title: Transcription factor Sp1 inhibition, memory, and cytokines in a mouse model of Alzheimer's disease.
abstract: Transcription factors are involved to varying extents in the health and survival of neurons in the brain and a better understanding of their roles with respect to the pathogenesis of Alzheimer's disease (AD) could lead to the development of additional treatment strategies. Sp1 is a transcription factor that responds to inflammatory signals occurring in the AD brain. It is known to regulate genes with demonstrated importance in AD, and we have previously found it upregulated in the AD brain and in brains of transgenic AD model mice. To better understand the role of Sp1 in AD, we tested whether we could affect memory function (measured with a battery of behavioral tests discriminating different aspects of cognitive function) in a transgenic model of AD by pharmaceutical modulation of Sp1. We found that inhibition of Sp1 function in transgenic AD model mice increased memory deficits, while there were no changes in sensorimotor or anxiety tests. Aβ42 and Aβ40 peptide levels were significantly higher in the treated mice, indicating that Sp1 elevation in AD could be a functionally protective response. Circulating levels of CXCL1 (KC) decreased following treatment with mithramycin, while a battery of other cytokines, including IL-1α, IL-6, INF-γ and MCP-1, were unchanged. Gene expression levels for several genes important to neuronal health were determined by qRT-PCR, and none of these appeared to change at the transcriptional level.
authors.affiliation: Laboratory of Molecular Biology, Research and Development 151, Bay Pines VA Healthcare SystemBay Pines, FL 33744; Department of Molecular Medicine, USF Morsani College of MedicineTampa, FL 33612.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Citron
authors.affiliation: Laboratory of Molecular Biology, Research and Development 151, Bay Pines VA Healthcare SystemBay Pines, FL 33744; Department of Molecular Medicine, USF Morsani College of MedicineTampa, FL 33612.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Saykally
authors.affiliation: Department of Pharmaceutical Sciences, USF College of PharmacyTampa FL 33612; USF-Health Byrd Alzheimer's Institute, USFTampa, FL 33613.
authors.forename: Chuanhai
authors.initials: C
authors.lastname: Cao
authors.affiliation: Laboratory of Molecular Biology, Research and Development 151, Bay Pines VA Healthcare System Bay Pines, FL 33744.
authors.forename: John S
authors.initials: JS
authors.lastname: Dennis
authors.affiliation: Department of Cellular and Molecular Biology, USF Tampa, FL 33620.
authors.forename: Melissa
authors.initials: M
authors.lastname: Runfeldt
authors.affiliation: Department of Cellular and Molecular Biology, USFTampa, FL 33620; Current Address: NeuroEM Therapeutics, Inc.Phoenix, AZ 85022.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Arendash
keywords: Alzheimer’s disease; Sp1; cognitive function; gene expression; neurodegeneration; neurons; transcription factor; transgenic mice