Increased expression of heme-binding protein 1 early in Alzheimer's disease is linked to neurotoxicity
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.
Article and author information
Author details
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.
Reviewing Editor
- Yukiko Goda, RIKEN, Japan
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.
Version history
- Received: April 8, 2019
- Accepted: August 25, 2019
- Accepted Manuscript published: August 27, 2019 (version 1)
- Version of Record published: September 10, 2019 (version 2)
Copyright
© 2019, Yagensky et al.
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.
Metrics
-
- 4,327
- views
-
- 436
- downloads
-
- 23
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
The brain’s ability to appraise threats and execute appropriate defensive responses is essential for survival in a dynamic environment. Humans studies have implicated the anterior insular cortex (aIC) in subjective fear regulation and its abnormal activity in fear/anxiety disorders. However, the complex aIC connectivity patterns involved in regulating fear remain under investigated. To address this, we recorded single units in the aIC of freely moving male mice that had previously undergone auditory fear conditioning, assessed the effect of optogenetically activating specific aIC output structures in fear, and examined the organization of aIC neurons projecting to the specific structures with retrograde tracing. Single-unit recordings revealed that a balanced number of aIC pyramidal neurons’ activity either positively or negatively correlated with a conditioned tone-induced freezing (fear) response. Optogenetic manipulations of aIC pyramidal neuronal activity during conditioned tone presentation altered the expression of conditioned freezing. Neural tracing showed that non-overlapping populations of aIC neurons project to the amygdala or the medial thalamus, and the pathway bidirectionally modulated conditioned fear. Specifically, optogenetic stimulation of the aIC-amygdala pathway increased conditioned freezing, while optogenetic stimulation of the aIC-medial thalamus pathway decreased it. Our findings suggest that the balance of freezing-excited and freezing-inhibited neuronal activity in the aIC and the distinct efferent circuits interact collectively to modulate fear behavior.
-
- Neuroscience
Motor learning is often viewed as a unitary process that operates outside of conscious awareness. This perspective has led to the development of sophisticated models designed to elucidate the mechanisms of implicit sensorimotor learning. In this review, we argue for a broader perspective, emphasizing the contribution of explicit strategies to sensorimotor learning tasks. Furthermore, we propose a theoretical framework for motor learning that consists of three fundamental processes: reasoning, the process of understanding action–outcome relationships; refinement, the process of optimizing sensorimotor and cognitive parameters to achieve motor goals; and retrieval, the process of inferring the context and recalling a control policy. We anticipate that this ‘3R’ framework for understanding how complex movements are learned will open exciting avenues for future research at the intersection between cognition and action.