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Decreased Proteasomal Function Induces Neuronal Loss and Memory Impairment

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Title: Decreased Proteasomal Function Induces Neuronal Loss and Memory Impairment
Authors: Tomaru, Utano Browse this author →KAKEN DB
Ito, Tomoki Browse this author
Ohmura, Yu Browse this author →KAKEN DB
Higashikawa, Kei Browse this author →KAKEN DB
Miyajima, Syota Browse this author
Tomatsu, Ruka Browse this author
Higashi, Tsunehito Browse this author →KAKEN DB
Ishizu, Akihiro Browse this author →KAKEN DB
Kuge, Yuji Browse this author →KAKEN DB
Yoshioka, Mitsuhiro Browse this author →KAKEN DB
Kasahara, Masanori Browse this author →KAKEN DB
Issue Date: Jan-2021
Publisher: Elsevier
Journal Title: The American Journal of Pathology
Volume: 191
Issue: 1
Start Page: 144
End Page: 156
Publisher DOI: 10.1016/j.ajpath.2020.10.004
Abstract: Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia worldwide. There is considerable evidence of age-related disruption of proteostasis being responsible for the development of AD. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and an age-related decline in its activity has been implicated in age-related pathologies. Although proteasomal dysfunction is assumed to be a key AD hallmark, it remains unclear whether its role in disease onset is causative or secondary. In this study, we demonstrate that mice with proteasomal dysfunction exhibited memory impairment with associated neuronal loss, accumulation of phosphorylated tau, and activation of endoplasmic reticulum (ER) stress-related apoptosis pathways. Impaired proteasomal activity also activated ER stress-related apoptosis pathways in HT-22, a murine hippocampal neuronal cell line. HT-22 cell death, caused by proteasomal inhibition, was prevented by an inhibitor of c-Jun N-terminal kinase, an ER stress-related molecule. Collective evidence suggests that impaired proteasomal activity alters proteostasis, and subsequent ER stress-mediated pathways play pivotal roles in neuronal loss. Because aging decreases proteasomal function, age-related impairment of proteasomes may be involved in the development and progression of AD in elderly patients.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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