Increased neuronal PreP activity reduces Aß accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model.
Hum Mol Genet
; 24(18): 5198-210, 2015 Sep 15.
Article
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| MEDLINE
| ID: mdl-26123488
ABSTRACT
Accumulation of amyloid-ß (Aß) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate Aß and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Aß 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 Aß-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 Aß 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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Sinapsis
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Serina Endopeptidasas
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Péptidos beta-Amiloides
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Enfermedad de Alzheimer
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Agregación Patológica de Proteínas
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Mitocondrias
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Neuronas
Límite:
Animals
Idioma:
En
Revista:
Hum Mol Genet
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA MEDICA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos