title: Chronic alpha-linolenic acid treatment alleviates age-associated neuropathology: Roles of PERK/eIF2α signaling pathway.
abstract: Aging is a principal risk factor for neurodegenerative diseases and especially shares similar pathologic mechanisms to Alzheimer's disease (AD). Amyloid-β (Aβ) plaques deposition and neurofibrillary tangles (NFTs) are the prominent age-dependent pathologies implicated in the cognitive deficits. Accumulation of mis-folded proteins in the endoplasmic reticulum triggers a cellular stress response called the unfolded protein response (UPR), the activation of which is increased in AD patients. However, the UPR relates to the pathological hallmarks of aging is still elusive. In this study, we report that long-term supplement of α-linolenic acid (ALA), starting before the onset of disease symptoms (6month-old), prevents the age-related memory deficits during natural aging. The amelioration of the memory impairment is associated with a decrease in UPR related markers [glucose regulated protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic Initiation Factor 2α (eIF2α)]. ALA suppressed the PERK/eIF2α signaling, which may be responsible for multifaceted memory-deteriorating and neurodegenerative mechanisms, including inhibition of Aβ production by suppressing β-site APP-cleaving enzyme 1 (BACE1) expression, enhancement of cAMP response element binding protein (CREB) function via down-regulating activating transcription factor 4 (ATF4), and suppression of Tau phosphorylation by inhibiting glycogen synthase kinase 3β (GSK-3β) pathway. Taken together, our findings provide new insights into the link between ALA and PERK/eIF2α signaling, which could contribute to a better understanding of an ALA-mediated protective effect in aging-associated neuropathology.
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Yan
authors.affiliation: MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Shuke
authors.initials: S
authors.lastname: Nie
authors.affiliation: Department of Product Processing and Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, PR China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, PR China.
authors.forename: Fenghong
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Product Processing and Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, PR China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, PR China.
authors.forename: Qianchun
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Product Processing and Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, PR China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, PR China.
authors.forename: Qingde
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Nanjing Entry-Exit Inspection and Quarantine Bureau, Nanjing, PR China.
authors.forename: Hailei
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yao
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.affiliation: Department of Product Processing and Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, PR China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, PR China. Electronic address: xujiqu@caas.cn.
authors.forename: Jiqu
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. Electronic address: lgliu@mails.tjmu.edu.cn.
authors.forename: Liegang
authors.initials: L
authors.lastname: Liu
mesh_terms: D000375:Aging / Q000187:drug effects*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008569:Memory Disorders / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D017962:alpha-Linolenic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D019892:eIF-2 Kinase / Q000187:drug effects*
chemical_list: D017962:alpha-Linolenic Acid; D019892:eIF-2 Kinase
keywords: Aging; Endoplasmic reticulum stress; Learning and memory; Unfold protein response; α-Linolenic acid