Upregulation of Cisd2 attenuates Alzheimer's-related neuronal loss in mice

Yi Fan Chen, Tzu Yu Chou, I. Hsuan Lin, Chung Guang Chen, Cheng Heng Kao, Guo Jen Huang, Liang Kung Chen, Pei Ning Wang, Ching Po Lin, Ting Fen Tsai

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Abstract

CDGSH iron–sulfur domain-containing protein 2 (Cisd2), a protein that declines in an age-dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid β (Aβ) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two-fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aβ-mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild-type mice. These findings highlight Cisd2-based therapies as a potential disease-modifying strategy for AD.

Original languageEnglish
Pages (from-to)299-311
Number of pages13
JournalJournal of Pathology
Volume250
Issue number3
DOIs
Publication statusPublished - Mar 1 2020

Keywords

  • Alzheimer's disease
  • Cisd2
  • mitochondria
  • track density imaging (TDI)
  • transcriptomics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Chen, Y. F., Chou, T. Y., Lin, I. H., Chen, C. G., Kao, C. H., Huang, G. J., Chen, L. K., Wang, P. N., Lin, C. P., & Tsai, T. F. (2020). Upregulation of Cisd2 attenuates Alzheimer's-related neuronal loss in mice. Journal of Pathology, 250(3), 299-311. https://doi.org/10.1002/path.5374