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XBP1 and PERK Have Distinct Roles in Aβ-Induced Pathology

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Abstract

Endoplasmic reticulum (ER) stress triggers multiple cellular signals to restore cellular function or induce proapoptosis that is altered in the brains of patients with Alzheimer’s disease (AD). However, the role of ER stress in β-amyloid (Aβ)-induced AD pathology remains elusive, and data obtained from different animal models and under different experimental conditions are sometimes controversial. The current study conducted in vivo genetic experiments to systematically examine the distinct role of each ER stress effector during disease progression. Our results indicated that inositol-requiring enzyme 1 was activated before protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation in Aβ42 transgenic flies. Proteasome activity played a key role in this sequential activation. Furthermore, our study separated learning deficits from early degeneration in Aβ-induced impairment by demonstrating that X-box binding protein 1 overexpression at an early stage reversed Aβ-induced early death without affecting learning performance in the Aβ42 transgenic flies. PERK activation was determined to only enhance Aβ-induced learning deficits. Moreover, proteasome overactivation was determined to delay PERK activation and improve learning deficits. Altogether, the findings of this study demonstrate the complex roles of ER stress during Aβ pathogenesis and the possibility of using different ER stress effectors as reporters to indicate the status of disease progression.

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Acknowledgements

We thank Dr. Kuei-Sen Hsu for the comments on the manuscript. We also thank Drs. Y. Zhong, P. Fernandez-Funez, S. Marciniak, U.B. Pandey, R. W. Ordway, M.J. Kang, L. Luo, M. Miura, and H. Steller; Bloomington Stock Center; VDRC, Vienna; and FlyORF for providing the experimental materials. Special thanks to the technical services from the “Bio-image Core Facility of the National Core Facility Program for Biotechnology, Ministry of Science and Technology, Taiwan.”

Funding

This work was supported by the Ministry of Science and Technology, Taiwan (MOST 104-2320-B-006-037-MY3 to H.C. Chiang).

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  1. Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Kuan-Chung Cheng & Hsueh-Cheng Chiang

  2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Kuan-Chung Cheng & Hsueh-Cheng Chiang

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  1. Kuan-Chung Cheng
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Correspondence to Hsueh-Cheng Chiang.

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Cheng, KC., Chiang, HC. XBP1 and PERK Have Distinct Roles in Aβ-Induced Pathology. Mol Neurobiol 55, 7523–7532 (2018). https://doi.org/10.1007/s12035-018-0942-y

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