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Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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2013 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 19, 7916-7921 p.Article in journal (Refereed) Published
Abstract [en]

It is well-established that subcompartments of endoplasmic reticulum (ER) are in physical contact with the mitochondria. These lipid raft-like regions of ER are referred to as mitochondria-associated ER membranes (MAMs), and they play an important role in, for example, lipid synthesis, calcium homeostasis, and apoptotic signaling. Perturbation of MAM function has previously been suggested in Alzheimer's disease (AD) as shown in fibroblasts from AD patients and a neuroblastoma cell line containing familial presenilin-2 AD mutation. The effect of AD pathogenesis on the ER-mitochondria interplay in the brain has so far remained unknown. Here, we studied ER-mitochondria contacts in human AD brain and related AD mouse and neuronal cell models. We found uniform distribution of MAM in neurons. Phosphofurin acidic cluster sorting protein-2 and sigma 1 receptor, two MAM-associated proteins, were shown to be essential for neuronal survival, because siRNA knockdown resulted in degeneration. Up-regulated MAM-associated proteins were found in the AD brain and amyloid precursor protein (APP)(Swe/Lon) mouse model, in which up-regulation was observed before the appearance of plaques. By studying an ER-mitochondria bridging complex, inositol-1,4,5-triphosphate receptor-voltage-dependent anion channel, we revealed that nanomolar concentrations of amyloid beta-peptide increased inositol-1,4,5-triphosphate receptor and voltage-dependent anion channel protein expression and elevated the number of ER-mitochondria contact points and mitochondrial calcium concentrations. Our data suggest an important role of ER-mitochondria contacts and cross-talk in AD pathology.

Place, publisher, year, edition, pages
2013. Vol. 110, no 19, 7916-7921 p.
Keyword [en]
AD mouse models, hippocampal neurons, human cortical brain tissue
National Category
Natural Sciences Engineering and Technology
URN: urn:nbn:se:su:diva-91531DOI: 10.1073/pnas.1300677110ISI: 000319327700084OAI: diva2:634616
Knut and Alice Wallenberg FoundationSwedish Research Council


Available from: 2013-07-01 Created: 2013-06-28 Last updated: 2013-09-10Bibliographically approved
In thesis
1. Mitochondria in Alzheimer's Disease: The Presequence Protease and Mitochondria-Associated ER Membranes
Open this publication in new window or tab >>Mitochondria in Alzheimer's Disease: The Presequence Protease and Mitochondria-Associated ER Membranes
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is one of the most prevalent age-related neurodegenerative disorders and the accumulation of the amyloid-β peptide (Aβ) in the temporal lobe has been implicated in the pathology of AD. Synaptic transmission in neuronal cells is a highly energy dependent process, which relies on the presence and proper function of mitochondria. A growing number of studies have analyzed the roles of mitochondria in AD. Interestingly, Aβ accumulation in mitochondria was detected in AD patient brains and in AD mouse models, which was associated with the formation of reactive oxygen species (ROS) and neuronal death. In mitochondria, the only protease capable of clearing Aβ is the Presequence Protease, PreP.

The aim of this thesis was to study the involvement of mitochondria and hPreP in AD. We investigated how the mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), which are involved in the regulation of Ca2+ signaling, phospholipids synthesis and apoptosis, are affected in AD. We observed MAM at synapses and found that these structures are essential for neuronal and astrocytic survival. We detected altered MAM protein levels in AD patient brains and in AD mouse models in early stages of the disease and found that MAM can be functionally modulated by Aβ. We analyzed human PreP (hPreP) activity in brain extracts from AD patients and different factors that can affect hPreP function. Interestingly, we detected low hPreP activity in AD patient brains and in AD mouse models, which were associated with increased ROS levels and lower cytochrome c oxidase activity. This suggested that protein oxidation could contribute to impaired activity. Furthermore, we investigated a potential correlation between 18 single nucleotide polymorphisms (SNPs) in the PITRM1 gene, encoding hPreP, and the risk for developing AD. Even though we could not find any genetic correlation in the Swedish population examined, biochemical analysis of four non-synonymous hPreP-SNPs, selected on the basis of their location in hPreP structure, showed lower hPreP activity. Furthermore, we demonstrated in vivo and in vitro that the hPreP presequence is processed at amino acid 28 by mitochondrial processing peptidase (MPP) and that inefficient processing does not affect the enzymatic activity of hPreP but it decreases the stability of the protein.

Together, these results indicate that MAM dysfunctions, inefficient Aβ clearance in mitochondria by hPreP, hPreP mutations or inefficient processing, may contribute to the development of AD.  

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2013. 79 p.
Alzheimer's Disease, Mitochondria, Mitochondria-associated ER membranes, human Presequence Protease
National Category
Biochemistry and Molecular Biology
Research subject
urn:nbn:se:su:diva-93285 (URN)978-91-7447-733-7 (ISBN)
Public defence
2013-10-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2013-09-19 Created: 2013-09-06 Last updated: 2013-09-11Bibliographically approved

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