Optimizations Of A Alzheimer's Disease Model And Effects Of Quchiling On The Model

Objective(1) The Alzheimer's disease (AD) model induced by D-galactose (D-gal) and aluminum chloride(AlCl3) successively for 12 weeks is a patent which our laboratory has gained several years ago. Optimize the model in order to illuminate the necessaries of the two drugs' combination by comparing with single factor-treated group; to shorten the possible cycle of model establishment by increasing dosage of aluminum; to investigate the potential ability of model maintaining which provide a credible base for futher drug therapeutic research.(2) Based on the researches above, observe the effects of Quchiling on the modified AD model mice.Methods(1) The Kung Ming healthy mice were randomly dived into four groups:One was control, the other three groups were treated receptively with D-gal 120 mg-kg-1·d-1, AICl320.0 mg·kg-1·d-1, the combined dosage of D-gal and AICl3. Each group was randomized into 3 subgroups (16 mice per subgroup) which would be tested respectively when administration last for 8 weeks,10 weeks and the time was 6 weeks after end administration. Morris water-maze test, biochemical assays of Ach, ChAT and AchE, immunohistochemical staining and bielshovsky sliver staining in brain tissue were carried out to evaluate the integrative effects of D-gal and AICl3 on mice.(2) In light of aboval research, Kung Ming healthy mice were treated with D-gal and AICl3 to rebuild a new AD animal model. The therapeutic groups were administrated Quchiling respectively with low, medium, and high doses (4.6 g-kg-1·d-1,9.2 g-kg-1·d-1,18.4 g-kg-1·d-1) through intragastric route for 5 weeks. Huperzine A (0.4 mg-kg-1·d-1) was used as a positive control drug. Morris water-maze test, biochemical assays of cholinergic system and expression of APP, immunohistochemical staining and bielshovsky sliver staining were carried out to evaluate the effects of Quchiling on the AD model mice.Results(1) The mice treated with AICl3 for 10 weeks put out disability of learnning and memory. When AICl3 was withdrawed for 6 weeks, the capability of learnning and memory was recovered to nomal level. Before and after adminstration, the activities of AchE and ChAT, the content of Ach kept unsuffered. Similar senile plaques (SPs) and neurofibrillary tangles (NFTs) in brain were uncospicuous.(2) The mice treated with D-gal for 10 weeks mimiced disabilitiy of learnning and memory. When D-gal was withdrawed for 6 weeks, the mice not only maintained its own behavior incompetence but also newly put up cholinergic functional deficiency, including activities of AchE and ChAT decreased, the content of Ach reduced, as well as SPs-like observed.(3) The mice treated with D-gal and AlCl3 in combination for 8 weeks mimiced the hunman AD characters completely, including the cability of learnning and memory suffered, the activities of AchE and ChAT decreased, the content of Ach reduced, as well as SPs-like and NFTs-like observed.When administration was last for 10weeks, those performances got more remarkable. End modeling for 6 weeks, those AD-like changes kept unrecovered.(4) Compared with model group, groups of Quchiling exhibited as follows: the capacity of learning and memory improved, the activities of AchE and ChAT inhanced, the content of Ach increased and the genic erpression of APP downregulated in AD mice brain, as well as SPs-like and NFTs-like decreased. The high dose group of Quchiling gave prominent performances.Conclusion(1) In AlCl3-treated group the AD-like changes were mimiced uncompletely and unsteadily, but D-gal-treated group mimiced AD-like changes completely with a long term. D-gal and AlCl3-treated group mimiced the the distinctive changes of human AD, including disability of learnning and memory, deficiency of cholinergic function and denseness of SPs-like and NFTs-like, and those AD-like charaeters could be obtained earlier and more steadily.(2) The combinated effects of D-gal and AlC13 were more remarkable at the 10th week than that of the 8th week. The cycle of model establishment was successfully shortened from 12 weeks to 10 weeks by increasing the dose of AICl3(3) The AD-like changes induced by D-gal and AICl3 for 10 weeks on mice could maintain 6 weeks, which was full of importances for AD pathogenesis and therapeutic research.(4) A new effective mulriple AD animal model can be induced by D-gal 120mg-kg-1·d-1 associated with AICl320 mg-kg-1·d-1 for 10 weeks.(5) The suitable dose of Quchiling could improve the AD mice's ability of learning and memory. The mechanism may be closely related to recover the impaired cholinergic neurons' function and decrease the content of APP, inhibit the production and futher development of amyloid P-protein (Ap).