In silico and in vitro analyses of a novel FoxO1 agonist reducing Aβ levels via downregulation of BACE1

Abstract

AimsFoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1‐specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molecules that upregulate the activity of FoxO1 to attenuate the symptoms of AD.MethodsFoxO1 agonists were identified by in silico screening and molecular dynamics simulation. Western blotting and reverse transcription‐quantitative polymerase chain reaction assays were used to assess protein and gene expression levels of P21, BIM, and PPARγ downstream of FoxO1 in SH‐SY5Y cells, respectively. Western blotting and enzyme‐linked immunoassays were performed to explore the effect of FoxO1 agonists on APP metabolism.ResultsN‐(3‐methylisothiazol‐5‐yl)‐2‐(2‐oxobenzo[d]oxazol‐3(2H)‐yl) acetamide (compound D) had the highest affinity for FoxO1. Compound D activated FoxO1 and regulated the expression of its downstream target genes, P21, BIM, and PPARγ. In SH‐SY5Y cells treated with compound D, BACE1 expression levels were downregulated, and the levels of Aβ1‐40 and Aβ1‐42 were also reduced.ConclusionsWe present a novel small‐molecule FoxO1 agonist with good anti‐AD effects. This study highlights a promising strategy for new drug discovery for AD.

FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

“…Furthermore, increased FoxO1 has been shown to reduce pathological AD features such as tau hyperphosphorylation and amyloid beta (Aβ) plaques ( 190 , 194 – 196 ). A recent study screened FoxO1 activators as potential therapeutics and demonstrated that one, Compound D, decreases Aβ1-40 and Aβ1-42 in SH-SY5Y cells ( 197 ). Additionally, exercise, an AD intervention, increases circulating FoxO1 in African American men with mild cognitive impairment ( 198 ), and upregulates FoxO1 to improve AD symptoms in early-onset AD mice ( 199 ).…”