Phytic Acid as a Potential Treatment for Alzheimer's Pathology: Evidence from Animal and in vitro Models

Article type: Research Article

Authors: Anekonda, Thimmappa S.^{a; b; *} | Wadsworth, Teri L.^{a; b} | Sabin, Robert^c | Frahler, Kate^a | Harris, Christopher^b | Petriko, Babett^a | Ralle, Martina^d | Woltjer, Randy^e | Quinn, Joseph F.^{a; b}

Affiliations: [a] Department of Neurology, Oregon Health & Science University, Portland, OR, USA | [b] Portland Veteran Administration Medical Center, Oregon Health & Science University, Portland, OR, USA | [c] Superfox Therapeutics Inc., Mill Neck, NY, USA | [d] Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, USA | [e] Department of Pathology, Oregon Health & Science University, Portland, OR, USA

Correspondence: [*] Correspondence to: Thimmappa S. Anekonda, Department of Neurology, Mail Code: R&D 67, Oregon Health & Science University, 3181 Sam Jackson Park Road, Portland, OR 97239, USA; Tel.: +1 503 220 8262 ext 52233; Fax: +1 503 494 7499; E-mail: [email protected].

Abstract: Alzheimer's disease (AD) causes progressive, age-dependent cortical and hippocampal dysfunction leading to abnormal intellectual capacity and memory. We propose a novel protective treatment for AD pathology with phytic acid (inositol hexakisphosphate), a phytochemical found in food grains and a key signaling molecule in mammalian cells. We evaluated the protective and beneficial effects of phytic acid against amyloid-β (Aβ) pathology in MC65 cells and the Tg2576 mouse model. In MC65 cells, 48–72-hour treatment with phytic acid provided complete protection against amyloid precursor protein-C-terminal fragment-induced cytotoxicity by attenuating levels of increased intracellular calcium, hydrogen peroxide, superoxide, Aβ oligomers, and moderately upregulated the expression of autophagy (beclin-1) protein. In a tolerance paradigm, wild type mice were treated with 2% phytic acid in drinking water for 70 days. Phytic acid was well tolerated. Ceruloplasmin activity, brain copper and iron levels, and brain superoxide dismutase and ATP levels were unaffected by the treatment. There was a significant increase in brain levels of cytochrome oxidase and a decrease in lipid peroxidation with phytic acid administration. In a treatment paradigm, 12-month old Tg2576 and wild type mice were treated with 2% phytic acid or vehicle for 6 months. Brain levels of copper, iron, and zinc were unaffected. The effects of phytic acid were modest on the expression of AβPP trafficking-associated protein AP180, autophagy-associated proteins (beclin-1, LC3B), sirtuin 1, the ratio of phosphorylated AMP-activated protein kinase (PAMPK) to AMPK, soluble Aβ1-40, and insoluble Aβ1-42. These results suggest that phytic acid may provide a viable treatment option for AD.

Keywords: Amyloid-β, amyloid-β protein precursor, antioxidant, autophagy, beclin-1, phosphorylated AMP-activated protein kinase, sirtuin 1

DOI: 10.3233/JAD-2010-101287

Journal: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 21-35, 2011