Current Drug Targets for Modulating Alzheimer's Amyloid Precursor Protein: Role of Specific Micro-RNA Species

Abstract

Alzheimer's disease (AD) is the most common form of dementia in the United States and is increasing in prevalence every year throughout the world. Recent clinical trial failures highlight the need for further insights into the molecular events that underlie the neurobiology of AD. Pathological aberrations in AD are believed to result, in part, from excess accumulation of amyloid-beta peptide (Aβ), a product of Aβ precursor protein (APP). Targeting APP levels would then be expected to reduce Aβ production in all forms of AD. Therefore, clarifying the regulatory network that governs APP expression is likely to reveal molecular players that could serve as novel drug targets. This review highlights recent work demonstrating the involvement of microRNA (miRNA) in this regulatory network. MiRNA are small, non-coding RNA that interact with target mRNA at sites of imperfect complementarity and mediate translational inhibition or transcript destabilization. We first review the neurobiology of AD and describe current therapeutic strategies. We then review transcriptional and post-transcriptional mechanisms utilized by cells to control APP expression. We conclude by highlighting recent work, including our own, which suggests miRNA are integral components of this regulatory framework and potential targets for future AD therapeutics.

MicroRNA-339-5p Down-regulates Protein Expression of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 (BACE1) in Human Primary Brain Cultures and Is Reduced in Brain Tissue Specimens of Alzheimer Disease Subjects

“…As has been described previously with APP (42,44,(47)(48)(49)45), there is likely an extensive network of miRNAs that act in collaboration with miR-339-5p to modulate BACE1 expression. Although the full repertoire has not been elucidated, several BACE1-targeting miRNAs have been described in the literature.…”

“…We and others have begun to describe the contributions that miRNAs bring to the post-transcriptional control of gene products implicated in AD, including APP (42)(43)(44)(45)(46)(47)(48)(49)(50). Others have previously identified and partially characterized miRNAs that also appear to negatively regulate BACE1 expression (18,(51)(52)(53).…”

Cdk5 activity in the brain – multiple paths of regulation

“…For example, several miRNA species, such as miR-101, miR-153 and miR-339-5p are dysregulated in AD (Long and Lahiri, 2011a;Long and Lahiri, 2011b;Long et al, 2014). In this context, p35 expression can be post-transcriptionally suppressed by miRNAs 103 and 107 (miR-103 and miR-107, respectively) (Moncini et al, 2011).…”

MicroRNA-153 Physiologically Inhibits Expression of Amyloid-β Precursor Protein in Cultured Human Fetal Brain Cells and Is Dysregulated in a Subset of Alzheimer Disease Patients

“…We and others have begun to describe the contributions that miRNAs bring to the post-transcriptional control of APP expression (34,35). Specifically, we have recently described the negative regulatory control exerted by miR-101 on APP expression (34,36).…”