Pathologic Aggregates Of Small Nuclear Ribonucleoproteins (snRNP) Are Present In Familial Alzheimer's Disease (P1.244)
Objective: To understand small nuclear ribonucleoprotein (snRNP) biochemical and pathologic features in familial AD.
Background: We recently identified U1 small nuclear ribonucleoprotein (snRNP) aggregates in sporadic Alzheimer’s disease (AD). We also found evidence for RNA processing dysfunction in AD. Little is known about snRNP changes in familial AD.
Design/Methods: We performed quantitative proteomics and immunohistochemistry in postmortem brain from familial AD cases including presenilin-1 and amyloid precursor protein mutation carriers as well as Down9s syndrome cases. We also utilized electron microscopy to characterize ultrastructural characteristics of pathologic aggregates. Finally, we performed similar studies in a transgenic mouse with amyloid precursor protein and presenilin-1 (APP/PS-1) mutations to understand species specificity.
Results: We saw biochemical enrichment of U1-70k and other snRNPs in the human familial AD insoluble fraction. We also visualized snRNP cytoplasmic tangle-like aggregates and snRNP immunogold labeling of paired helical filaments. Interestingly, APP/PS-1 transgenic mouse brain demonstrated normal snRNP localization and no shift in snRNP solubility. We also saw variability in the enrichment of other proteins when comparing human familial AD and the APP/PS-1 transgenic mouse proteomes as well as many similarly affected pathways.
Conclusions: These studies identify U1-snRNP pathologic changes in familial AD as seen previously in sporadic AD and suggest that the novel pathologic findings are influenced by aberrant amyloid processing. Other cellular changes, like tau aggregation, may also be necessary since the APP/PS1 mouse did not have snRNP pathology. The comparison of human familial AD and rodent transgenic APP/PS1 proteomes highlights challenges with using this model to recapitulate human disease and study snRNP changes in particular. Disclosure: Dr. Hales has nothing to disclose. Dr. Dammer has nothing to disclose. Dr. Duong has nothing to disclose. Dr. Yi has nothing to disclose. Dr. Gearing has nothing to disclose. Dr. Levey has received personal compensation for activities with GenoMind. Dr. Levey has received research support from Janssen Pharmaceutica, Merck & Co. Inc., Ceregene, and Medivation. Dr. Lah has received research support from Elan Corp., Medivation, Merck & Co. Inc., and Ceregene. Dr. Seyfried has nothing to disclose.