Molecular Cross Talk between Misfolded Proteins in Animal Models of Alzheimer’s and Prion Diseases
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2010-03-31Metadata
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Morales, Rodrigo
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Molecular Cross Talk between Misfolded Proteins in Animal Models of Alzheimer’s and Prion Diseases
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Abstract
The central event in protein misfolding disorders (PMDs) is the accumulation of a misfolded form of a naturally expressed protein.
Despite the diversity of clinical symptoms associated with different PMDs, many similarities in their mechanism suggest that distinct
pathologies may cross talk at the molecular level. The main goal of this study was to analyze the interaction of the protein misfolding
processes implicated in Alzheimer’s and prion diseases. For this purpose, we inoculated prions in an Alzheimer’s transgenic mouse
model that develop typical amyloid plaques and followed the progression of pathological changes over time. Our findings show a dramatic
acceleration and exacerbation of both pathologies. The onset of prion disease symptoms in transgenic mice appeared significantly faster
with a concomitant increase on the level of misfolded prion protein in the brain. A striking increase in amyloid plaque deposition was
observed in prion-infected mice compared with their noninoculated counterparts. Histological and biochemical studies showed the
association of the two misfolded proteins in the brain and in vitro experiments showed that protein misfolding can be enhanced by a
cross-seeding mechanism. These results suggest a profound interaction between Alzheimer’s and prion pathologies, indicating that one
protein misfolding process may be an important risk factor for the development of a second one. Our findings may have important
implications to understand the origin and progression of PMDs.
Patrocinador
This work was supported in part by National Institutes of Health Grants AG028821 and NS050349 and an award
from the Mitchell Foundation (C.S.).
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URI: https://repositorio.uchile.cl/handle/2250/119054
DOI: DOI:10.1523/JNEUROSCI.5924-09.2010
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The Journal of Neuroscience, March 31, 2010 • 30(13):4528–4535
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