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

eLife

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[1] Biomedical Engineering and Sciences Department, School of Mechanical and Manufacturing Engineering (SMME), National University of Sciences and Technology (NUST), Islamabad, Pakistan;Clinical Dementia Center, Department of Neurology, German Center for Neurodegenerative Diseases, University Medical Center Göttingen, Göttingen, Germany;Clinical Dementia Center, Department of Neurology, German Center for Neurodegenerative Diseases, University Medical Center Göttingen, Göttingen, Germany;Department of Genes and Behavior, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany;Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany;Interactomics and Intracellular Trafficking Laboratory, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore;Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany;Research Group Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany;Bioanalytics Group, Institute for Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany;Research Group Protein Trafficking in Synaptic Development and Function, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany;Research Group Protein Trafficking in Synaptic Development and Function, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany;Interactomics and Intracellular Trafficking Laboratory, Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore;LSI Neurobiology Programme, National University of Singapore, Singapore, Singapore;Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore;Institute for Health Innovation and Technology, National University of Singapore, Singapore, Singapore;

关键词: neuron;    Alzheimer's disease;    Hebp1;    Human;    Mouse;    Rat;   

DOI  :  10.7554/eLife.47498

来源: publisher

【 摘 要 】

10.7554/eLife.47498.001Alzheimer’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.

【 授权许可】

CC BY