P2‐055: Cellular prion protein and class‐specific Aβ oligomers mediate plaque‐associated cytopathology in a mouse model of Alzheimer's disease

Background: Increasing evidence indicates that plaque-associated amyloid-b (Ab) oligomers might be responsible for neuronal architecture changes occurring in the vicinity of amyloid deposits in Alzheimer’s disease. However, the underlying mechanism regulating these changes remains unclear. Cellular prion protein (PrP) has recently been proposed to act as a receptor for Ab oligomers that mediates amyloid toxicity. We here investigate whether PrPmediates oligomeric Ab-induced cytopathology associated with amyloid plaques. Methods: To understand whether PrP mediates plaqueassociated neuronal architectural abnormalities, we stained densecore Ab plaques using thioflavin S and axonal structure using SMI-312, a monoclonal anti-neurofilament antibody, in brain sections of 12-month-old hAPP-J20 and hAPP-J20/PrP-null mice. Neuronal morphology analyses were performed to assess axonal curvature ratios and the numbers of dystrophic neurites per plaque. Using conformation-sensitive antibodies OC and A11, which recognize distinct structural epitopes of amyloid proteins, we performed co-immunoprecipitation assays on water-soluble brain extracts of hAPP-J20mice to identify what class of brain-derived Ab oligomers might bind to PrP. Finally, unbiased stereology and non-denaturing immunoblotting were used to evaluate the consequence of Prnpgene ablation on amyloid burden and oligomeric Ab levels in hAPP-J20 and hAPP-J20/PrP-null mice. Results: Genetic ablation of PrP ameliorated neuronal architecture abnormalities in the vicinity of plaques in hAPP-J20 mice. PrP immunoprecipitated with Ab oligomers immunoreactive to OC antibodies, known to recognize the inregister, parallel b-sheet structure of amyloid fibrils. In contrast, PrP was not pulled down with A11-immunoreactive oligomers. Stereological analyses revealed that Prnp ablation reduced densecore and 6E10-immunoreactive plaque loads by 28% and 37%, respectively. Genetic ablation of PrPalso affected levels of Ab oligomers but did not alter levels of amyloid precursor protein (APP) or APP processing. Conclusions: We found that PrP interacts with OC-immunoreactive Ab oligomers, but not with A11-positive oligomers, and mediates plaque-associated cytopathology. Overall, these results suggest that PrP-mediated neurotoxicity is specific for a given class of Ab oligomers.