Abstract Details

Title Aqueously diffusible RNA-bound amyloid-ß aggregates in Alzheimer disease brain

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P1 - Poster Session 1 (8:00 AM-9:00 AM)

Poster/Presentation
Number 7-004

Background 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.

Objective 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.

Design/Methods 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.

Results 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.

Conclusions

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.
	No disclosure on file
	No disclosure on file
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.