title: The Ca2+ sensor S100A1 modulates neuroinflammation, histopathology and Akt activity in the PSAPP Alzheimer's disease mouse model.
abstract: The contribution of the Ca(2+) sensor S100A1 to in vivo Alzheimer's disease (AD) pathobiology has not been elucidated although S100A1 regulates numerous cellular processes linked to AD. This study uses genetic ablation to ascertain the effects of S100A1 on neuroinflammation, beta-amyloid (Aβ) plaque deposition and Akt activity in the PSAPP AD mouse model. PSAPP/S100A1(-/-) mice exhibited decreases in astrocytosis (GFAP burden), microgliosis (Iba1 burden) and plaque load/number when compared to PSAPP/S100A1(+/+) mice at six and twelve months of age. The presence of detectable S100A1 staining in human AD specimens is consistent with a detrimental gain of S100A1 function in AD. S100A1 ablation also reduced plaque associated and increased non-plaque associated PO4-Akt and PO4-GSK3β staining. S100A1·Akt complexes were undetectable in PC12 cells and AD brain tissue suggesting that S100A1 indirectly modulates Akt activity. In contrast, S100A1·RyR (ryanodine receptor) complexes were present in human/mouse AD brain and exhibited Ca(2+)-dependent formation in neuronal cells. This is the first direct demonstration of an S100A1· target protein complex in tissue/cells and identifies the RyR as a primary S100A1 target protein in the brain. Collectively, these data suggest that S100A1 inhibition may be a novel strategy for normalizing aberrant Ca(2+) signaling in AD.
authors.affiliation: Center for Biomolecular Therapeutics, Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Lauriaselle
authors.initials: L
authors.lastname: Afanador
authors.affiliation: LSU Health Science Center, School of Medicine, 1901 Perdido St., New Orleans, LA 70112, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Roltsch
authors.affiliation: Psychiatry and Behavioral Science, Texas A&M Health Science Center, College of Medicine, and Central Texas Veterans Health Care System Neuropsychiatry Research Program, Temple, TX, USA.
authors.forename: Leigh
authors.initials: L
authors.lastname: Holcomb
authors.affiliation: Center for Biomolecular Therapeutics, Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.affiliation: Center for Biomolecular Therapeutics, Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Keeling
authors.affiliation: Center for Biomolecular Therapeutics, Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Biomolecular Therapeutics, Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: dzimmer@som.umaryland.edu.
authors.forename: Danna B
authors.initials: DB
authors.lastname: Zimmer
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016716:PC12 Cells; D058225:Plaque, Amyloid / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; C110294:S100A1 protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D002118:Calcium
keywords: Astrocytosis; GSK3β; Microgliosis; Neurodegeneration; PC12 cells; Plaque load; Ryanodine receptor; S100B