Decreased Proteasomal Function Induces Neuronal Loss and Memory Impairment
| Autor: | Yu Ohmura, Tsunehito Higashi, Utano Tomaru, Tomoki Ito, Ruka Tomatsu, Masanori Kasahara, Yuji Kuge, Syota Miyajima, Mitsuhiro Yoshioka, Akihiro Ishizu, Kei Higashikawa |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Enzyme complex Programmed cell death Proteasome Endopeptidase Complex Apoptosis Mice Transgenic tau Proteins Pathology and Forensic Medicine 03 medical and health sciences Mice 0302 clinical medicine Alzheimer Disease medicine Memory impairment Animals Neurons Memory Disorders Kinase business.industry Endoplasmic reticulum Brain medicine.disease Endoplasmic Reticulum Stress Cell biology Mice Inbred C57BL 030104 developmental biology Proteostasis Proteasome Alzheimer's disease business 030217 neurology & neurosurgery |
| Zdroj: | The American journal of pathology. 191(1) |
| ISSN: | 1525-2191 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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