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

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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. © 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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Most cited references 35

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Robust determination of the fibre orientation distribution in diffusion MRI: non-negativity constrained super-resolved spherical deconvolution.

J-Donald Tournier, Fernando Calamante, Alan Connelly (2007)

Diffusion-weighted (DW) MR images contain information about the orientation of brain white matter fibres that potentially can be used to study human brain connectivity in vivo using tractography techniques. Currently, the diffusion tensor model is widely used to extract fibre directions from DW-MRI data, but fails in regions containing multiple fibre orientations. The spherical deconvolution technique has recently been proposed to address this limitation. It provides an estimate of the fibre orientation distribution (FOD) by assuming the DW signal measured from any fibre bundle is adequately described by a single response function. However, the deconvolution is ill-conditioned and susceptible to noise contamination. This tends to introduce artefactual negative regions in the FOD, which are clearly physically impossible. In this study, the introduction of a constraint on such negative regions is proposed to improve the conditioning of the spherical deconvolution. This approach is shown to provide FOD estimates that are robust to noise whilst preserving angular resolution. The approach also permits the use of super-resolution, whereby more FOD parameters are estimated than were actually measured, improving the angular resolution of the results. The method provides much better defined fibre orientation estimates, and allows orientations to be resolved that are separated by smaller angles than previously possible. This should allow tractography algorithms to be designed that are able to track reliably through crossing fibre regions.

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The postsynaptic architecture of excitatory synapses: a more quantitative view.

Morgan Sheng, Casper C. Hoogenraad (2007)

Excitatory (glutamatergic) synapses in the mammalian brain are usually situated on dendritic spines, a postsynaptic microcompartment that also harbors organelles involved in protein synthesis, membrane trafficking, and calcium metabolism. The postsynaptic membrane contains a high concentration of glutamate receptors, associated signaling proteins, and cytoskeletal elements, all assembled by a variety of scaffold proteins into an organized structure called the postsynaptic density (PSD). A complex machine made of hundreds of distinct proteins, the PSD dynamically changes its structure and composition during development and in response to synaptic activity. The molecular size of the PSD and the stoichiometry of many major constituents have been recently measured. The structures of some intact PSD proteins, as well as the spatial arrangement of several proteins within the PSD, have been determined at low resolution by electron microscopy. On the basis of such studies, a more quantitative and geometrically realistic view of PSD architecture is emerging.

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Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease.

Marcus Calkins, Maria Manczak, Peizhong Mao … (2011)

Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of Aβ in mitochondrial activity and synaptic alterations in neurons from a mouse model of AD. Using primary neurons from a well-characterized Aβ precursor protein transgenic (AβPP) mouse model (Tg2576 mouse line), for the first time, we studied mitochondrial activity, including axonal transport of mitochondria, mitochondrial dynamics, morphology and function. Further, we also studied the nature of Aβ-induced synaptic alterations, and cell death in primary neurons from Tg2576 mice, and we sought to determine whether the mitochondria-targeted antioxidant SS31 could mitigate the effects of oligomeric Aβ. We found significantly decreased anterograde mitochondrial movement, increased mitochondrial fission and decreased fusion, abnormal mitochondrial and synaptic proteins and defective mitochondrial function in primary neurons from AβPP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed a large number of small mitochondria and structurally damaged mitochondria, with broken cristae in AβPP primary neurons. We also found an increased accumulation of oligomeric Aβ and increased apoptotic neuronal death in the primary neurons from the AβPP mice relative to the WT neurons. Our results revealed an accumulation of intraneuronal oligomeric Aβ, leading to mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in AβPP cultures. However, we found that the mitochondria-targeted antioxidant SS31 restored mitochondrial transport and synaptic viability, and decreased the percentage of defective mitochondria, indicating that SS31 protects mitochondria and synapses from Aβ toxicity.

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Author and article information

Contributors

Ching‐Po Lin: cplin@ym.edu.tw

Ting‐Fen Tsai:

ORCID: https://orcid.org/0000-0003-3239-4430

tftsai@ym.edu.tw

Journal

Journal ID (nlm-ta): J Pathol

Journal ID (iso-abbrev): J. Pathol

Journal ID (doi): 10.1002/(ISSN)1096-9896

Journal ID (publisher-id): PATH

Title: The Journal of Pathology

Publisher: John Wiley & Sons, Ltd (Chichester, UK )

ISSN (Print): 0022-3417

ISSN (Electronic): 1096-9896

Publication date (Electronic): 13 January 2020

Publication date (Print): March 2020

Volume: 250

Issue: 3 ( doiID: 10.1002/path.v250.3 )

Pages: 299-311

Affiliations

[ ¹ ] The Ph.D. Program for Translational Medicine, College of Medical Science and Technology Taipei Medical University Taipei Taiwan

[ ² ] TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei Taiwan

[ ³ ] Department of Life Sciences and Institute of Genome Sciences National Yang‐Ming University Taipei Taiwan

[ ⁴ ] Department of Biomedical Imaging and Radiological Sciences National Yang‐Ming University Taipei Taiwan

[ ⁵ ] Aging and Health Research Center National Yang‐Ming University Taipei Taiwan

[ ⁶ ] Department of Geriatric Medicine National Yang‐Ming University Taipei Taiwan

[ ⁷ ] Brain Research Center National Yang‐Ming University Taipei Taiwan

[ ⁸ ] Institute of Neuroscience National Yang‐Ming University Taipei Taiwan

[ ⁹ ] Center for Geriatrics and Gerontology Neurological Institute, Taipei Veterans General Hospital Taipei Taiwan

[ ¹⁰ ] Department of Neurology Neurological Institute, Taipei Veterans General Hospital Taipei Taiwan

[ ¹¹ ] Center of General Education Chang Gung University Taoyuan Taiwan

[ ¹² ] Department of Biomedical Science Chang Gung University Taoyuan Taiwan

[ ¹³ ] Institute of Molecular and Genomic Medicine National Health Research Institutes Zhunan Taiwan

[ ¹⁴ ] Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes Zhunan Taiwan

Author notes

[*] [* ] Correspondence to: C‐P Lin, Institute of Neuroscience, National Yang‐Ming University, 155 Li‐Nong St., Sec. 2, Beitou, Taipei 112, Taiwan. E‐mail: cplin@ 123456ym.edu.tw ; or T‐F Tsai, Department of Life Sciences and Institute of Genome Sciences, National Yang‐Ming University, 155 Li‐Nong St., Sec. 2, Beitou, Taipei 112, Taiwan. E‐mail: tftsai@ 123456ym.edu.tw

Author information

Yi‐Fan Chen https://orcid.org/0000-0002-0793-8769

Ting‐Fen Tsai https://orcid.org/0000-0003-3239-4430

Article

Publisher ID: PATH5374

DOI: 10.1002/path.5374

PMC ID: 7065100

PubMed ID: 31837018

SO-VID: c3b19fd7-1bc7-44d2-aef6-e3f9f3f7d756

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date received : 18 June 2019

Date revision received : 01 December 2019

Date accepted : 04 December 2019

Page count

Figures: 6, Tables: 0, Pages: 13, Words: 6701

Funding

Funded by: National Health Research Institutes , open-funder-registry 10.13039/501100004737;

Funded by: Ministry of Science and Technology , open-funder-registry 10.13039/100007225;

Award ID: MOST 107‐2634‐F‐010 ‐001

Award ID: MOST 107‐3011‐B‐010‐001

Award ID: MOST105‐2320‐B‐038‐022‐MY3

Funded by: National Yang‐Ming University , open-funder-registry 10.13039/501100005382;

Custom metadata

source-schema-version-number 2.0

cover-date March 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.7 mode:remove_FC converted:11.03.2020

ScienceOpen disciplines: Pathology

Keywords: alzheimer's disease,cisd2,mitochondria,track density imaging (tdi),transcriptomics

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ScienceOpen disciplines: Pathology

Keywords: alzheimer's disease, cisd2, mitochondria, track density imaging (tdi), transcriptomics

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

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Abstract

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Alternative approaches to Alzheimer's Disease

Most cited references 35

Robust determination of the fibre orientation distribution in diffusion MRI: non-negativity constrained super-resolved spherical deconvolution.

The postsynaptic architecture of excitatory synapses: a more quantitative view.

Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease.

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