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Early Presymptomatic Changes in the Proteome of Mitochondria-Associated Membrane in the APP/PS1 Mouse Model of Alzheimer’s Disease

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Abstract

Intracellular β-amyloid (Aβ) accumulation is an early event in Alzheimer’s disease (AD) progression. Recently, it has been uncovered that presenilins (PSs), the key components of the amyloid precursor protein (APP) processing and the β-amyloid producing γ-secretase complex, are highly enriched in a special sub-compartment of the endoplasmic reticulum (ER) functionally connected to mitochondria, called mitochondria-associated ER membrane (MAM). A current hypothesis of pathogenesis of Alzheimer’s diseases (AD) suggests that MAM is involved in the initial phase of AD. Since MAM supplies mitochondria with essential proteins, the increasing level of PSs and β-amyloid could lead to metabolic dysfunction because of the impairment of ER-mitochondrion crosstalk. To reveal the early molecular changes of this subcellular compartment in AD development MAM fraction was isolated from the cerebral cortex of 3 months old APP/PS1 mouse model of AD and age-matched C57BL/6 control mice, then mass spectrometry-based quantitative proteome analysis was performed. The enrichment and purity of MAM preparations were validated with EM, LC-MS/MS and protein enrichment analysis. Label-free LC-MS/MS was used to reveal the differences between the proteome of the transgenic and control mice. We obtained 77 increased and 49 decreased protein level changes in the range of − 6.365 to + 2.988, which have mitochondrial, ER or ribosomal localization according to Gene Ontology database. The highest degree of difference between the two groups was shown by the ATP-binding cassette G1 (Abcg1) which plays a crucial role in cholesterol metabolism and suppresses Aβ accumulation. Most of the other protein changes were associated with increased protein synthesis, endoplasmic-reticulum-associated protein degradation (ERAD), oxidative stress response, decreased mitochondrial protein transport and ATP production. The interaction network analysis revealed a strong relationship between the detected MAM protein changes and AD. Moreover, it explored several MAM proteins with hub position suggesting their importance in Aβ induced early MAM dysregulation. Our identified MAM protein changes precede the onset of dementia-like symptoms in the APP/PS1 model, suggesting their importance in the development of AD.

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Acknowledgements

This work was supported by the KTIA NAP_13-2-2014-0004 (Katalin Völgyi and Edina Brigitta Udvari), KTIA_NAP_13-2-2015-0003 (Péter Gulyássy, László Drahos and Gábor Juhász) and FIEK_16-1-2016-0005 (Katalin Adrienna Kékesi and Gábor Juhász).

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Authors and Affiliations

  1. Laboratory of Proteomics, Institute of Biology, Eötvös Loránd University, Budapest, Hungary

    Katalin Völgyi, Kata Badics, Edina Brigitta Udvari, Katalin Adrienna Kékesi & Gábor Juhász

  2. MTA-ELTE NAP B Laboratory of Molecular and Systems Neurobiology, Institute of Biology, Hungarian Academy of Sciences and Eötvös Loránd University, Pázmány Péter sétány 1C, Budapest, H-1117, Hungary

    Katalin Völgyi & Edina Brigitta Udvari

  3. Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria

    Fernando J. Sialana & Gert Lubec

  4. MTA-TTK NAP B MS Neuroproteomics Research Group, Hungarian Academy of Sciences, Budapest, Hungary

    Péter Gulyássy, László Drahos & Gábor Juhász

  5. Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary

    Viktor Kis

  6. Paracelsus Medical University, Salzburg, Austria

    Gert Lubec

  7. Department of Physiology and Neurobiology, Eötvös Loránd University, Budapest, Hungary

    Katalin Adrienna Kékesi

  8. CRU Hungary Ltd., Göd, Hungary

    Gábor Juhász

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  1. Katalin Völgyi
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  2. Kata Badics
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Völgyi, K., Badics, K., Sialana, F.J. et al. Early Presymptomatic Changes in the Proteome of Mitochondria-Associated Membrane in the APP/PS1 Mouse Model of Alzheimer’s Disease. Mol Neurobiol 55, 7839–7857 (2018). https://doi.org/10.1007/s12035-018-0955-6

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