Effects of the Therapeutic Correction of U1 SnRNP Complex on Alzheimer's Disease

Overview

Journal Sci Rep

Specialty Science

Date 2024 Dec 3

PMID 39627450

Authors

Caio Bruno Q S Leal

Camila G M Zimmer

Vanessa V C Sinatti

Ericks S Soares

Britt Poppe

Adrien Carton de Wiart

Xue Ying Chua

Ronan V da Silva

Margaret H Magdesian

Michael S Rafii

Luc Buee

Rafael M Bottos

Affiliations

Soon will be listed here.

Abstract

The U1 snRNP complex recognizes pre-mRNA splicing sites in the early stages of spliceosome assembly and suppresses premature cleavage and polyadenylation. Its dysfunction may precede Alzheimer's disease (AD) hallmarks. Here we evaluated the effects of a synthetic single-stranded cDNA (APT20TTMG) that interacts with U1 snRNP, in iPSC-derived neurons from a donor diagnosed with AD and in the SAMP8 mouse model. APT20TTMG effectively binds to U1 snRNP, specifically decreasing TAU in AD neurons, without changing mitochondrial activity or glutamate. Treatment enhanced neuronal electrical activity, promoted an enrichment of differentially expressed genes related to key processes affected by AD. In SAMP8 mice, APT20TTMG reduced insoluble pTAU in the hippocampus, amyloid-beta and GFAP in the cortex, and U1-70 K in both brain regions, without cognitive changes. This study highlights the correction of the U1 snRNP complex as a new target for AD.

Citing Articles

Proximity labeling of the Tau repeat domain enriches RNA-binding proteins that are altered in Alzheimer's disease and related tauopathies.

Shapley S, Shantaraman A, Kearney M, Dammer E, Duong D, Bowen C bioRxiv. 2025; .

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