Byline: Chao-Chao. Yu, Chuan. He, Yan-Jun. Du, Shan. Gao, Yuan-Fang. Lin, Shu-Qin. Wang, Li. Wang, Jia. Wang, Xue-Song. Wang, Tao. Jiang, Li-Hong. Kong
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-3ß protein 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-3ß gene was increased. The effects of preventive electroacupuncture were stronger than those of preventive acupuncture. Intraperitoneal injection of 0.4 mg/kg 5-aza-2'-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-3ß gene 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.
Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia among older adults. It usually manifests clinically as progressive memory loss and executive dysfunction (McKhann et al., 2011; Zhao et al., 2016; Sumbria, 2020). As the worldwide population ages, it is estimated that nearly 1 million new cases per year globally will be expected by 2050, conferring a tremendous challenge on global healthcare systems (Alzheimer's Association, 2016). Extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are the main pathological features of AD (Long and Holtzman, 2019). Though acetylcholinesterase inhibitors and the N-methyl-D-aspartate-type glutamate receptor antagonist memantine have been approved by the U.S. Food and Drug Administration for AD, their efficacy is modest and transient (Cummings, 2004). Because AD is insidious and difficult to reverse, it is important to develop effective prevention strategies.
The distribution pattern of NFTs resulting from tau hyperphosphorylation is highly predictable (Goedert et al., 2017), and it is the NFTs (Giannakopoulos et al., 2003), rather than senile plaques, that are associated with the severity of dementia. Considerable evidence suggests that NFT lesions first occur in the brainstem dorsal raphe nucleus (DRN) (Grinberg et al., 2009; Simic et al., 2009), and NFT-associated lesions in the DRN can even be observed in presymptomatic stages (Rüb et al., 2000). The DRN contains long projection neurons that are abundant in serotonin. These neurons project to several brain areas associated with cognitive function, such as the frontal cortex, hippocampus, septum, striatum and...