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Targeting mRNA for Alzheimer's and related dementias
1Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, H.I.M. 754, Boston, MA 02115, USA.
Abstract:
Brain deposition of the amyloid beta-protein (A β ) and tau are characteristic features in Alzheimer's disease (AD). Mutations in the A β precursor protein (APP) and a protease involved in A β production from APP strongly argue for a pathogenic role of A β in AD, while mutations in tau are associated with related disorders collectively called frontotemporal lobar degeneration (FTLD). Despite intense effort, therapeutic strategies that target A β or tau have not yet yielded medications, suggesting that alternative approaches should be pursued. In recent years, our laboratory has studied the role of mRNA in AD and FTLD, specifically those encoding tau and the A β -producing protease BACE1. As many FTLD-causing tau mutations destabilize a hairpin structure that regulates RNA splicing, we have targeted this structure with small molecules, antisense oligonucleotides, and small molecule-antisense conjugates. We have also discovered that microRNA interaction with the 3'-untranslated region of tau regulates tau expression. Regarding BACE1, we found that alternative splicing leads to inactive splice isoforms and antisense oligonucleotides shift splicing toward these inactive isoforms to decrease A β production. In addition, a G-quadruplex structure in the BACE1 mRNA plays a role in splice regulation. The prospects for targeting tau and BACE1 mRNAs as therapeutic strategies will be discussed.
Insights
Investigating messenger RNA (mRNA) offers new therapeutic avenues for Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Targeting tau and beta-secretase 1 (BACE1) mRNAs shows promise for developing novel treatments.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are characterized by brain deposition of amyloid beta-protein (Aβ) and tau.
- Current therapeutic strategies targeting Aβ or tau have not yielded effective medications, necessitating alternative approaches.
- The role of mRNA in AD and FTLD pathogenesis, particularly for tau and BACE1, is an emerging area of research.
Purpose of the Study:
- To explore novel therapeutic strategies for AD and FTLD by targeting specific mRNAs.
- To investigate the regulation of tau and BACE1 expression through RNA splicing and microRNA interactions.
- To assess the potential of modulating mRNA structures and splicing for therapeutic benefit.
Main Methods:
- Utilized small molecules, antisense oligonucleotides, and conjugates to target tau mRNA hairpin structures.
- Investigated microRNA interactions with the 3'-untranslated region of tau mRNA.
- Analyzed alternative splicing of BACE1 mRNA and employed antisense oligonucleotides to shift splicing towards inactive isoforms.
- Studied the role of G-quadruplex structures in BACE1 mRNA splice regulation.
Main Results:
- Demonstrated that targeting tau mRNA structures can influence splicing and expression.
- Identified microRNA regulation of tau expression.
- Showed that BACE1 mRNA alternative splicing produces inactive isoforms.
- Confirmed that antisense oligonucleotides can decrease Aβ production by promoting inactive BACE1 splice isoforms.
- Revealed the involvement of a G-quadruplex structure in BACE1 mRNA splicing.
Conclusions:
- Targeting tau and BACE1 mRNAs presents a promising alternative therapeutic strategy for AD and FTLD.
- Modulating RNA splicing and microRNA interactions offers potential for developing novel neurodegenerative disease treatments.
- Further research into mRNA-based therapeutics could lead to effective interventions for debilitating neurological disorders.
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