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Increased neuronal PreP activity reduces A beta accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model
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Number of Authors: 19
2015 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 18, 5198-5210 p.Article in journal (Refereed) Published
Abstract [en]

Accumulation of amyloid-beta (A beta) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate A beta and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial A beta degrading enzyme. Here, we demonstrate for the first time that increased expression of active human PreP in cortical neurons attenuates Alzheimer disease's (AD)-like mitochondrial amyloid pathology and synaptic mitochondrial dysfunction, and suppresses mitochondrial oxidative stress. Notably, PreP-overexpressed AD mice show significant reduction in the production of proinflammatory mediators. Accordingly, increased neuronal PreP expression improves learning and memory and synaptic function in vivo AD mice, and alleviates A beta-mediated reduction of long-term potentiation (LTP). Our results provide in vivo evidence that PreP may play an important role in maintaining mitochondrial integrity and function by clearance and degradation of mitochondrial A beta along with the improvement in synaptic and behavioral function in AD mouse model. Thus, enhancing PreP activity/expression may be a new therapeutic avenue for treatment of AD.

Place, publisher, year, edition, pages
2015. Vol. 24, no 18, 5198-5210 p.
National Category
Biological Sciences
URN: urn:nbn:se:su:diva-121879DOI: 10.1093/hmg/ddv241ISI: 000361317200011PubMedID: 26123488OAI: diva2:862642
Available from: 2015-10-23 Created: 2015-10-19 Last updated: 2015-10-23Bibliographically approved

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Glaser, Elzbieta
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Department of Biochemistry and Biophysics
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