Alzheimer’s disease(AD)is the primary type of dementia in the elderly.It remains incurable and poses a huge socio-economic challenge for developed countries with an aging population.AD manifests by progressive decline in cognitive functions and alterations in behaviour,which are the result of the extensive degeneration of brain neurons.The AD pathogenic mechanism involves the accumulation of amyloid beta peptide(Aβ),an aggregating protein fragment that self-associates to form neurotoxic fibrils that trigger a cascade of cellular events leading to neuronal injury and death.Researchers from academia and the pharmaceutical industry have pursued a rational approach to AD drug discovery and targeted the amyloid cascade.Schemes have been devised to prevent the over-production and accumulation of Aβ in the brain.The most progressed mechanism-based therapies to date consist of immunological interventions to clear Aβ,and pharmacological drugs to inhibit BACE1 that produce Aβ.Despite the failure of early BACE inhibitors that lacked potency and specificity,a new generation of BACE inhi-bitors provides strong candidates in AD therapy.Our research aims at vestigating the effects of bcc 01,bcc 02,bcc 03,bcc 04,bcc 327-1,bcc 327-2,bcc 327-3 on BACE1.During the study,dissolution,cytotoxicity and cell pharmacodynamics of these drugs were estimated.The APP / PS1 transgenic mouse model was used to simulate the overgrowth of the cerebral cortex and hippocampus.After the animal pharmacodynamics experiment,immunohistochemistry,THS staining and Western Blot verification was then carried out to evaluate effect in model mice to evaluate.The results of cell pharmacodynamics showed that bcc 01 and bcc327-1 could inhibit the cleavage of APP via BACE1.The results of immunohistochemistry and THS staining showed that bcc 327-1,bcc 02 and bcc 03 could significantly inhibit the deposition of senile plaques.Western Blot results showed that bcc 02 and bcc 327-1 significantly inhibited the downstream products of APP hydrolysis and the level of BACE1,probably through the expression process of BACE1.The results provide reference for further preclinical testing,improvement and follow-up clinical trials of these drugs. |