Electroacupuncture Alleviates Memory Deficits in APP/PS1 Mice by Targeting Serotonergic Neurons in Dorsal Raphe Nucleus

Objective Alzheimer’s disease(AD)has become a significant global concern,but effective drugs able to slow down AD progression is still lacked.Electroacupuncture(EA)has been demonstrated to ameliorate cognitive impairment in individuals with AD.However,the underlying mechanisms remains poorly understood.This study aimed at examining the neuroprotective properties of EA and its potential mechanism of action against AD.Methods APP/PS1 transgenic mice were employed to evaluate the protective effects of EA on Shenshu(BL 23)and Baihui(GV 20).Chemogenetic manipulation was used to activate or inhibit serotonergic neurons within the dorsal raphe nucleus(DRN).Learning and memory abilities were assessed by the novel object recognition and Morris water maze tests.Golgi staining,western blot,and immunostaining were utilized to determine EA-induced neuroprotection.Results EA at Shenshu(BL 23)and Baihui(GV 20)effectively ameliorated learning and memory impairments in APP/PS1 mice.EA attenuated dendritic spine loss,increased the expression levels of PSD95,synaptophysin,and brain-derived neurotrophic factor in hippocampus.Activation of serotonergic neurons within the DRN can ameliorate cognitive deficits in AD by activating glutamatergic neurons mediated by 5-HT1B.Chemogenetic inhibition of serotonergic neurons in the DRN reversed the effects of EA on synaptic plasticity and memory.Conclusion EA can alleviate cognitive dysfunction in APP/PS1 mice by activating serotonergic neurons in the DRN.Further study is necessary to better understand how the serotonergic neurons-related neural circuits involves in EA-induced memory improvement in AD.

High-frequency electroacupuncture evidently reinforces hippocampal synaptic transmission in Alzheimer＇s disease rats

The frequency range of electroacupuncture in treatment of Alzheimer＇s disease in rats is commonly 2-5 Hz（low frequency） and 50-100 Hz（high frequency）. We established a rat model of Alzheimer＇s disease by injecting β-amyloid 1-42（Aβ1-42） into the bilateral hippocampal dentate gyrus to verify which frequency may be better suited in treatment. Electroacupuncture at 2 Hz or 50 Hz was used to stimulate Baihui（DU20） and Shenshu（BL23） acupoints. The water maze test and electrophysiological studies demonstrated that spatial memory ability was apparently improved, and the ranges of long-term potentiation and long-term depression were increased in Alzheimer＇s disease rats after electroacupuncture treatment. Moreover, the effects of electroacupuncture at 50 Hz were better than that at 2 Hz. These findings suggest that high-frequency electroacupuncture may enhance hippocampal synaptic transmission and potentially improve memory disorders in Alzheimer＇s disease rats.

High-frequency (50 Hz) electroacupuncture ameliorates cognitive impairment in rats with amyloid beta 1–42-induced Alzheimer＇s disease

Acupuncture has been shown to ameliorate cognitive impairment of Alzheimer’s disease.Acupoints and stimulation frequency influence the therapeutic effect of electroacupuncture.Rat models of Alzheimer’s disease were established by injecting amyloid beta 1–42（Aβ_（1–42））into the bilateral lateral ventricles.Electroacupuncture at 2,30,and 50 Hz was carried out at Baihui（GV20;15°obliquely to a depth of 2mm）and Shenshu（BL23;perpendicularly to 4–6 mm depth）,once a day for 20 minutes（each）,for 15 days,taking a break every 7 days.The Morris water maze test was conducted to assess the learning and memory.The expression levels of glycogen synthase kinase-3β（GSK-3β）,p Ser9-GSK-3β,p Tyr216-GSK-3β,amyloid precursor protein and Aβ_（1–40） in the hippocampus were determined by western blot assay.Results demonstrated that electroacupuncture treatment at different frequencies markedly improved learning and memory ability,increased synaptic curvatures,decreased the width of synaptic clefts,thickened postsynaptic densities,and downregulated the expression of GSK-3β,amyloid precursor protein,and Aβ_（1–40）.pSer9-GSK-3βexpression markedly decreased,while p Tyr216-GSK-3βexpression increased.High-frequency（50 Hz）electroacupuncture was more effective than low（2 Hz）or medium-frequency（30 Hz）electroacupuncture.In conclusion,electroacupuncture treatment exerts a protective effect against Aβ_（1–42）-induced learning and memory deficits and synapse-ultrastructure impairment via inhibition of GSK-3βactivity.Moreover,high-frequency electroacupuncture was the most effective therapy.

Preventive electroacupuncture reduces cognitive deficits in a rat model of D-galactose-induced aging

Acupuncture can reduce cognitive deficits in Alzheimer’s disease.However,whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood.Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline.Therefore,we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications.A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks.Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration.Preventive electroacupuncture alleviated memory impairment,decreased tau hyperphosphorylation,and reduced glycogen synthase kinase-3βprotein and mRNA expression levels in the brainstem dorsal raphe nucleus,where intracellular neurofibrillary tangle lesions first occur.In addition,the DNA methylation level in the promoter region of the glycogen synthase kinase-3βgene was increased.The effects of preventive electroacupuncture were stronger than those of preventive acupuncture.Intraperitoneal injection of 0.4 mg/kg 5-aza-2ʹ-deoxycytidine,an inhibitor of DNA methyltransferase that blocks epigenetic modifications,antagonized the effects of preventive electroacupuncture.Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3βgene in the dorsal raphe nucleus.This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine,China(approval No.HUCMS201712001)on November 28,2017.

Epigenetic Regulation of Amyloid-beta Metabolism in Alzheimer’s Disease

Senile plaques(SPs)are one of the pathological features of Alzheimer’s disease(AD)and they are formed by the overproduction and aggregation of amyloid-beta(Aβ)peptides derived from the abnormal cleavage of amyloid precursor protein(APP).Thus,understanding the regulatory mechanisms during Aβ metabolism is of great importance to elucidate AD pathogenesis.Recent studies have shown that epigenetic modulation-including DNA methylation,non-coding RNA alterations,and histone modifications-is of great significance in regulating Aβ metabolism.In this article,we review the aberrant epigenetic regulation of Aβ metabolism.