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Brain Behav Immun. 2016 Oct;57:314-325. doi: 10.1016/j.bbi.2015.09.012. Epub 2015 Sep 21.

Chronic alpha-linolenic acid treatment alleviates age-associated neuropathology: Roles of PERK/eIF2α signaling pathway.

Author information

1
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.
2
MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
3
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
4
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.
5
Nanjing Entry-Exit Inspection and Quarantine Bureau, Nanjing, PR China.
6
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
7
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.
8
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.

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.

KEYWORDS:

Aging; Endoplasmic reticulum stress; Learning and memory; Unfold protein response; α-Linolenic acid

PMID:
26399745
DOI:
10.1016/j.bbi.2015.09.012
[Indexed for MEDLINE]

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