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Long-Term Dietary Alpha-Linolenic Acid Supplement Alleviates Cognitive Impairment Correlate with Activating Hippocampal CREB Signaling in Natural Aging Rats

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Abstract

Alpha-linolenic acid (ALA) is a major precursor of the essential n-3 polyunsaturated fatty acid (PUFA), whose deficiency alters the structure and function of membranes and induces cerebral dysfunctions. The major purpose of this study was to investigate the protective effect of prolonged ALA intake on cognitive function during natural aging. Female Sprague–Dawley rats aged 6 months were chronically treated with ALA and/or lard per day for 12 months. Regular diet-treated rats, both young and old (4 and 18 months old, respectively) served as controls. Rats fed on regular diet during aging showed memory deficits in Morris water maze, which were further exacerbated by lard intake. However, supplementation with ALA for 12 months dose-dependently improved the performance in spatial working memory tasks. Memory performance correlated well with the activation of cAMP response element-binding protein (CREB) and increases in both levels of brain-derived neurotrophic factor (BDNF) and its specific receptor tyrosine kinase B (TrkB) phosphorylation in the hippocampus. Further study identified that hippocampal extracellular signal-related kinase (ERK) and Akt rather than calcium calmodulin kinase IV (CaMKIV) and protein kinase A (PKA), the upstream signalings of CREB, were also activated by ALA supplement. Moreover, memory improvement was accompanied with alterations of hippocampal synaptic structure and number, suggestive of enhancement in synaptic plasticity. Together, these results suggest that long-term dietary intake of ALA enhances CREB/BDNF/TrkB pathway through the activation of ERK and Akt signalings in hippocampus, which contributes to its ameliorative effects on cognitive deficits in natural aging.

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Abbreviations

AA:

Arachidonic acid

ALA:

α-Linolenic acid

ANOVA:

Analyses of variance

BDNF:

Brain-derived neurotrophic factor

CaMKIV:

Calcium calmodulin kinase IV

CNS:

Central nervous system

CREB:

Cyclic AMP response element-binding protein

DHA:

Docosahexaenoic acid

EPA:

Eicosapentaenoic acid

ERK:

Extracellular signal-regulated kinase

FAME:

Fatty acid methyl esters

FO:

Flaxseed oil

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HFD:

High-fat diet

LSD:

Least significant difference

LTM:

Long-term memory

LTP:

Long-term potentiation

MAPK:

Mitogenactivated protein kinase

MUFA:

Monounsaturated fatty acid

MWM:

Morris water maze

PI-3K:

Phosphoinositide-3 kinase

PKA:

Protein kinase A

PKB:

Protein kinase B

PSD:

Postsynaptic density

PUFAs:

Polyunsaturated fatty acids

RT-PCR:

Reverse transcription-polymerase chain reaction

S:

Synapse

SC:

Synaptic cleft

SD:

Standard deviation

SFA:

Saturated fatty acid

SV:

Synaptic vesicle

TrkB:

Tyrosine kinase B

UI:

Unsaturated index

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Acknowledgments

We thank Mengjing Xu (research fellow), Yilin Jin (research fellow), and Shuke Nie (doctoral student) for helping raise the animals.

Role of Funding Source

This work was supported by the National Natural Science Foundation of China (NSFC-31171681 and NSFC-81472978) and the earmarked fund for Modern Agro-industry Technology Research System (CARS-17), China. The funding source had no further role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the paper for publication.

Contributors

Author Hui Gao designed and wrote a first draft of the paper. Peipei Yan and Hao Huang carried out all the experiments. Shun Zhang and Fenghong Huang undertook the statistical analysis and created the figures. Taoping Sun, Sijing Chen, and Qianchun Deng performed dissection procedures. Qingde Huang managed the literature searches. Keqiang Ye assisted with the preparation and proof-reading of the manuscript. Jiqu Xu and Liegang Liu contributed to the design of the study, reviewed the manuscript, and contributed to the final version. All authors contributed to and have approved the final manuscript.

Conflict of Interest

The authors can identify no potential conflicts of interest.

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Authors and Affiliations

  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, People’s Republic of China

    Hui Gao, Peipei Yan, Hao Huang, Taoping Sun, Sijing Chen & Liegang Liu

  2. MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    Hui Gao, Peipei Yan, Shun Zhang, Hao Huang, Taoping Sun, Sijing Chen & Liegang Liu

  3. Department of Product Processing and Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, People’s Republic of China

    Fenghong Huang, Qianchun Deng, Qingde Huang & Jiqu Xu

  4. Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, Wuhan, People’s Republic of China

    Fenghong Huang, Qianchun Deng, Qingde Huang & Jiqu Xu

  5. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Keqiang Ye

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  1. Hui Gao
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Correspondence to Jiqu Xu or Liegang Liu.

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Gao, H., Yan, P., Zhang, S. et al. Long-Term Dietary Alpha-Linolenic Acid Supplement Alleviates Cognitive Impairment Correlate with Activating Hippocampal CREB Signaling in Natural Aging Rats. Mol Neurobiol 53, 4772–4786 (2016). https://doi.org/10.1007/s12035-015-9393-x

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