Targeting mRNA for Alzheimer’s and Related Dementias

Abstract

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.

Synthetic RNA Modulators in Drug Discovery

“…94 However, tau is not easily druggable, and alternative approaches are needed. 95 In this context, Artigas and Marchań reported four classes of ametantrone-based small molecules, i.e., ametantrone 176, guanidinoneamine 186, neamine 187, and azaquinolone 189, that target tau pre-mRNAs, and investigated their RNA-binding ability. 96 Ametantrone itself (176, in which Boc is replaced by H) was identified as a promising RNA ligand with low cytotoxicity in eukaryotic cells.…”

Nucleic Acid-Based Theranostics for Tackling Alzheimer's Disease

“…Wolfe et al . 110 designed splice-modulating AOs to target BACE1, since alternatively spliced transcript variants at exons 2 and 3 do not show β-secretase activity. The AOs reduced Aβ production significantly in cells without altering total BACE1 mRNA.…”

“…The conjugate also inhibited exon 10 splicing in cell-free conditions more effectively than mitoxantrone or the bipartite AO alone, but induced cytotoxicity. The same group used a PNA-modified bipartite AO conjugated to mitoxantrone that inhibited tau splicing but was also cytotoxic 110 .…”

“…Mi34a reduces endogenous tau expression at both the mRNA and protein level in M17D cells by binding to the 3' UTR region of tau 110 , whereas miR-34c levels are elevated in the hippocampus of AD patients and mouse AD models 138 . Wolfe et al 110 used LNA antimiRs to inhibit miR-34a,‑34b and -34c and found increased tau expression. Zovolis et al 138 found that an antimiR that targets miR-34c rescued learning in mouse models.…”

Intranasal Delivery and Transfection of mRNA Therapeutics in the Brain Using Cationic Liposomes

“…In addition, the mRNA therapeutics have great potential in particular for brain-related disorders, where protein function is altered such as Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and other diseases, although the research is still in its novice stage. 19 A recent publication on the Alzheimer's disease model showed promising results, where an increase in clearance of β-amyloid was observed after intracerebral administration of neprilysin mRNA using polyplex nanomicelles. 20 In particular, the cationic liposomebased delivery systems for brain delivery warrant attention as they can assist in complexing highly anionic mRNA as well as intracellular entry.…”