title: Age-related formaldehyde interferes with DNA methyltransferase function, causing memory loss in Alzheimer's disease.
abstract: Hippocampus-related topographic amnesia is the most common symptom of memory disorders in Alzheimer's disease (AD) patients. Recent studies have revealed that experience-mediated DNA methylation, which is regulated by enzymes with DNA methyltransferase (DNMT) activity, is required for the formation of recent memory as well as the maintenance of remote memory. Notably, overexpression of DNMT3a in the hippocampus can reverse spatial memory deficits in aged mice. However, a decline in global DNA methylation was found in the autopsied hippocampi of patients with AD. Exactly, what endogenous factors that affect DNA methylation still remain to be elucidated. Here, we report a marked increase in endogenous formaldehyde levels is associated with a decline in global DNA methylation in the autopsied hippocampus from AD patients. In vitro and in vivo results show that formaldehyde in excess of normal physiological levels reduced global DNA methylation by interfering DNMTs. Interestingly, intrahippocampal injection of excess formaldehyde before spatial learning in healthy adult rats can mimic the learning difficulty of early stage of AD. Moreover, injection of excess formaldehyde after spatial learning can mimic the loss of remote spatial memory observed in late stage of AD. These findings suggest that aging-associated formaldehyde contributes to topographic amnesia in AD patients.
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Alzheimer's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Tong
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of the Chinese Academy of Sciences, Beijing, China.
authors.forename: Chanshuai
authors.initials: C
authors.lastname: Han
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of the Chinese Academy of Sciences, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Qiang
authors.affiliation: Beijing Geriatric Hospital, Beijing, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Beijing Geriatric Hospital, Beijing, China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Lv
authors.affiliation: Beijing Geriatric Hospital, Beijing, China.
authors.forename: Shouzi
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Shantou University Medical College, Guangdong, China.
authors.forename: Wenhong
authors.initials: W
authors.lastname: Luo
authors.affiliation: Central Laboratory, Shantou University Medical College, Guangdong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Central Laboratory, Shantou University Medical College, Guangdong, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Luo
authors.affiliation: University of Science and Technology of China, Anhui, China.
authors.forename: Jiangning
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of the Chinese Academy of Sciences, Beijing, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of the Chinese Academy of Sciences, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Science, Huazhong Normal University, Wuhan, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Alzheimer's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Alzheimer's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China; Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China. Electronic address: herq@sun5.ibp.ac.cn.
authors.forename: Rongqiao
authors.initials: R
authors.lastname: He
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000523:psychology*; D000544:Alzheimer Disease / Q000209:etiology* / Q000523:psychology*; D000647:Amnesia / Q000209:etiology / Q000523:psychology; D000818:Animals; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005260:Female; D005557:Formaldehyde / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D065853:Spatial Learning; D065852:Spatial Memory
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D005557:Formaldehyde; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: Alzheimer's disease (AD); DNA methyltransfarases (DNMTs); Endogenous formaldehyde; Topographic amnesia