Lipid Rafts Act as a Common Platform for Amyloid-β Oligomer-Induced Alzheimer’s Disease Pathology

Article type: Research Article

Authors: Kawarabayashi, Takeshi^{a; b; d; *} | Nakamura, Takumi^{b; d} | Sato, Kaoru^c | Seino, Yusuke^e | Ichii, Sadanobu^b | Nakahata, Naoko^{b; f} | Takatama, Masamitsu^a | Westaway, David^g | George-Hyslop, Peter St.^h | Shoji, Mikio^{a; b; d}

Affiliations: [a] Department of Neurology, Geriatrics Research Institute and Hospital, Maebashi, Gunma, Japan | [b] Department of Social Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan | [c] Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan | [d] Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan | [e] Department of Neurology, Hirosaki National Hospital, Hirosaki, Aomori, Japan | [f] Department of Speech and Hearing, Hirosaki University of Health and Welfare/JuniorCollege, Hirosaki, Aomori, Japan | [g] Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada | [h] Tanz Centre for Research in Neurodegenerative Diseases and Departments of Medicine, Medical Biophysics, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

Correspondence: [*] Correspondence to: Takeshi Kawarabayashi, MD, PhD, Department of Neurology, Geriatrics Research Institute and Hospital, 3-26-8, Otomo-machi, Maebashi, Gunma, 371-0847, Japan. Tel.: +81 27 253 3311; E-mail: tkawara@ronenbyo.or.jp.

Abstract: Background:Amyloid-β (Aβ) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer’s disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. Objective:We demonstrated that lipid rafts function as a common platform for the pathological cascades of AD. Methods:Cellular and synaptosomal lipid rafts were prepared from the brains of Aβ amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed. Results:Aβ dimers, the cellular prion protein (PrPc), and Aβ dimer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N-methyl-D-aspartate receptor, glycogen synthase kinase 3β, total tau, phosphorylated tau, and tau oligomers increased with Aβ dimer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aβ accumulation in the amyloid model mice. Conclusion:Lipid rafts act as a common platform for the progression of AD pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.

Keywords: Alzheimer’s disease, Aβ oligomers, Fyn, lipid rafts, NMDA receptors, phosphorylated tau, platform, PrP^c , synaptosome, tau oligomers

DOI: 10.3233/JAD-215662

Journal: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1189-1203, 2022