Journal
JOURNAL OF PATHOLOGY
Volume 250, Issue 3, Pages 299-311Publisher
WILEY
DOI: 10.1002/path.5374
Keywords
Alzheimer's disease; Cisd2; mitochondria; track density imaging (TDI); transcriptomics
Funding
- Clinical and Industrial Genomic Application Development Service Center of National Core Facility for Biopharmaceuticals, Taiwan [MOST 107-2319-B-010-002]
- Ministry of Science and Technology [MOST 108-2321-B-010-013-MY2, MOST 107-2634-F-010-001, MOST 108-2321-B-010-010-MY2, MOST 108-2634-F-010-001, MOST105-2320-B-038-022-MY3]
- National Health Research Institutes [MG-106-PP-17, MG-107-PP-17, MG-108-PP-14]
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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 beta (A beta) 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 (similar to two-fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against A beta-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. (c) 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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