title: Enriched endogenous n-3 polyunsaturated fatty acids alleviate cognitive and behavioral deficits in a mice model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accompanied by memory deficits and neuropsychiatric dysfunction. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have seemly therapeutic potential in AD, but the benefit of n-3 PUFAs is still in debates. Here, we employed a transgenic mice carry fat-1 gene to encode n-3 desaturase from Caenorhabditis elegans, which increase endogenous n-3 PUFAs by converting n-6 PUFAs to n-3 PUFAs crossed with amyloid precursor protein (APP) Tg mice to evaluate the protective effects of endogenous n-3 PUFAs on cognitive and behavioral deficits of APP Tg mice. We fed APP, APP/fat-1 and fat-1 mice with n-6 PUFAs rich diet. Brain tissues were collected at 3, 9 and 12 months for fatty acid and gene expression analysis, histology and protein assays. Morris Water Maze Test, open field test and elevated plus maze test were performed to measure the behavior capability. From the results, the expression of fat-1 transgene increased cortical n-3: n-6 PUFAs ratio and n-3 PUFAs concentrations, and sensorimotor dysfunction and cognitive deficits in AD were significantly less severe in APP/fat-1 mice with endogenous n-3 PUFAs than in APP mice controls. The protection against disturbance of spontaneous motor activity and cognitive deficits in AD was strongly correlated with increased n-3: n-6 PUFAs ratio and endogenous n-3 PUFAs, reduced APP generation, inhibited amyloid β peptide aggregation, suppressed nuclear factor-kappa B and astroglia activation, and reduced death of neurons in the cortex of APP/fat-1 mice compared with APP mice controls. In conclusion, our study demonstrates that an available medication with the maintenance of enriched n-3 PUFAs in the brain could slow down cognitive decline and prevent neuropsychological disorder in AD.
authors.affiliation: Guangdong Key Laboratory for Research and Development of Natural Drug, Guangdong Medical College, Zhanjiang, Guangdong, China.
authors.forename: Kefeng
authors.initials: K
authors.lastname: Wu
authors.affiliation: Stem Cell Research and Cellular Therapy Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Guangdong Key Laboratory for Research and Development of Natural Drug, Guangdong Medical College, Zhanjiang, Guangdong, China; Guangdong Key laboratory of Laboratory Animal, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China.
authors.forename: Baoyan
authors.initials: B
authors.lastname: Shi
authors.affiliation: Guangdong Key Laboratory for Research and Development of Natural Drug, Guangdong Medical College, Zhanjiang, Guangdong, China; Guangdong Key laboratory of Laboratory Animal, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Chen
authors.affiliation: Guangdong Key Laboratory for Research and Development of Natural Drug, Guangdong Medical College, Zhanjiang, Guangdong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Guangdong Medical College, Zhanjiang, Guangdong 524023, China.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Guangdong Medical College, Zhanjiang, Guangdong 524023, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Gan
authors.affiliation: Guangdong Key Laboratory for Research and Development of Natural Drug, Guangdong Medical College, Zhanjiang, Guangdong, China; Department of Pharmacology, Guangdong Medical College, Zhanjiang, Guangdong 524023, China.
authors.forename: Liao
authors.initials: L
authors.lastname: Cui
authors.affiliation: The Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital, Boston 02114, USA.
authors.forename: Jing Xuan
authors.initials: JX
authors.lastname: Kang
authors.affiliation: Guangdong Key Laboratory for Research and Development of Natural Drug, Guangdong Medical College, Zhanjiang, Guangdong, China; Guangdong Key laboratory of Laboratory Animal, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China. Electronic address: lwd@gdlami.com.
authors.forename: Wende
authors.initials: W
authors.lastname: Li
authors.affiliation: Guangdong Key laboratory of Laboratory Animal, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China. Electronic address: labking@sohu.com.
authors.forename: Ren
authors.initials: R
authors.lastname: Huang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000008:administration & dosage; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D029742:Caenorhabditis elegans Proteins; D043371:Fatty Acids, Omega-6; D016328:NF-kappa B; C466741:fat-1 protein, C elegans; D044943:Fatty Acid Desaturases
keywords: Alzheimer’s disease; amyloid precursor protein; polyunsaturated fatty acids