High molecular weight amyloid β1‐42 oligomers induce neurotoxicity via plasma membrane damage: Molecular and cell biology/APP/Abeta/amyloid. (7th December 2020)

• Record Type: Journal Article
• Authors: Yasumoto, Taro; Takamura, Yusaku; Tsuji, Mayumi; Nakayama, Takahiro; Imamura, Keiko; Inoue, Haruhisa; Nakamura, Shiro; Inoue, Tomio; Kimura, Atsushi Michael; Yano, Satoshi; Nishijo, Hisao; Kiuchi, Yuji; Teplow, David B.; Ono, Kenjiro
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.037546
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Amyloid β protein (Aβ) molecules that may contribute to Alzheimer's disease (AD) form low molecular weight (LMW‐Aβ), high molecular weight oligomer (HMW‐Aβ) such as protofibrils, and ultimately fibrils. Recent evidence suggests that oxidative stress and plasma membrane damage induced by soluble Aβ oligomers elicit neurotoxicity and play an initiating role in the development of AD pathology. But the precise mechanisms still remain unclear. In this study, we focused on clarifying the detailed mechanism of the HMW‐Aβ neurotoxicity. Method: The elution of LMW‐Aβ and HMW‐Aβ was carried out using size exclusion chromatography. SH‐SY5Y cells (Human glioblastoma) were exposed to 5 μM of LMW‐Aβ and HMW‐Aβ for 30 min. To detect cytotoxicity, Aβexposed‐cells were measured mitochondrial activity and release of lactate dehydrogenase. Oxidative stress biomarkers (reactive oxygen species and phospholipid peroxidation of plasma membrane) were assessed. We also assayed intracellular Ca 2+ ([Ca 2+ ]i ) level and membrane fluidity, and membrane electrical resistance by whole‐cell patch‐clamp. Result: SH‐SY5Y cells exposed to Aβ oligomers had significantly increased cytotoxicity and oxidative stress compared to untreated cells. The damaging effects of HMW‐Aβ were significantly greater than those of LMW‐Aβ. Exposure of SH‐SY5Y cells to LMW‐Aβ or HMW‐Aβ triggered an elevation in [Ca 2+ ]i . [Ca 2+ ]i levels in SH‐SY5Y cells exposed to HMW‐Aβ rose and maintained high level of [Ca 2+ ]i, while pretreatment with nicardipine and memantine suppressed this continuous rising. Furthermore, both HMW‐Aβ and LMW‐Aβ significantly reduced SH‐SY5Y cell membrane fluidity compared with untreated control cell while, HMW‐Aβ produced a larger decrease in fluidity than did LMW‐Aβ. The resting potential was significantly elevated in SH‐SY5Y cells exposed to HMW‐Aβ compared with untreated control cells and LMW‐Aβ exposed cells and the input resistance was significantly lower following HMW‐Aβ exposure. Conclusion: These results suggest that HMW‐Aβchanged the structure of lipid bilayer due to cell membrane phospholipid peroxidation and disrupted the homeostasis of ions across the cell membrane. It was speculated that HMW‐Aβ induced neurotoxicity was induced by membrane structural changes such as the formation of small pores in the cell membrane. Accordingly, we propose that the therapeutic reduction of HMW‐Aβ has important implications for the development of AD therapies.