Targeting mRNA for Alzheimer’s and Related Dementias

• Main Author: Michael S. Wolfe
• Format: Article
• Language: English
• Published: Hindawi Limited 2014-01-01
• Series: Scientifica
• Online Access: http://dx.doi.org/10.1155/2014/757549

Brain deposition of the amyloid beta-protein (Aβ) and tau are characteristic features in Alzheimer’s disease (AD). Mutations in the Aβ precursor protein (APP) and a protease involved in Aβ production from APP strongly argue for a pathogenic role of Aβ in AD, while mutations in tau are associated with related disorders collectively called frontotemporal lobar degeneration (FTLD). Despite intense effort, therapeutic strategies that target Aβ 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 Aβ-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 Aβ 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.