Screening Of A Novel Inhibitor Of Glutaminyl Cyclase And Its Anti AD Effect In Vivo

Alzheimer’s disease(AD) is a kind of more heterogeneous disease, there is still not successful drug to treat AD. With the rapid development of population aging, the incidence of AD is getting higher and higher, and the prevention and treatment of AD has become the focus of global attention. Abeta plaque is an important cause of AD in the traditional theory(β-Amyloid Cascade Hypothesis). However, recent studies have found that the Aβ variants(pEAβ), which N terminal glutamate is truncated and cyclizated to form focal glutamate, have a stronger neurotoxicity. The production of pEAβ is a specific pathological change of AD. And the study confirmed that Gutaminyl Cyclase(QC) catalyzes the formation of pE-Aβ, and the high expression of QC is a key event in the early stage of AD Therefore, QC is expected to become an important target for the cause of anti AD drugs,QC inhibitors also become this topic focuses on the research content.In this paper,the article main research content include:(1) By the dehydrogenase-QC acid enzyme linked test model and QC test kit as the main means, LBQI series compounds designed and synthesized in our laboratory were evaluated for QC inhibition activity. The results showed that LBQI series compounds have significant QC inhibitory activity. There were 17 compounds(32%) with a QC inhibitory rate of more than 85% in 53 compounds. IC50 values of some compounds were lower than the positive control, the results verify the initial idea of the subject.With double transgenic mouse(B6C3-Tg APPswe(PSEN1dE9) 85Dbo/MmJNju) as a model animal, we studied the anti AD effect and mechanism of LBQI-35 in vivo. Experiment behavioral studies, Aging score, open field test and nesting, have shown that mice memory space and exploring ability were improved after treatment, symptoms of the disease were significantly improved; Immunohistochemistry, Elisa and other experimental results confirmed that LBQI-35 can significantly inhibit the brain QC activity in AD mice, significantly reduce the formation of pEAβ and senile plaques in the brain; The results of Ths staining showed that LBQI-35 could significantly decrease the formation of Aβ and pEAβ accumulation in brain tissue. By the above results, LBQI series compounds has a significant anti AD effect in vivo, and mainly through the inhibition of QC activity.Through this study of the activity evaluation in vitro and action research in vivo, We found efficient and specific inhibitor of QC class anti AD lead drug, and its anti AD effect is directly related to the inhibition of QC activity in vivo. This provides an important support for the development of innovative anti AD drug.