Baicalein Rescues Synaptic Plasticity And Memory Deficits In A Mouse Model Of Alzheimer’s Disease

Objectives:Increasing evidence suggests that disruptions of synaptic functions correlates with the severity of cognitive deficit in Alzheimer’s disease(AD). Our previous study demonstrates that baicalein enhance NMDAR-dependent LTP in acute rat hippocampal slices. Given that baicalein possess various biological activities, especially its effects on synaptic plasticity and cognitive function, we examined the effect of baicalein on synaptic function in an AD model in vivo.Methods:Baicalein was administered orally via drinking water to the APP/PS1 mice and age-matched wild-type C57BL/6J mice. Treatment started at 5 months of age and mice were assessed for cognition and AD-like pathology at 7-month-old. Learning and memory in mice was analyzed by Morris water maze test, fear conditioning test, and novel object recognition test. Phosphorylation of Akt(at Ser473), glycogen synthase kinase 3β inactive form(GSK3β-Ser-9) and the active GSK3β form(GSK3β-Tyr-216), and β-secretase enzyme(BACE1) were analysed by Western blot. The level of Aβ was quantified by a human Aβ40 or Aβ42 enzyme-linked immunosorbent assay(ELISA) kits. The LTP at the schaffer collateral-CA1 pathways in mouse hippocampal slices were investigated by electrophysiological methods. The levels of several synaptic proteins in synaptoneurosomes from hippocampus of mice were measured by Western blot. The density of dendritic spines along individual dendrites of pyramidal neurons in hippocampus CA1 region and cortex were evaluated by Golgi-cox staining.Results:The transgenic mice that received baicalein treatment significantly elevated p-Akt at serine 473 in comparison to that of water-treated APP/PS1 mice(P < 0.05). No difference in the total protein expressions of Akt was observed between four groups(P > 0.05). The reduced level of p-GSK3β-Ser9 in water-treated transgenic mice was fully reversed by administration of baicalein(P < 0.05). In contrast, the expression of p-GSK3b-Tyr-216, the active GSK3β form, increased in water-treated transgenic mice and was normalized to those found in water-treated WT mice(P < 0.05). No statistical difference was found in total GSK3β among groups(P > 0.05). The BACE1 levels were dramatically increased in hippocampus of water-treated APP/PS1 mice compared with water-treated WT(P < 0.05), whereas baicalein obviously reduced BACE1 level(P < 0.05). Baicalein reduced the levels of total Aβ40 and Aβ42(P < 0.05). Baicalein administration completely restored the reduced LTP in response to HFS in APP/PS1 mice, even on a level comparable with water-treated wild-type mice(P < 0.05). In order to further demonstrate the effect of baicalein on LTP, we applied another stimulation pattern, HFS. Interesting, we obtained similar results, impaireded LTP in water-treated APP/PS1 mice were reversed by baicalein(P < 0.05). Baicalein administration increased levels of the presynaptic protein(synapsin I) and postsynaptic proteins(NR2A, NR2 B, Glu R1, PSD95, and spinophilin) compared with water-treated transgenic mice(P < 0.05). The density of dendritic spines was significantly decreased in the APP/PS1 mice compared with the water-treated wild-type(P < 0.05), and this deficit was rescued by baicalein treatment(P < 0.05). Water-treated transgenic mice showed that learning in locating the hidden platform was impaired, as indicated by the increased escape latency in the consecutive trials compared with water-treated WT(P < 0.05), while high dose baicalein treatment transgenic mice dramatically shortened the escape latency to a level comparable with water-treated wild-type(P < 0.05). A mixed two-way ANOVA on swim path distance revealed a significant main effect of training day(F(4, 252) = 38.87, P < 0.05), but no effect of group(F(5, 65) = 2.34, P > 0.05) or interaction(F(20, 252) = 1.58, P > 0.05). Baicalein had no effect on swim speeds(P > 0.05). water- and low dose baicalein-treated transgenic mice spent obvious lower percentage of their time in the target quadrant versus water-treated WT mice(P < 0.05). The percentage of time spent in the target quadrant between water- and high dose baicalein-treated transgenic mice had major difference(P < 0.05). Contextual freezing response of the high dose baicalein-treated transgenic mice was comparable to water-treated WT(P < 0.05), whereas the percentage of freezing in the water- and low dose baicalein-treated transgenic mice was significantly lower than water-treated wild-type(P < 0.05). In the cued fear-conditioning paradigms, we found that there was no major difference in freezing among groups(P > 0.05). Distance travelled in open field test among groups had no statistically differences(P > 0.05). The thresholds for flinching in response to the shock did not differ between all groups(P > 0.05). High dose baicalein-treated APP/PS1 mice exhibited stronger discrimination index than control APP/PS1 mice to a comparable level of water-treated WT mice(P < 0.05).Conclusions:By a combination of behavioral, electrophysiological, and biochemical techniques, chronic oral administration of baicalein increased p-Akt, reduced GSK3β and BACE1 activity, alleviated the concentration of total Aβ in APP/PS1 mice. Meanwhile, baicalein restored spine number, synaptic plasticity, and memory deficits. Our present results strengthen the potential of the flavonoid baicalein as a novel and promising oral bioactive therapeutic agent that prevents memory deficits in AD.