ALZHEIMER'S DISEASE: MODELING PATHOLOGIC STRAIN-LIKE VARIANTS OF MULTIMERIC A?

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the past year, we have continued and expanded our analysis of strain-like structural variants of multimeric aggregates of the protein A¿. We have shown that, unlike in Alzheimer's disease, naturally occurring A¿ in nonhuman primates does not bind the A¿-binding ligand PIB with high affinity, despite an identical amino acid sequence. This finding suggests that PIB may recognize a polymorphic site on multimeric A¿. Unexpectedly, in the course of this investigation, we also discovered a single case of Alzheimer's disease with very high A¿ levels, yet negligible high-affinity PIB binding, indicating that the binding site may vary among humans with the disease. The findings support growing evidence that protein aggregates may assume several multidimensional shapes that could govern their pathogenic nature.