Tianma-Gouteng pair ameliorates the cognitive deficits on two transgenic mouse models of Alzheimer's disease

Ethnopharmacological relevance: Alzheimer's disease (AD) is a progressive neurodegenerative disease. TianmaGouteng Pair (TGP), commonly prescribed as a pair-herbs, can be found in many Chinese medicine formulae to treat brain diseases. However, the neuroprotective effects and molecular mechanisms of TGP remained unexplored. Aim of the study: This study investigated the difference between the TgCRND8 and 5 x FAD transgenic mice, the anti-AD effects of TGP, and underlying molecular mechanisms of TGP against AD through the two mouse models. Methods: Briefly, three-month-old TgCRND8 and 5 x FAD mice were orally administered with TGP for 4 and 6 months, respectively. Behavioral tests were carried out to determine the neuropsychological functions. Moreover, immunofluorescence and western blotting assays were undertaken to reveal the molecular mechanisms of TGP. Results: Although TgCRND8 and 5 x FAD mice had different beta-amyloid (A beta) burdens, neuroinflammation status, and cognition impairments, TGP exerted neuroprotective effects against AD in the two models. In detail, behavioral tests revealed that TGP treatment markedly ameliorated the anxiety-like behavior, attenuated the recognition memory deficits, and increased the spatial learning ability as well as the reference memory of TgCRND8 and 5 x FAD mice. Moreover, TGP treatment could regulate the beta-amyloid precursor protein (APP) processing by inhibiting the A beta production enzymes such as beta- and gamma-secretases and activating A beta degrading enzyme to reduce A beta accumulation. In addition, TGP reduced the A beta 42 level, the ratio of A beta 42/& Acy;beta 40, A beta accumulation, and tau hyperphosphorylation in both the 5 x FAD and TgCRND8 mouse models. Furthermore, TGP ameliorated neuroinflammation by decreasing the densities of activated microglia and astrocytes, and inhibiting the production of inflammatory cytokines. TGP upregulated the SIRT1 and AMPK, and downregulated sterol response element binding protein 2 (SREBP2) in the brain of TgCRND8 mice and deactivation of the EPhA4 and c-Abl in the brain tissues of 5 x FAD mice. Conclusion: Our experiments for the first time revealed the neuroprotective effects and molecular mechanism of TGP on 5 x FAD and TgCRND8 transgenic mouse models of different AD stages. TGP decreased the level of A beta aggregates, improved the tauopathy, and reduced the neuroinflammation by regulation of the SIRT1/AMPK/ SREBP2 axis and deactivation of EPhA4/c-Abl signaling pathway in the brains of TgCRND8 and 5 x FAD mice, respectively. All these findings unequivocally confirmed that the TGP would be promising in developing into an anti-AD therapeutic pharmaceutical.