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Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
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2011 (Engelska)Ingår i: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 27, nr 1, s. 75-87Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD.

Ort, förlag, år, upplaga, sidor
2011. Vol. 27, nr 1, s. 75-87
Nyckelord [en]
Mitochondrial amyloid-β, mitochondrial function, oxidative stress, presequence protease (PreP), proteolysis
Nationell ämneskategori
Biokemi och molekylärbiologi Neurovetenskaper
Forskningsämne
biofysik; biokemi
Identifikatorer
URN: urn:nbn:se:su:diva-70949DOI: 10.3233/JAD-2011-101716ISI: 000296570400007PubMedID: 21750375OAI: oai:DiVA.org:su-70949DiVA, id: diva2:483330
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authorCount :8

Tillgänglig från: 2012-01-25 Skapad: 2012-01-25 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
Ingår i avhandling
1. Mitochondria in Alzheimer's Disease: The Presequence Protease and Mitochondria-Associated ER Membranes
Öppna denna publikation i ny flik eller fönster >>Mitochondria in Alzheimer's Disease: The Presequence Protease and Mitochondria-Associated ER Membranes
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.  

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2013. s. 79
Nyckelord
Alzheimer's Disease, Mitochondria, Mitochondria-associated ER membranes, human Presequence Protease
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-93285 (URN)978-91-7447-733-7 (ISBN)
Disputation
2013-10-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

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

Tillgänglig från: 2013-09-19 Skapad: 2013-09-06 Senast uppdaterad: 2013-09-11Bibliografiskt granskad

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Alikhani, NyoshaPinho, Catarina MoreiraGlaser, Elzbieta
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