Pyruvate Prevents the Inhibition of the Long-term Potentiation Induced by Amyloid-β through Protein Phosphatase 2A Inactivation

Article type: Research Article

Authors: Wang, Xiaonan^{a; *} | Takata, Toshihiro^{b; d} | Bai, Xiaojuan^a | Ou, Fengrong^e | Yokono, Koichi^b | Sakurai, Takashi^{b; c}

Affiliations: [a] Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, China | [b] Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Kobe, Japan | [c] National Center for Geriatrics and Gerontology, Obu City, Japan | [d] Saiseikai Nakatsu Hospital, Osaka, Japan | [e] Department of Clinical Nutrition, The First Affiliated Hospital of China Medical University, Shenyang, China

Correspondence: [*] Correspondence to: Xiaonan Wang, MD, PhD, Department of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, 110001 Shenyang, China. Tel.: +86 24 8328 2306; Fax: +86 24 8328 2693; E-mail: [email protected].

Abstract: Amyloid-β (Aβ) oligomers are derived from proteolytic cleavage of amyloid-β protein precursor and can impair memory and hippocampal long-term potentiation (LTP) in vivo and in vitro. They are recognized as the primary neurotoxic agents in Alzheimer's disease. Pyruvate has a protective effect against Aβ-induced neuronal cell death in hippocampal slice cultures. However, whether pyruvate also has a protective effect against the inhibition of neuronal plasticity induced by Aβ remains to be elucidated. This study examined the effect of pyruvate on the Aβ-induced inhibition of LTP in the rat hippocampus. We found that pyruvate prevented the Aβ-induced inhibition of LTP as strong as fostriecin, a specific protein phosphatase 2A (PP2A) inhibitor. Pyruvate prevented the Aβ block of Ca2+/calmodulin dependent protein kinase 2 (CaMK2) autophosphorylation and the Aβ-induced PP2A activation. Pyruvate, but not lactate, decreased reactive oxygen species levels in CA1 slices exposed to Aβ. We propose that pyruvate could prevent the Aβ-induced inhibition of LTP by the re-autophosphorylation of CaMK2 through PP2A inactivation. The reduction of reactive oxygen species production is considered to be the upstream mechanism of this observed pyruvate protection.

Keywords: Amyloid-β oligomer, calmodulin dependent protein kinase 2, long-term potentiation, protein phosphatase 2A, pyruvate, reactive oxygen species

DOI: 10.3233/JAD-2012-101869

Journal: Journal of Alzheimer's Disease, vol. 30, no. 3, pp. 665-673, 2012