title: Mithramycin A Alleviates Cognitive Deficits and Reduces Neuropathology in a Transgenic Mouse Model of Alzheimer's Disease.
abstract: Increasing evidence has shown that specificity protein 1 (Sp1) is abnormally increased in the brains of subjects with Alzheimer's disease (AD) and transgenic AD models. However, whether the Sp1 activation plays a critical role in the AD pathogenesis and selective inhibition of Sp1 activation may have a disease-modifying effect on the AD-like phenotypes remain elusive. In this study, we reported that Sp1 mRNA and protein expression were markedly increased in the brain of APPswe/PS1dE9 transgenic mice, whereas chronic administration of mithramycin A (MTM), a selective Sp1 inhibitor, potently inhibited Sp1 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, we found that MTM treatment resulted in a significant improvement of learning and memory deficits, a dramatic reduction in cerebral Aβ levels and plaque burden, a profound reduction in tau hyperphosphorylation, and a marked increase in synaptic marker in the APPswe/PS1dE9 mice. In addition, MTM treatment was powerfully effective in inhibiting amyloid precursor protein (APP) processing via suppressing APP, beta-site APP cleaving enzyme 1 (BACE1), and presenilin-1 (PS1) mRNA and protein expression to preclude Aβ production in the APPswe/PS1dE9 mice. Furthermore, MTM treatment strongly inhibited phosphorylated CDK5 and GSK3β signal pathways to reduce tau hyperphosphorylation in the APPswe/PS1dE9 mice. Collectively, our findings provide evidence that Sp1 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. The present study highlights that selective Sp1 inhibitors may be considered as disease-modifying therapeutic agents for AD.
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.|Institute of Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.|Institute of Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.|Institute of Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.|Institute of Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China. lizhuyi@fmmu.edu.cn.|Institute of Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China. lizhuyi@fmmu.edu.cn.
authors.forename: Zhuyi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China. jtmiao@fmmu.edu.cn.
authors.forename: Jianting
authors.initials: J
authors.lastname: Miao
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D016329:Sp1 Transcription Factor; C066851:mithramycin A; D008926:Plicamycin
keywords: Alzheimer’s disease; Cognitive deficits; Mithramycin A; Specificity protein 1; Tau hyperphosphorylation; β-amyloid protein