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S100A1 modulates inflammation and PI3/Akt signaling
Author(s) -
Zimmer Danna B,
Keeling David,
Campbell Kerry,
Campbell Katie,
Afanador Lauriaselle
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb516
Subject(s) - protein kinase b , phosphorylation , microbiology and biotechnology , signal transduction , pi3k/akt/mtor pathway , biology , cancer research , chemistry
The Ca 2+ sensor protein S100A1 regulates numerous processes involved in Alzheimer's disease (AD) that include Ca 2+ homeostasis, APP expression, tau phosphorylation, Aβ toxicity, synaptogenesis, neuronal survival and cognitive function. Nonetheless, S100A1's contribution to AD pathobiology has not been elucidated. This study uses genetic ablation in an AD mouse model (PSAPP) and neuronal cell line (PC12) to ascertain the effects of S100A1 inhibition on AD pathobiology. In PC12 cells, S100A1 ablation resulted in a 2‐fold increase in phospho‐Akt and phsopho‐GSK3β levels. Since Akt has an S100 binding motif, these results are most likely attributable to a direct interaction between S100A1 and Akt. In the PSAPP mouse model, S100A1 ablation also increased phospho‐Akt levels but decreased plaque‐associated Akt staining. These changes were accompanied by beneficial reductions in microgliosis (Iba1 burden), astrocytosis (GFAP burden) and plaque load/burden. This is the first report that S100A1 regulates PI3/Akt signaling in neuronal cells and is pro‐inflammatory in AD. Studies are underway to identify other downstream events regulated by S100A1‐Akt‐GSK3β signaling in neuronal cells and AD. Collectively, these data suggest that S100A1 inhibition may be a novel strategy for AD drug development. Supported by the Center for Biomolecular Therapeutics.