S100A1 and S100B: Novel Drug Targets for Alzheimer's Disease Therapy
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Numerous factors/gene products, including S100A1 and S100B, have been implicated in the onset and progression of Alzheimer's disease (AD). However, deciphering S100A1/S100B's role in AD has been hampered by their antipodal effects and ability to act as both intracellular calcium receptors and secreted neuropeptides. This study utilizes two approaches, genetic ablation and passive immunotherapy, to inhibit S100A1 and/or S100B in the PSAPP AD mouse model to ascertain the net contribution of these proteins to AD pathology. In addition, a combination of microarray profiling, post-array validation and bioinformatics were used to identify changes in miRNA expression in response to S100A1/S100B ablation. In 6 month old mice, S100B ablation resulted in a 3-fold decrease in cortical but not hippocampal plaque load while S100A1 ablation resulted in a 3.5-fold reduction in cortical and a 2.4-fold reduction in hippocampal plaque load. Interestingly, ablation of both S100A1 and S100B was synergistic resulting in an age-, region- and end point- specific manner. Diminished plaque load was accompanied by decreased GFAP-positive astrocytes and Iba-1 positive microglia. The effects of S100A1/S100B on plaque load were not limited to early stages of plaque deposition. Even though older (12 month old) PSAPP animals had over 6-fold increase in plaque load, S100A1 or S100A1/S100B ablation still diminished cortical/hippocampal plaque load by 60-65%. Similar results were observed when passive immunotherapy was used to inhibit S100A1/S100B function. Anti-S100 treatment of mice from 3-6 months of age decreased cortical/hippocampal plaque load, and decreased cortical but not hippocampal GFAP staining. The effects of passive immunotherapy with S100A1/S100B antibodies were not limited to pre-plaque treatment. Anti-S100 treated mice from 6-9 months of age exhibited decreased cortical, but not hippocampal, plaque load and cortical/hippocampal GFAP staining. In addition, these S100A1/S100B mediated decreases were accompanied by downregulated expression of miR- 448, miR-133a, miR-204, and miR-206 as well as upregulated expression of miR-34a. Collectively, these data demonstrate that inhibition of S100A1 and S100B synergistically reduce AD pathology and suggest that the detrimental gain of function of S100A1/S100B contributes to AD. Therefore, development of drugs to inhibit S100 function in patients will be beneficial in the treatment of AD and slowing disease progression.
Roltsch, Emily 1983- (2011). S100A1 and S100B: Novel Drug Targets for Alzheimer's Disease Therapy. Doctoral dissertation, Texas A & M University. Available electronically from