Alzheimer's disease is a tenacious neurodegenerative dementia,accompanied by the accumulation of intracellular neurofibrillary tangles,neuropil threads, as well as extracellular amyloid-β (Aβ) containing senile plaques, cerebrovascular Aβ deposits, and selective nerve cell and synapse loss.EGFP-tagged C99 (the carboxyl-terminal fragment of APP) fusion (LGC) as the substrate of γ-secrease was expressed in Chinese hamster ovary (CHO) cells under control of tetracycline (Tet) inducible system for identification of anti-amyloid candidates, which was tested and identified by RT-PCR, ELISA, Western blot, and fluorescence.A drug screening cell model (Tet-CHO)expressing LGC fusion was obtained and then validated by LiC1 and pepstatin A for discovery of new γ-secretase inhibitors.The activities of some 2-substituted-1,2,3,4-tetrahydroisoquinoline derivatives to inhibit LGC binding to γ-secretase based on the Tet-CHO cell model was measured by microplate reader using ELISA and MTT assays.Our research results indicated that the compounds with phenylsulfonyl, benzyl and benzoyl groups at position 2 of 1,2,3,4-tetrahydroisoquinoline showed higher anti-Aβ activities with lower IC50 values of inhibiting ADP-induced human platelet aggregation, suggesting a potential role of fibrin-guided signal pathway in Alzheimer's Diseases therapy.The cell model was capable of screening potential candidates for γ-secretase inhibitors.Further evaluation is under investigation.