Amyloid β‐protein (Aβ) molecules tend to aggregate and subsequently form low MW (LMW) oligomers, high MW (HMW) aggregates such as protofibrils, and ultimately fibrils. These Aβ species can generally form amyloid plaques implicated in the neurodegeneration of Alzheimer disease (AD), but therapies designed to reduce plaque load have not demonstrated clinical efficacy. Recent evidence implicates amyloid oligomers in AD neuropathology, but the precise mechanisms are uncertain. We examined the mechanisms of neuronal dysfunction from HMW‐Aβ _1‐42 exposure by measuring membrane integrity, reactive oxygen species (ROS) generation, membrane lipid peroxidation, membrane fluidity, intracellular calcium regulation, passive membrane electrophysiological properties, and long‐term potentiation (LTP). HMW‐Aβ _1‐42 disturbed membrane integrity by inducing ROS generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and impaired LTP. The damaging effects of HMW‐Aβ _1‐42 were significantly greater than those of LMW‐Aβ _1‐42 Therapeutic reduction of HMW‐Aβ _1‐42 may prevent AD progression by ameliorating direct neuronal membrane damage.—Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe‐Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., Nishijo, H., Kiuchi, Y., Teplow, D. B., Ono, K. High molecular weight amyloid β _1‐42 oligomers induce neurotoxicity via plasma membrane damage. FASEB J. 33, 9220–9234 (2019). www.fasebj.org

Worldwide, Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease and is characterized by unique pathological hallmarks in the brain, including plaques composed of amyloid β-protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that Aβ is responsible for the pathogenesis of AD (i.e., the amyloid hypothesis). Indeed, Aβ molecules tend to aggregate, forming oligomers, protofibrils, and mature fibrils. However, while these Aβ species form amyloid plaques of the type implicated in AD neurodegeneration, recent clinical trials designed to reduce the production of Aβ and/or the plaque burden have not demonstrated clinical efficacy. In addition, recent studies using synthetic Aβ peptides, cell culture models, Arctic transgenic mice, and human samples of AD brain tissues have suggested that the pre-fibrillar forms of Aβ, particularly Aβ protofibrils, may be the most critical species, compared with extracellular fibrillar forms. We recently reported that protofibrils of Aβ_1-42 disturbed membrane integrity by inducing reactive oxygen species generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and synaptic toxicity. Therefore, the therapeutic reduction of protofibrils may prevent the progression of AD by ameliorating neuronal damage and cognitive dysfunction through multiple mechanisms.