Toxic Amyloid-β₄₂ Conformer May Accelerate the Onset of Alzheimer’s Disease in the Preclinical Stage

Article type: Research Article

Authors: Futamura, Akinori^a | Hieda, Sotaro^a | Mori, Yukiko^a | Kasuga, Kensaku^b | Sugimoto, Azusa^a | Kasai, Hideyo^a | Kuroda, Takeshi^a | Yano, Satoshi^a | Tsuji, Mayumi^c | Ikeuchi, Takeshi^b | Irie, Kazuhiro^d | Ono, Kenjiro^{a; *}

Affiliations: [a] Division of Neurology, Department of Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan | [b] Department of Molecular Genetics, Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan | [c] Pharmacological Research Center, Showa University, Shinagawa-ku, Tokyo, Japan | [d] Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan

Correspondence: [*] Correspondence to: Kenjiro Ono, Division of Neurology, Department of Medicine, Showa University School of Medicine, 1-5-8, Hatanodai Shinagawa-Ku, Tokyo 142-8666, Japan. Tel.: +81 3 3784 8710; Fax: +81 3784 8710; E-mail: onoken@med.showa-u.ac.jp.

Abstract: Background:Toxic amyloid-β protein (Aβ) conformers play an important role in the progression of Alzheimer’s disease (AD). The ratio of toxic conformer to total Aβ42 in cerebrospinal fluid (CSF) was significantly high in AD and mild cognitive impairment (MCI) due to AD using an enzyme-linked immunosorbent assay kit with a 24B3 antibody. Objective:We compared the toxic Aβ42, conformer at different stages of AD to identify its contribution to AD pathogenesis. Methods:We compared 5 patients with preclinical AD, 11 patients with MCI due to AD, 21 patients with AD, and 5 healthy controls to measure CSF levels of total Aβ42, total tau, tau phosphorylated at threonine 181 (p-tau), and toxic Aβ conformers. All were classified using the Clinical Dementia Rating. Cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE-J). Results:Toxic Aβ conformer level was insignificant between groups, but its ratio to Aβ42 was significantly higher in AD than in preclinical AD (p < 0.05). Toxic Aβ42 conformer correlated positively with p-tau (r = 0.67, p < 0.01) and p-tau correlated negatively with MMSE-J (r = –0.38, p < 0.05). Conclusion:Toxic Aβ conformer triggers tau accumulation leading to neuronal impairment in AD pathogenesis.

Keywords: Alzheimer’s disease, amyloid-β protein, cerebrospinal fluid, preclinical Alzheimer’s disease, tau protein, toxic conformer

DOI: 10.3233/JAD-201407

Journal: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 639-646, 2021