期刊
BRAIN PATHOLOGY
卷 22, 期 5, 页码 636-653出版社
WILEY
DOI: 10.1111/j.1750-3639.2011.00560.x
关键词
Alzheimer's disease; APP; PS1 transgenic mice; mitochondria; oxidative stress; synapses; tau phosphorylation; ubiquitin-proteasome system; a-synuclein; ss-amyloid
资金
- Spanish Ministry of Health, Instituto de Salud Carlos III [FIS PI08/0582]
- Spanish Ministry of Science and Innovation [PETRI PET2007-0397, SAF2007-66148-C02-02, SAF2010-22114-C02-01]
- Spanish Ministry of Education and Science [BFU2009-11879/BFI, AGL2006-12433]
- Generalitat of Catalunya [2009SGR-735]
- Spanish Ministry of Health [PI08-1843]
- La Caixa Foundation
- BESAD-P project (Carlos III Institute)
- COST B-35 Action
- ICREA Funding Source: Custom
Double-transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mice express a chimeric mouse/human APP bearing the Swedish mutation (Mo/HuAPP695swe) and a mutant human PS1-dE9 both causative of familial Alzheimer's disease (FAD). Transgenic mice show impaired memory and learning performance from the age of 6 months onwards. Double-transgenic APP/PS1 mice express altered APP and PS1 mRNAs and proteins, reduced beta-secretase 1 (BACE1) mRNA and normal BACE1 protein, all of which suggest a particular mechanism of amyloidogenesis when compared with sporadic AD. The first beta-amyloid plaques in APP/PS1 mice appear at 3 months, and they increase in number and distribution with disease progression in parallel with increased levels of brain soluble beta-amyloid 142 and 140, but also with reduced 142/140 ratio with age. Amyloid deposition in plaques is accompanied by altered mitochondria and increased oxidative damage, post-translational modifications and accumulation of altered proteins at the dystrophic neurites surrounding plaques. Degradation pathways are also modified with disease progression including activation of the immunoproteasome together with variable alterations of the different protease activities of the ubiquitin-proteasome system. Present observations show modifications in the production of beta-amyloid and activation and malfunction of the subcellular degradation pathways that have general implications in the pathogenesis of AD and more particularly in specificities of FAD amyloidogenesis.
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