ABSTRACT
Accumulation of tau protein aggregation plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). Uncontrollable neuroinflammation and tau pathology form a vicious circle that further aggravates AD progression. Herein, we reported the synthesis of usnic acid derivatives and evaluation of their inhibitory activities against tau-aggregation and neuroinflammation. The inhibitory activity of the derivatives against the self-fibrillation of the hexapeptide AcPHF6 was initially screened by ThT fluorescence assay. Using circular dichroism and transmission electron microscopy, compound 30 showed the most potent inhibitory activity against AcPHF6 self-fibrillation. Compound 30 was further confirmed to inhibit the aggregation of full-length 2N4R tau protein by a heparin-induced mechanism. In addition, we investigated the anti-inflammatory activity of compound 30, and showed that compared with sodium usnate, it reduced NO release in LPS-stimulated mouse microglia BV2 cells. More importantly, 30 showed significant protective effects against okadaic acid-induced memory impairment in rats. Thus, 30 was a novel tau-aggregation and neuroinflammation inhibitor that represented a potential therapeutic candidate for AD.
Subject(s)
Alzheimer Disease/drug therapy , Benzofurans/pharmacology , Inflammation/drug therapy , Maze Learning/drug effects , tau Proteins/antagonists & inhibitors , Alzheimer Disease/metabolism , Animals , Benzofurans/chemical synthesis , Benzofurans/chemistry , Cell Line, Tumor , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Inflammation/metabolism , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Male , Mice , Models, Molecular , Molecular Structure , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Protein Aggregates/drug effects , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , tau Proteins/metabolismABSTRACT
The formation of amyloid-ß (Aß) plaques in the brain is one of the main pathological features of Alzheimer's disease (AD). The imaging probes, capable of detecting Aß deposition, are important tools for early diagnosis of AD. In this article, we designed, synthesized and evaluated a cyanine-based near-infrared fluorescence (NIRF) probe ZT-1 for the detection of Aß deposits in the brain. The probe had excellent fluorescent properties with an emission maximum above 720â¯nm upon binding to Aß aggregates with affinity of 445.0â¯nM (Kd). Furthermore, ZT-1 exhibited good biostability, photostability, and binding selectivity toward Aß1-42 aggregates by in vitro fluorescence staining experiments. In vivo NIRF imaging result also revealed that our probe could efficiently differentiate transgenic and wild-type mice. All these studies indicated that ZT-1 is a promising fluorescent probe for Aß plaques in the AD brains.
