Research ReportArachidonic acid diet attenuates brain Aβ deposition in Tg2576 mice
Introduction
Accumulation of the amyloid β-protein (Aβ), which is the major component of senile plaques in the brains of Alzheimer׳s disease (AD) patients, was hypothesized to initiate a pathologic cascade that eventually leads to AD, and several lines of evidence have converged recently to demonstrate that the soluble oligomers of Aβ, but not monomers or insoluble amyloid fibrils, may be responsible for synaptic dysfunction in the brains of AD patients and AD animal models (Hardy and Selkoe, 2002). Aβ is generated from the amyloid precursor protein (APP) through its sequential proteolytic cleavage catalyzed by β- and γ-secretases. β-Site APP-cleaving enzyme (BACE) is a typical aspartyl protease, and γ-secretase is an aspartyl protease complex composed of four individual proteins (presenilin, nicastrin, APH-1, and PEN-2), with presenilin carrying the protease active site and working intramembrane site (Haass, 2004). The nonamyloidogenic pathway is mediated by α-secretase, which is a member of the disintegrin and metalloprotease (ADAM) family. This secretase produces a soluble fragment of APP (sAPPα), which is considered to have neurotrophic and neuroprotective properties (Thornton et al., 2006).
Since APP, BACE, and proteins consisting of the γ-secretase complex are membrane proteins, it is reasonable to assume that APP metabolism is modulated by membrane lipid composition. In support of this notion, it has been shown that the proteolytic activities of β-secretase and γ-secretase are modulated by membrane lipids, neutral glycosphingolipids, anionic glycerophospholipids, and cholesterol (Ehehalt et al., 2003, Sawamura et al., 2004, Simons et al., 1998). In addition to glycosphingolipids, glycerophospholipids, and cholesterol, neural tissues of mammals contain the highest concentrations of polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (ARA) and docosahexaenoic acid (DHA) (Diau et al., 2005). Both ARA and DHA are major constituents of cell membranes, and thus play important roles in the preservation of physiological and psychological functions, and the development and maintenance of the central nervous system (Uauy and Dangour, 2006).
Low levels of ARA and DHA have been shown in the brain membrane of AD patients compared with that of normal controls (Prasad et al., 1998). Recently, DHA has been extensively investigated for its potential neuroprotective properties (Hooijmans et al., 2009, King et al., 2006). Several studies have shown that dietary intake of DHA decreases brain Aβ levels in APP transgenic mice (Calon et al., 2004, Green et al., 2007, Hooijmans et al., 2009, Oksman et al., 2006, Sahlin et al., 2007). However, the effect of another group of fatty acids, n-6 PUFAs, particularly ARA, on the impairment of learning memory and pathophysiology of AD remains unknown.
In this study, we examined the effects of dietary supplementation with ARA or DHA on the cognitive function of Tg2576 mice. In addition, we determined whether the ARA+ or DHA+ diet alters Aβ levels and APP processing in vivo and in vitro.
Section snippets
Effects of ARA+ and DHA+ diets on Aβ deposition and Aβ levels
In Tg2576 mice, the level of Aβ begins to increase at 6–7 months and the subsequent Aβ deposition is observed at approximately 9 months of age. Between 15 and 23 months of age, Aβ deposition level in the Tg2576 brain increases with age, which is similarly observed in the AD brain (Kawarabayashi et al., 2001). To investigate the effect of dietary PUFA on Aβ deposition and Aβ levels, Tg2576 mice at 9 months of age, at which brain Aβ deposition starts to occur, were fed with a diet containing PUFA
Discussion
In this study, we report the novel findings that ARA+ diet reduces Aβ deposition assayed by immunohistochemistry using anti-Aβ antibodies and thioflavin-S staining in 17-month-old Tg2576 mouse cortices. ARA+ diet also reduces insoluble Aβ40 levels demonstrated by ELISA in 17-month-old Tg2576 mouse cortices. In addition, sAPPα, sAPPβ and CTF-α levels are decreased in ARA+ diet mouse cortices. However, ARA+ diet has no effect on the expression levels of ADAM10, BACE1, PS-1 and nicastrin and also
Diets and animals
This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Center for Geriatrics and Gerontology. The protocol was approved by the Committee on the Ethics of Animal Experiments of the National Center for Geriatrics and Gerontology (Permit Number: Dou23-02-3). All surgery was performed under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering. We prepared three different diets, a
Acknowledgments
This work was supported by the Grant-in-Aid for Scientific Research on Priority Areas-Research on Pathomechanisms of Brain Disorders from the Ministry of Education, Culture, Sports, Science and Technology of Japan, A Grant from the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBRO), A Grant from the Ministry of Health, Labor and Welfare of Japan (Research on Dementia, Health and Labor Sciences Research Grants H20-007), A
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