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.