Memantine combined with environmental enrichment improves spatial memory and alleviates Alzheimer's disease-like pathology in senescence-accelerated prone-8(SAMP8) mice

Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease (AD). Environmental enrichment (EE) has shown significant beneficial effects on func- tional improvement in AD. In this study, we sought to determine whether combining these two distinct therapies would yield greater benefit than either drug used alone. We investigated the effect of memantine combined with EE on spatial learning and memory and AD-like pathology in a widely used AD model, the senescence-accelerated prone mice (SAMP8). The SAMP8 mice were randomly assigned to enriched housing (EH) or standard housing (SH), where either memantine (20 mg/kg) or saline was given by gastric lavage once daily continuously for eight weeks. Our results showed that, when provided separately, memantine and EE significantly improved spatial learning and memory by shortening escape latencies and increasing the frequency of entrance into the target quadrant. When combined, memantine and EE showed additive effect on learning and memory as evidenced by significant shorter escape latencies and higher frequency of target entrance than either drug alone. Consistent with the behavior results, pathological studies showed that both memantine and EE significantly reduced hippocampal CA1 neurofibrilliary tangles (NFTs) as well as amyloid beta precursor protein (APP) levels. Combining both therapies synergistically lessened NFTs and APP expression compared to either drug alone in SAMP8 mice, indicating that the combination of memantine with EE could offer a novel and efficient therapeutic strategy for the treatment of AD.

Effects of electroacupuncture on functions of hippocampal mitochondrial respiratory chain in SAMP8 mice

Objective To investigate the mechanism of electroacupuncture （EA） in treating Alzheimer＇s disease （AD） from aspect of mitochondria. Methods Twelve 8-month old SAMP8 mice were randomly divided into a model group （Group Mod, n=6） and an electroacupuncture group （Group EA, n=6）, and six 8-month old SAMR1 mice were selected as a control group （Group Cont）. Animals in Group EA was treated with EA at ＂Baihui＂ （百会 GV 20）, ＂Dazhui＂ （大椎 GV 14）, ＂Shenshu （肾俞 BL 23） and ＂Taixi＂ （太溪 KI 3） for 20 min, once daily with 20 days of treatments as a therapeutic course, lasting for 3 courses. Mice in the other two groups were fixed in the same way as those in Group EA at the same time without any treatment. After treatment, learning and memory abilities of the mice were measured by Morris water maze, activities of enzyme complex of hippocampal mitochondrial respiratory chain were measured by spectrophotometry, and levels of adenosine triphosphate （ATP） were detected by reverse phase high performance liquid chromatography （HPLC） method. Results Compared with Group Cont, the average escape latency in Group Mod was significantly prolonged, the residence time on the platform quadrant was shortened, the activities of enzyme complex Ⅰ, Ⅱ, Ⅲ and Ⅳ in hippocampal mitochondrial respiratory chain was decreased, and ATP contents was lessened in Group Mod. Compared with Group Mod, the average escape latency was significantly shortened, the residence time on the platform quadrant was lengthened, the activities of enzyme complex Ⅰ, Ⅱ, Ⅲ and Ⅳ in hippocampal mitochondria respiratory chain were significantly increased, and ATP contents were also increased in Group EA. Conclusion Electroacupuncture can elevate the activities of enzyme complex in hippocampal mitochondrial respiratory chain and ATP contents, and improve mitochondrial functions, which may be one of the underlying mechanisms of EA in treatment of AD.

Pharmacological inhibition of asparaqinyl endopeptidase by δ-secretase inhibitor 11 mitigates Alzheimer's disease-related pathologies in a senescence-accelerated mouse model

Background:Currently,there is no cure for Alzheimer's disease(AD).Therapeutics that can modify the early stage of AD are urgently needed.Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase(AEP).Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD.However,more than 90% of AD cases are age-related sporadic AD rather than hereditary AD.The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown.Methods:The senescence-accelerated mouse prone 8(SAMP8)was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,δ-secretase inhibitor 11.Activation of AEP was determined by enzymatic activity assay.Concentration of soluble amyloid β(Aβ)in the brain was determined by ELISA.Morris water maze test was performed to assess the learning and memory-related cognitive ability.Pathological changes in the brain were explored by morphological and western blot analyses.Results:The enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the agematched SAMR1 mice.The half maximal inhibitory concentration(IC_(50))for δ-secretase inhibitor 11 to inhibit AEP in vitro was around 150 nM.Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity,reduced the generation of Aβ_(1-40/42) and ameliorated memory loss.The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation,but also attenuated neuroinflammation in the form of microglial activation.Moreover,treatment with 6-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain.Conclusions:Pharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD.The up-regulated AEP in the brain could be a promising target for early treatment of AD.The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.