title: Chronic Estradiol Administration During the Early Stage of Alzheimer's Disease Pathology Rescues Adult Hippocampal Neurogenesis and Ameliorates Cognitive Deficits in Aβ1-42Mice.
abstract: Alzheimer's disease (AD) is the leading cause of dementia and has become an important public health concern. Accumulating evidence indicates that estradiol can both facilitate and impair memory-related processes and, as a result, the precise nature of the role that estradiol plays during AD pathology remains elusive. Therefore, the present study established a mouse model of AD using stereotactic brain injection of Aβ1-42in which the mice were bilaterally ovariectomized to investigate the effects of 17β-estradiol (E2) treatment during different stages of the AD process (early and late stages). The cognitive deficits associated with this AD model were significantly ameliorated, and there was a significant increase in hippocampal neurogenesis in Aβ1-42mice that received E2 treatment during the early stage of AD pathology. On the other hand, Aβ1-42mice that received E2 treatment during the late stage of AD pathology did not exhibit any improvements in cognitive function or hippocampal neurogenesis. To reveal the mechanisms, underlying these effects, levels of oxidative stress, activity in death-associated pathways, gliosis, and synaptic function were assessed in the hippocampus. The Aβ1-42mice that received E2 treatment during the early stage of AD pathology exhibited significant reductions in the production of nitric oxide (NO) and reactive oxygen species (ROS), a marked decrease in the activation of Cytochrome-c/Bax/Bcl-2/caspase-3 pathway, a notable decrease in the level of gliosis a significant increase in the number of synapses (ultrastructural investigation), and a marked upregulation in synaptic function-related proteins compared to mice that received E2 treatment during the late stage of AD pathology. Taken together, these findings indicate that E2 treatment during the early stage of AD pathology might be an efficient approach to ameliorate the development of this disease.
authors.affiliation: Department of Neurosurgery, The Affiliated Huai'an Hospital of Xuzhou Medical College, No. 62 South Huaihai Road, Huai'an, Jiangsu Province, 223002, People's Republic of China.
authors.forename: Jin-Yu
authors.initials: JY
authors.lastname: Zheng
authors.affiliation: Department of Neurology, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, No. 107 Wenhuaxi Road, Jinan, Shandong, 250012, People's Republic of China.|Department of Neurology, Pingyi Branch of Qilu Hospital, Shandong University, No. 07 Jinhua Road, Pingyi, Shandong Province, 273300, People's Republic of China.
authors.forename: Ke-Shan
authors.initials: KS
authors.lastname: Liang
authors.affiliation: Department of Neurology, Linyi People's Hospital, No. 49 Yizhou Road, Linyi, Shandong, 276000, People's Republic of China.
authors.forename: Xian-Jun
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Neurology, Shangdong University of Traditional Chinese Medicine, Jinan, Shandong, 250031, China.
authors.forename: Xue-Ying
authors.initials: XY
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology, Maternal and Child Health Hospital of Huai'an, No. 104 South Renmin, Huai'an, Jiangsu Province, 223002, China. sj_cosmo@hotmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Neurology, Qilu Hospital of Shandong University and Brain Science Research Institute, Shandong University, No. 107 Wenhuaxi Road, Jinan, Shandong, 250012, People's Republic of China. zhou_shengn@126.com.
authors.forename: Sheng-Nian
authors.initials: SN
authors.lastname: Zhou
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D004343:Drug Implants; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004958:Estradiol
keywords: Alzheimer’s disease; Estradiol; Gliosis; Neurogenesis; Synaptic function