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

Journal article

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

Authors: Chopra, N; Wang, R; Maloney, B; Nho, K; Beck, JS

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature [academic journals on nature.com]
• Journal: Molecular Psychiatry
• Volume: 26
• Issue: 10
• Pages: 5636-5657
• Publication date: 2020-01-15
• DOI: 10.1038/s41380-019-0610-2
• EISSN: 1476-5578
• ISSN: 1359-4184
• Language: English
• Keywords: Chemistry; Medicine; Extracellular; Intracellular; Biochemistry of Alzheimer's disease; Amyloid precursor protein secretase; Cell biology; microRNA; Biology; BACE1-AS; Alzheimer's disease; Amyloid precursor protein; Tau protein; Protein precursor; Molecular biology; Gene silencing; Internal medicine; Disease; Enzyme; Biochemistry; Gene; P3 peptide