Increased expression of heme-binding protein 1 early in Alzheimer's disease is linked to neurotoxicity

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Abstract

Alzheimer's disease is the most prevalent neurodegenerative disorder leading to progressive cognitive decline. Despite decades of research, understanding AD progression at the molecular level, especially at its early stages, remains elusive. Here, we identified several presymptomatic AD markers by investigating brain proteome changes over the course of neurodegeneration in a transgenic mouse model of AD (3×Tg-AD). We show that one of these markers, heme-binding protein 1 (Hebp1), is elevated in the brains of both 3×Tg-AD mice and patients affected by rapidly-progressing forms of AD. Hebp1, predominantly expressed in neurons, interacts with the mitochondrial contact site complex (MICOS) and exhibits a perimitochondrial localization. Strikingly, wildtype, but not Hebp1-deficient, neurons showed elevated cytotoxicity in response to heme-induced apoptosis. Increased survivability in Hebp1-deficient neurons is conferred by blocking the activation of the mitochondrial-associated caspase signaling pathway. Taken together, our data highlight a role of Hebp1 in progressive neuronal loss during AD progression.

Data availability

All data generated or analysed during this manuscript are included in the manuscript and supporting files. Source data files have been provided for Figs 2, 6, 7, 8 and 9.

The following previously published data sets were used

1. Benes F
2. Schadt E
(2011) HBTRC-MLC Human Visual Cortex Agilent (Jun11) mlratio
GeneNetwork Accession, GN327.

http://www.genenetwork.org/webqtl/main.py?FormID=sharinginfo&GN_AccessionId=327
1. Benes F
2. Schadt E
(2011) HBTRC-MLC Human Prefrontal Cortex Agilent (Jun11) mlratio
GeneNetwork Accession, GN328.

http://www.genenetwork.org/webqtl/main.py?FormID=sharinginfo&GN_AccessionId=328
1. Benes F
2. Schadt E
(2011) HBTRC-MLC Human Cerebellum Agilent (Jun11) mlratio
GeneNetwork Accession, GN326.

http://www.genenetwork.org/webqtl/main.py?FormID=sharinginfo&GN_AccessionId=326

Article and author information

Author details

Oleksandr Yagensky

Research Group Protein Trafficking in Synaptic Development and Function, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

For correspondence
oleksandr.yagensky@mpibpc.mpg.de

Competing interests
The authors declare that no competing interests exist.
Mahdokht Kohansal-Nodehi

Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3898-5197
Saravanan Gunaseelan

Interactomics and Intracellular Trafficking Laboratory, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.
Tamara Rabe

Department of Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

Competing interests
The authors declare that no competing interests exist.
Saima Zafar

Clinical Dementia Center, Department of Neurology, German Center for Neurodegenerative Diseases, University Medical Center Göttingen, Göttingen, Germany

Competing interests
The authors declare that no competing interests exist.
Inga Zerr

Clinical Dementia Center, Department of Neurology, German Center for Neurodegenerative Diseases, University Medical Center Göttingen, Göttingen, Germany

Competing interests
The authors declare that no competing interests exist.
Wolfgang Haertig

Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany

Competing interests
The authors declare that no competing interests exist.
Henning Urlaub

Bioanalytics, Institute of Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany

Competing interests
The authors declare that no competing interests exist.
John JE Chua

Interactomics and Intracellular Trafficking Laboratory, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

For correspondence
phsjcje@nus.edu.sg

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5615-1014

Funding

Deutsche Forschungsgemeinschaft (CH 1385/1-1)

John JE Chua

National University of Singapore

John JE Chua

Max-Planck-Gesellschaft (Open-access funding)

John JE Chua

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures used here fully comply with the guidelines as stipulated in the section 4 of the Animal Welfare Law of the Federal Republic of Germany (section 4 of TierSchG, Tierschutzgesetz der Bundesrepublik Deutschland) or in accordance with the Principles of Laboratory Animal Care, and approved by the Institutional Animal Care and Use Committee of the National University of Singapore (protocol number: 2015-01121 (R15-1121)). Procedures performed in the animal facility at the Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany were registered accordingly to the section 11 Abs. 1 TierSchG as documented by 39 20 00_2a Si/rö, dated 11th Dec 2013 ("Erlaubnis, Wirbeltiere zur Versuchszwecken zu züchten und zu halten"), by the Veterinär- und Verbraucherschutzamt für den Landkreis und die Stadt Göttingen and examined regularly by the supervisory veterinary authority of the Landkreis Göttingen. All procedures were supervised by the animal welfare officer and the animal welfare committee of the Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany established accordingly to the TierSchG and the regulation about animal used in experiments, dated on 1st Aug 2013 (TierSchVersV, Tierschutz-Versuchstier-Verordung).

Human subjects: All experimental protocols were approved and the study conformed to the Code of Ethics of the World Medical Association. All study participants or their legal next of kin gave informed consent and the study was approved by the local ethics committee in Göttingen (No. 24/8/12). All samples were anonymized with regard to their personal data.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.