A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid

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http://www.jneurosci.org/cgi/content/abstract/25/12/3032

 

A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid

Reduces Amyloid Burden in an Aged Alzheimer Mouse Model

 

Giselle P. Lim,1,3 Frédéric Calon,1,3 Takashi Morihara,1,3 Fusheng

Yang,1,3 Bruce Teter,1,3 Oliver Ubeda,1,3 Norman Salem, Jr,5 Sally A.

Frautschy,1,3,2,4 and Greg M. Cole1,3,2,4

 

Departments of 1Medicine and 2Neurology, University of California Los

Angeles, Los Angeles, California 90095, 3Veterans Affairs Greater Los

Angeles Healthcare System and 4Geriatric Research Educational Clinical

Center, North Hills, California 91343, and 5Section of Nutritional

Neuroscience, Laboratory of Membrane Biochemistry and Biophysics,

Division of Intramural Clinical and Biological Research, National

Institute on Alcohol Abuse and Alcoholism, National Institutes of

Health, Rockville, Maryland 20852

 

Epidemiological studies suggest that increased intake of the omega-3

(n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is

associated with reduced risk of Alzheimer's disease (AD). DHA levels

are lower in serum and brains of AD patients, which could result from

low dietary intake and/or PUFA oxidation. Because effects of DHA on

Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we

used the APPsw (Tg2576) transgenic mouse model to evaluate the impact

of dietary DHA on amyloid precursor protein (APP) processing and

amyloid burden. Aged animals (17-19 months old) were placed in one of

three groups until 22.5 months of age: control (0.09% DHA), low-DHA

(0%), or high-DHA (0.6%) chow. {beta}-Amyloid (A{beta}) ELISA of the

detergent-insoluble extract of cortical homogenates showed that

DHA-enriched diets significantly reduced total A{beta} by >70% when

compared with low-DHA or control chow diets. Dietary DHA also

decreased A{beta}42 levels below those seen with control chow. Image

analysis of brain sections with an antibody against A{beta} (amino

acids 1-13) revealed that overall plaque burden was significantly

reduced by 40.3%, with the largest reductions (40-50%) in the

hippocampus and parietal cortex. DHA modulated APP processing by

decreasing both {alpha}- and {beta}-APP C-terminal fragment products

and full-length APP. BACE1 ({beta}-secretase activity of the

{beta}-site APP-cleaving enzyme), ApoE (apolipoprotein E), and

transthyretin gene expression were unchanged with the high-DHA diet.

Together, these results suggest that dietary DHA could be protective

against {beta}-amyloid production, accumulation, and potential

downstream toxicity.

 

Key words: DHA; polyunsaturated fatty acid; A{beta}; APP; secretase;

Alzheimer

 

Received Oct 11, 2004; revised February 8, 2005; accepted February 9,

2005.