title: Tolfenamic acid interrupts the de novo synthesis of the β-amyloid precursor protein and lowers amyloid beta via a transcriptional pathway.
abstract: Amyloid beta (Aβ) peptides are related to the pathogenesis of Alzheimer's disease (AD). The search for therapeutic strategies that lower these peptides has mainly focused on the proteolytic processing of the β-amyloid precursor protein (APP), and other post-transcriptional pathways. The transcription factor specificity protein 1 (Sp1) is vital for the regulation of several genes involved in AD including APP and the beta site APP cleaving enzyme 1 (BACE1). We have previously reported that tolfenamic acid promotes the degradation of Sp1 protein (SP1) in pancreatic human cancer cells and mice tumors. This study examines the ability of tolfenamic acid to reduce SP1 levels, and thereby decrease APP transcription and Aβ levels in rodent brains. Tolfenamic acid was administered by oral gavage to C57BL/6 mice at variable dosages and for different time periods. Results have shown that tolfenamic acid was able to down regulate brain protein levels of SP1, APP, and Aβ. These findings demonstrate that interference with upstream transcriptional pathways can lower pathogenic intermediates associated with AD, and thus tolfenamic acid represents a novel approach for the development of a therapeutic intervention for AD.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: L I
authors.initials: LI
authors.lastname: Adwan
authors.forename: R
authors.initials: R
authors.lastname: Basha
authors.forename: M
authors.initials: M
authors.lastname: Abdelrahim
authors.forename: G M
authors.initials: GM
authors.lastname: Subaiea
authors.forename: N H
authors.initials: NH
authors.lastname: Zawia
mesh_terms: D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid