Tolfenamic acid downregulates BACE1 and protects against lead-induced upregulation of Alzheimer's disease related biomarkers

•The effects of tolfenamic acid exposure on amyloid pathology in vivo and in vitro.•Tolfenamic acid lowers the transcription and activity of the enzyme BACE1 in vivo.•Tolfenamic acid protects against Pb-induced increases in APP and Aβ in vitro.•Tolfenamic acid is a multi-target drug that can be repurposed for AD.•This is a novel approach for counteracting environmentally-induced AD pathogenesis.

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.