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Abstract Details

Aqueously diffusible RNA-bound amyloid-ß aggregates in Alzheimer disease brain
Aging, Dementia, Cognitive, and Behavioral Neurology
P1 - Poster Session 1 (8:00 AM-9:00 AM)
7-004
Aqueously extractable and diffusible aggregates of Aβ (often called “oligomers” or “protofibrils”) are principal drug targets in AD, including for lecanemab. The structure, size, and molecular binding partners of these aggregates obtained from human brain are unknown.
To define the macromolecular properties of naturally occurring, aqueously diffusible aggregates of amyloid-β protein (Aβ) to inform the next generation of treatments for Alzheimer disease.
Diffusible “soaking extracts” of AD brain were made by soaking minced cerebral cortex in aqueous buffer followed by ultracentrifugation. The soaking extracts were analyzed by isopycnic cesium chloride centrifugation, rate-zonal centrifugation, and size exclusion chromatography (SEC), followed by high-sensitivity Aβ42 ELISA, as well as immunoprecipitation and RNA urea-PAGE.
Aβ aggregates in aqueous soaking extracts of AD brain exhibited higher density by isopycnic centrifugation than did synthetic Aβ fibrils, suggesting the presence of nucleic acids. RNAse treatment reduced the density of Aβ aggregates but increased their mass as measured by rate-zonal centrifugation. SEC using a high molecular weight cutoff resin showed three size peaks of Aβ, one of which disappeared with RNAse treatment. RNAse did not affect the total amount of monomeric or aggregated Aβ measurable in the AD brain soaking extracts. Aβ aggregate-directed antibodies immunoprecipitated a small RNA population from AD but not control brain soaking extracts.

A sub-population of diffusible Aβ aggregates in human AD brain is bound to small RNAs. Its importance for disease progression and treatment is under investigation.

Authors/Disclosures
Andrew Stern, MD (Brigham and Women's Hospital)
PRESENTER
Dr. Stern has nothing to disclose.
Angela Lynn Meunier, Other (Brigham and Women's Hospital) Miss Meunier has nothing to disclose.
Wen Liu, Other (Brigham and women's) Mrs. Liu has nothing to disclose.
Dennis J. Selkoe, MD, FAAN (Brigham and Women's Hospital) Dr. Selkoe has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Prothena Biosciences. Dr. Selkoe has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EISAI.