A new neuroprotective candidate TJ1 targeting amyloidogenesis in 5xFAD Alzheimer's disease mice

As one of the main pathmechanisms of Alzheimer's disease (AD), amyloid-β (Aβ) is widely considered to be the prime target for the development of AD therapy. Recently, imidazolylacetophenone oxime ethers or esters (IOEs) have shown neuroprotective effects against neuronal cells damage, suggesting their potential use in the prevention and treatment of AD. Thirty IOEs compounds from our lab in-house library were constructed and screened for the inhibitory effects on Aβ₄₂-induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aβ₄₂-induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aβ₄₂ aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aβ₄₂-stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H₂O₂- and RSL3-stimulated PC12 cells. The cognitive improvement of TJ1 was assessed in 5xFAD (C57BL/6J) transgenic mouse. These results showed that TJ1 had strong neuroprotective effects and high blood-brain barrier (BBB) permeability without obvious cytotoxicity. TJ1 impeded the self-accumulation process of Aβ₄₂ by acting on Aβ oligomerization and fibrilization. Besides, TJ1 reversed Aβ-, H₂O₂- and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aβ₄₂ and Aβ plaques, and attenuated the glia reactivation and inflammatory response in the brain,. Taken together, our results demonstrate that TJ1 improves cognitive impairments as a new neuroprotective candidate via targeting amyloidogenesis, which suggests the potential of TJ1 as a treatment for AD.