Alzheimer Aβ Assemblies Accumulate in Excitatory Neurons upon Proteasome Inhibition and Kill Nearby NAKα3 Neurons by Secretion

Hitomi Komura; Shota Kakio; Tomoya Sasahara; Yoshie Arai; Naomi Takino; Michio Sato; Kaori Satomura; Takayuki Ohnishi; Yo-Ichi Nabeshima; Shin-Ichi Muramatsu; Isao Kii; Minako Hoshi

doi:10.1016/j.isci.2019.01.018

Alzheimer Aβ Assemblies Accumulate in Excitatory Neurons upon Proteasome Inhibition and Kill Nearby NAKα3 Neurons by Secretion

iScience. 2019 Mar 29:13:452-477. doi: 10.1016/j.isci.2019.01.018. Epub 2019 Feb 28.

Authors

Affiliations

¹ Department of Brain and Neurodegenerative Disease Research, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe 650-0047, Japan; TAO Health Life Pharma Co., Ltd., Med-Pharma Collaboration Bldg, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
² Division of Neurology, Jichi Medical University, Shimotsuke 329-0498, Japan.
³ Meiji University, Graduate School of Agriculture, Meiji University, Kawasaki 214-8571, Japan.
⁴ Department of Gerontology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe 650-0047, Japan.
⁵ Division of Neurology, Jichi Medical University, Shimotsuke 329-0498, Japan; Center for Gene & Cell Therapy, The Institute of Medical Science, University of Tokyo, Tokyo 108-0071, Japan.
⁶ RIKEN Center for Life Science Technologies, Division of Bio-Function Dynamics Imaging, Kobe 650-0047, Japan.
⁷ Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. Electronic address: minako.hoshi.9w@lmls-kobe.org.

Abstract

We identified ∼30-mer amyloid-β protein (Aβ) assemblies, termed amylospheroids, from brains of patients with Alzheimer disease (AD) as toxic entities responsible for neurodegeneration and showed that Na⁺,K⁺-ATPase α3 (NAKα3) is the sole target of amylospheroid-mediated neurodegeneration. However, it remains unclear where in neurons amylospheroids form and how they reach their targets to induce neurodegeneration. Here, we present an in vitro culture system designed to chronologically follow amylospheroid formation in mature neurons expressing amyloid precursor protein bearing early-onset AD mutations. Amylospheroids were found to accumulate mainly in the trans-Golgi network of excitatory neurons and were initially transported in axons. Proteasome inhibition dramatically increased amylospheroid amounts in trans-Golgi by increasing Aβ levels and induced dendritic transport. Amylospheroids were secreted and caused the degeneration of adjacent NAKα3-expressing neurons. Interestingly, the ASPD-producing neurons later died non-apoptotically. Our findings demonstrate a link between ASPD levels and proteasome function, which may have important implications for AD pathophysiology.

Keywords: Cellular Neuroscience; Neuroscience; Pathophysiology.