Arachidonic or Docosahexaenoic Acid Diet Prevents Memory Impairment in Tg2576 Mice

Article type: Research Article

Authors: Hosono, Takashi^{a; b} | Mouri, Akihiro^{c; d} | Nishitsuji, Kazuchika^{b; e} | Jung, Cha-Gyun^{b; f} | Kontani, Masanori^g | Tokuda, Hisanori^g | Kawashima, Hiroshi^g | Shibata, Hiroshi^g | Suzuki, Toshiharu^h | Nabehsima, Toshitaka^{d; i} | Michikawa, Makoto^{b; j; *}

Affiliations: [a] Department of Chemistry and Life Science, Nihon University Graduate School of Bioresource Sciences, Fujisawa, Japan | [b] Department of Alzheimer’s Disease, National Center for Geriatrics and Gerontology, Obu, Japan | [c] Division of Clinical Sciences and Neuropsychopharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan | [d] NPO Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan | [e] Department of Molecular Pathology, Institute of Biomedical Science, The University of Tokushima Graduate School, Tokushima, Japan | [f] Department of Neurophysiology and Brain Science, Nagoya City University, School of Medical Sciences, Nagoya, Japan | [g] Institute for Health Care Science, Suntory Wellness Ltd., Osaka, Japan | [h] Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan | [i] Nabeshima Laboratory, Department of Pharmacy, Meijyo University, Nagoya, Japan | [j] Department of Biochemistry, Nagoya City University, School of Medical Sciences, Nagoya, Japan

Correspondence: [*] Correspondence to: Makoto Michikawa, Department of Biochemistry, Nagoya City University, School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan. Tel.: +81 52 853 8139; Fax: +81 52 841 3480; michi@med.nagoya-cu.ac.jp

Abstract: It is believed that the amyloid β-protein (Aβ) plays a causative role in the development of Alzheimer’s disease (AD). The amyloid-β protein precursor (AβPP), a substrate of Aβ, and β-secretase and γ-secretase complex proteins, which process AβPP to generate Aβ, are all membrane proteins. Thus, it is reasonable to assume that alterations in brain lipid metabolism modulate AβPP and/or Aβ metabolism. However, the role of cellular polyunsaturated fatty acids in AβPP processing has not been completely understood yet. We report here that 4 months of treatment of Tg2576 mice with an arachidonic acid (ARA)- or a docosahexaenoic acid (DHA)-containing (ARA+ or DHA+) diet prevented memory impairment at 13 months of age. Although, AβPP processing to generate soluble AβPP and induce Aβ synthesis was enhanced, Aβ 1 - 42/Aβ 1 - 40 ratio decreased in 14-month-old Tg2576 mice fed with the ARA+ or DHA+ diet. The ARA+ or DHA+ diet did not alter the AβPP levels and the expression levels of Aβ-degrading enzymes. In cortical primary neuron cultures, ARA or DHA treatment also increased soluble AβPP and Aβ1 - 40 levels, and decreased Aβ 1 - 42/Aβ 1 - 40 ratio, which are similar to what were observed in Tg2576 mice fed with ARA+ or DHA+ diet. These findings suggest that not only the DHA+ diet, but also the ARA+ diet could prevent cognitive dysfunction in Tg2576 mice through the alteration of AβPP processing.

Keywords: Alzheimer’s disease, amyloid β-protein, amyloid β-protein precursor, arachidonic acid, docosahexaenoic acid, memory impairment

DOI: 10.3233/JAD-150341

Journal: Journal of Alzheimer's Disease, vol. 48, no. 1, pp. 149-162, 2015