Aβ Aggregates Bind the U1 Spliceosomal Ribonucleoprotein in Alzheimer Disease Brain.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Spliceosome dysfunction, specifically U1 small nuclear ribonucleoprotein (U1 snRNP) insolubilization, is implicated in Alzheimer disease (AD).
• Previous studies noted partial co-localization of U1 snRNP with tau tangles and suggested a link between insoluble U1 snRNP binding proteins and Aβ, rather than tau.

Purpose of the Study:

• To investigate the association between amyloid-beta (Aβ) aggregates and RNA in Alzheimer disease (AD) brain tissue.
• To determine if U1 small nuclear ribonucleoprotein (U1 snRNP) is involved in Aβ aggregation and its potential link to spliceosome dysfunction.

Main Methods:

• Investigated sedimentation characteristics of Aβ aggregates from AD brain tissue.
• Utilized Aβ immunoprecipitation followed by deep sequencing to identify bound RNA.
• Confirmed U1 snRNA binding using reverse immunoprecipitation and oligonucleotide hybridization.
• Employed double immunoelectron microscopy and immunofluorescence with RNA in situ hybridization to visualize U1 snRNP components and U1 snRNA localization relative to Aβ and tau.

Main Results:

• Unexpectedly found that some Aβ aggregates were bound to small RNA, specifically U1 snRNA.
• Confirmed specific binding of U1 snRNA to Aβ aggregates.
• Double immunoelectron microscopy showed U1-70k protein decorating Aβ fibrils more than tau fibrils.
• Immunofluorescence revealed U1-70k and U1 snRNA at the edges of some amyloid plaques in unfixed AD brain tissue.

Conclusions:

• A subset of Aβ aggregates in AD brain tissue are bound to U1 snRNP at the periphery of amyloid plaques.
• This binding provides a potential mechanistic link between Aβ aggregation and spliceosome dysfunction in Alzheimer disease.
• These findings align Aβ with other fibril-forming proteins implicated in neurodegenerative diseases that interact with RNA.