Tolfenamic acid downregulates BACE1 and protects against lead-induced upregulation of Alzheimer's disease related biomarkers.
Environmental exposure to lead (Pb) early in life results in a latent upregulation of genes and products associated with Alzheimer's disease (AD), particularly the plaque forming protein amyloid beta (Aβ). Furthermore, animals exposed to Pb as infants develop cognitive decline and memory impairments in old age. Studies from our lab demonstrated that tolfenamic acid lowers the levels of the amyloid β precursor protein (APP) and its aggregative cleavage product Aβ by inducing the degradation of the transcription factor specificity protein 1 (Sp1). These changes were accompanied by cognitive improvement in transgenic APP knock-in mice. In this study, we examined the effects of tolfenamic acid on beta site APP cleaving enzyme 1 (BACE1) which is responsible for Aβ production and tested its ability to reverse Pb-induced upregulation in the amyloidogenic pathway. Mice were administered tolfenamic acid for one month and BACE1 gene expression as well as its enzymatic activity were analyzed in the cerebral cortex. Tolfenamic acid was also tested for its ability to reverse changes in Sp1, APP and Aβ that were upregulated by Pb in vitro. Differentiated SH-SY5Y neuroblastoma cells were either left unexposed, or sequentially exposed to Pb followed by tolfenamic acid. Our results show that tolfenamic acid reduced BACE1 gene expression and enzyme activity in mice. In neuroblastoma cells, Pb upregulated Sp1, APP and Aβ, while tolfenamic acid lowered their expression. These results along with previous data from our lab provide evidence that tolfenamic acid, a drug that has been used for decades for migraine, represents a candidate which can reduce the pathology of AD and may mitigate the damage of environmental risk factors associated with this disease.
Department of Biomedical & Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA.
Lina
L
Adwan
Department of Biomedical & Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA.
Gehad M
GM
Subaiea
Department of Biomedical & Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA; Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI, USA. Electronic address: nzawia@uri.edu.
Nasser H
NH
Zawia
D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007854:Lead / Q000633:toxicity; D020263:Lead Poisoning, Nervous System / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D018696:Neuroprotective Agents; D016329:Sp1 Transcription Factor; D062367:ortho-Aminobenzoates; D007854:Lead; C009500:tolfenamic acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse
Alzheimer's disease; Amyloid beta; BACE1; Pb; Sp1; Tolfenamic acid