Molecular Cross Talk between Misfolded Proteins in Animal Models of Alzheimer's and Prion Diseases

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.

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

“…The presence of PrP enhances A␤ accumulation, and vice versa (15). Thus, in transgenic mice, the two proteins mutually accelerate the progression of both pathologies (16). In AD transgenic mice, the onset of prion disease symptoms developed at a rate proportional to the A␤ brain levels (16).…”

“…Thus, in transgenic mice, the two proteins mutually accelerate the progression of both pathologies (16). In AD transgenic mice, the onset of prion disease symptoms developed at a rate proportional to the A␤ brain levels (16). For humans, significant levels of A␤ deposition, similar to those found in AD patients, were seen in the brains of relatively young individuals who had died from Creutzfeldt-Jakob disease (17).…”

Insoluble cellular prion protein and its association with prion and Alzheimer diseases

“…86 Sc aggregates also seem to facilitate Aβ42 aggregation in vivo and AD mice developed a strikingly higher load of cerebral amyloid plaques that appeared much faster in prioninfected than in uninfected mice. 85 Our finding that Aβ42 binds to iPrP suggests that iPrP (the PrP Sc -like forms in uninfected human brains) may facilitate fibrillization of Aβ42 in AD (Fig. 1).…”

“…[82][83][84] Although the exact biological relevance of the interaction between iPrP C and Aβ is unclear at present, it has been revealed that aggregation of one protein may facilitate aggregation of the other. 85 Synergistic interactions between other amyloidogenic proteins associated with neurodegeneration also have been reported to promote each other's fibrillization, amyloid deposition and formation of filamentous inclusions in transgenic mice. 86 Sc aggregates also seem to facilitate Aβ42 aggregation in vivo and AD mice developed a strikingly higher load of cerebral amyloid plaques that appeared much faster in prioninfected than in uninfected mice.…”

Prion Protein and Amyloid Beta Peptide Interact in the Yeast Saccharomyces Cerevisiae

“…Недавние исследования также показали, что процессы, связанные с неправильной укладкой одного из этих белков, являются серьезным фактором риска для индукции агрега-ции другого (Morales et al, 2010). На основании этих данных представля-ется перспективным изучение возможности взаимодействия и взаимного влияния агрегатов prp и aβ.…”