Rapamycin Ameliorates Cognitive Impairment Of Apoe-5XFAD Mice Via Regulating Autophagosome–lysosome System Function

Object The aberrant Amyloid-β (Aβ) metabolism is one of the most important hallmarks inthe pathogenesis of Alzheimer’s disease (AD). Autophagy is proposed a double-edged sword inAD. Studies have showed that autophagy may affect the dynamic homeostasis of amyloid-β (Aβ)by modifying the production and degradation process. In fact, autophagy could accelerateprogression of neurodegeneration disease while playing a crucial neuroprotection role on certernconditions. Apolipoprotein e4allele (APOE e4) is the major genetic risk factor for thedevelopment of AD so far. ApoE may regulate the neurotoxicity of Aβ by its specific subtypes.However, the relationship between autophagy and APOE4is yet to be determined in AD. So weexamined the difference in autophagosome–lysosome system, neuropathology and animalbehavior manifestation of diverse age and genotype transgenic mice expressing familial AD (FAD)mutations (5XFAD) and human APOE, EFAD-Tg mice, which was induced autophagy viarapamycin.Methods1.5,3and6month old male EFAD-Tg mice were randomly assigned to avehicle control groups and rapamycin treatment groups which were added at a concentration of1mg/kg via intragastric administration for30days, once a day, respectively. There were8to10mice each group. Morris water maze were conducted to test animal’s spatial learning and memoryperformance. The ultrastructure and numbers of autophagosome–lysosome in the hippocampalCA1region was observed by electron microscopy. LC3，a marker of autophagosome formation，CathepsinD， synapse plasticity related proteins PSD-95, beclin-1and autophagy signalingpathway pmTOR/mTOR were tested by Western blot. Aβ levels were determined by ELISA andImmunohistochemistry staining. Immunofluorescence staining was used to observedautophagosome and lysosomes, including the number.Result Rpamycin treatment improved learning and memory in EFAD-Tg mice to somedegree, especially6-month old apoE3/5XFAD and apoE4/5XFAD. Rapamycin reducedelectron-dense deposits in the autophagosome of various month age and genotype mice. Rapamycin also inhibited the phosphorylation of mTOR and increased the expresion ofautophagosome maker LC-3and CathepsinD. Additionally, rapamycin reduced insoluble Aβlevelsin hippocampal, which was most pronounced in apoE4/5XFAD of6-month old.Conlusions The different genotype apoE/5XFAD transgenic mice display gradually spatialand memory deficits with increasing month and the APOE4/5XFAD and APOE-KO/5XFAD micereduced the greatest levels. Rapamycin induces autophagy through inhibiting phosphorylatedmTOR to regulate autophagosome–lysosome system function. Meanwhile, rapamycin suppressesthe production of insoluble Aβand contribute to Aβ degradation. Therefore, rapamycin ameliorateslearning and memory function of EFAD-Tg mice and may be a valid therapeutic approach toprevent or treat AD.