Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly

• DOI: 10.1073/pnas.1421182112
• Publication Date: 2015-07-30T03:24:43Z
• Authors: Takayuki Ohnishi; Masako Yanazawa; Tomoya Sasahara; Yasuki Kitamura; Hidekazu Hiroaki; Yugo Fukazawa; Isao Kii; Takashi Nishiyama; Akiyoshi Kakita; Hiroyuki Takeda; Akihide Takeuchi; Yoshie Arai; Akane Ito; Hitomi Komura; Hajime Hirao; Kaori Satomura; Masafumi Inoue; Shin-ichi Muramatsu; Ko Matsui; Mari Tada; Michio Sato; Eri Saijo; Yoshiki Shigemitsu; Satoko Sakai; Yoshitaka Umetsu; Natsuko Goda; Naomi Takino; Hitoshi Takahashi; Masatoshi Hagiwara; Tatsuya Sawasaki; Genji Iwasaki; Yu Nakamura; Yo-ichi Nabeshima; David B. Teplow; Minako Hoshi
• Keywords: computational modeling; Models, Molecular; 0301 basic medicine; Aging; Hyperexcitotoxicity; Neurodegenerative; Alzheimer's Disease; Mass Spectrometry; Models; 2.1 Biological and endogenous factors; abnormal protein–protein interaction in synapse; Homeostasis; Aetiology; Cells, Cultured; Neurons; Cultured; Cell Death; Computational modeling; abnormal protein-protein interaction in synapse; Molecular Imaging; 3. Good health; protein-protein interaction inhibitors; Neurological; Sodium-Potassium-Exchanging ATPase; hyperexcitotoxicity; Signal Transduction; Protein Binding; 570; Abnormal protein–protein interaction in synapse; Cells; Molecular Sequence Data; 610; Models, Biological; Protein Aggregates; 03 medical and health sciences; Alzheimer Disease; Acquired Cognitive Impairment; Animals; Humans; Amino Acid Sequence; Amyloid beta-Peptides; Sodium; Neurosciences; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Molecular; Biological; NMR; Brain Disorders; Rats; Molecular Weight; HEK293 Cells; protein–protein interaction inhibitors; Dementia; Protein-protein interaction inhibitors; Calcium; Peptides

Significance

Alzheimer’s disease (AD) involves neuron dysfunction and loss. This brain damage is thought to be caused by a small protein, the amyloid β-protein (Aβ), which forms aggregates that are neurotoxic. This neurotoxicity has been explained by multiple mechanisms. We reveal here a new neurotoxic mechanism that involves the interaction between patient-derived Aβ assemblies, termed amylospheroids, and the neuron-specific Na + /K + -ATPase α3 subunit. This interaction causes neurodegeneration through pre-synaptic calcium overload, which explains earlier observations that such neuronal hyperactivation is an early indicator of AD-related neurodegeneration. Importantly, amylospheroid concentrations correlate with disease severity and progression in AD patients. Amylospheroid:neuron-specific Na + /K + -ATPase α3 subunit interactions may be a useful therapeutic target for AD.