippocampal protein levels between nontransgenic (WT) and 152F7 mice by a proteomic approach. Protein extracts were run on two-dimensional gel electrophoresis, protein spots were analyzed by mass spectrometry (MALDI-TOF-TOF) followed by quantification by specific software. Three hundred and nineteen different gene products were identified, and 48 proteins were assigned as signaling-related proteins. Stringent statistical analysis considering P < 0.005 as statistically significant based upon multiple testing revealed that growth factor receptor-bound protein 2 (Grb2) levels were decreased and an expression form of fascin 1 was increased in 152F7 mice when compared with WT. A series of proteins showed trends for increased and decreased hippocampal levels (P > 0.005 and P < 0.05). Only 2 out of 319 different gene products were dysregulated, pointing to the specificity of the analysis. Decreased Grb2 levels in the hippocampus of 152F7 mice may contribute to impaired cytoskeleton functions because dynamin 1 binds to Grb2 and involved in the formation of the endocytic process. Fascin dysregulation is of relevance for actin bundling in vesicle trafficking and may represent or lead to impaired neurotransmission that, in turn, may lead to the cognitive defect observed in this mouse model of Down syndrome.
(c) 2007 Wiley-Liss, Inc.