MicroRNA-298 reduces levels of human amyloid-\u03b2 precursor protein (APP), \u03b2-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

Nipun Chopra,John S Beck,Debomoy K Lahiri,Andrew J Saykin,Scott E Counts,Naemeh Pourshafie,Kwangsik Nho,Carlo Rinaldi,Bryan Maloney,Ruizhi Wang,Alexander Niculescu

doi:10.1038/s41380-019-0610-2

Abstract

Alzheimer’s disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.

Highlights

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a phenotypic spectrum that includes memory loss as well as decline in other cognitive domains, Supplementary information The online version of this article contains supplementary material, which is available to authorized users.functional decline and especially in later stages neuropsychiatric symptoms [1]
Senile plaques are generated by oligomerization of soluble βamyloid (Aβ) peptide, which is generated by the sequential cleavage of amyloid- β precursor protein (APP) by β-site amyloid-β precursor protein (APP)-cleaving enzyme 1 (BACE1) and the γ-secretase complex [5]
For the APP 3′-untranslated regions (UTR), miR-298 has two possible target sites: A 7-mer-m8 target sequence and a 7-mer-A1 sequence (Fig. 2a). Both these target sites are highly conserved across the seed sequence, with weaker homology for the rest of miR-298. miR-298 has one 7-mer-A1 predicted site on the BACE1 3′-UTR (Fig. 2b) which is wellconserved across species

Summary

Introduction

Senile plaques are generated by oligomerization of soluble βamyloid (Aβ) peptide, which is generated by the sequential cleavage of amyloid- β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex [5]. Reduction of soluble Aβ by targeting APP and BACE1 is a therapeutic goal, in accordance with the amyloid hypothesis [6]. Both APP and BACE1 play an important role in normal physiological function of neuronal and glial cells [7,8,9]. Any endogenous target that could potentially regulate both would be a valuable route of study for effective treatment

Methods

Results

Conclusion