Faculty, Staff and Student Publications

Publication Date

3-31-2010

Journal

The Journal of Neuroscience

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.

Keywords

Alzheimer Disease, Amyloid, Amyloid beta-Peptides, Animals, Brain, Mice, Mice, Inbred C57BL, Mice, Transgenic, PrPSc Proteins, Prion Diseases, Prions, Protein Folding

DOI

10.1523/JNEUROSCI.5924-09.2010

PMID

20357103

PMCID

PMC2859074

PubMedCentral® Posted Date

3-31-2010

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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