IDENTIFICATION OF SERUM MICRORNA AS A POTENTIAL BIOMARKER RELATED TO THE PROGRESSION OF ALZHEIMER’S DISEASE

Abstract

Alzheimer's disease (AD) is characterized by two neuropathological hallmarks: extracellular senile plaques (SPs) and intraneuronal neurofibrillary tangles (NFTs). These two lesions are thought to eventually lead to progressive synaptic dysfunction followed by neuronal cell death in the brain. The spreading of NFTs across the human brain is well correlated with the cognitive severity of AD. As the genetic background contributes to a course of the development of AD, genome-wide association studies have been performed to identify genetic risk factor. A number of genetic risk variants have been identified and almost all variants are located in introns or intergenic regions. Consequently, non-coding RNAs including microRNA (miRNA) are attractive molecules involved in post-transcriptional regulation on AD pathology. We attempted to identify the serum miRNA accompanied with pathological changes in the brain because miRNAs are relatively stable in serum or plasma. To determine serum miRNA by next-generation sequencing, we first surveyed 45 serum samples (discovery set) consist of 27 AD patients (SP stage: C, NFT stage: IV through VI) and 18 controls (SP stage: 0 and A, NFT stage: 0 through II) that were obtained within two weeks before neuropathological diagnosis. Significant miRNAs were validated with clinical sample set composed of 36 AD patients and 22 age-matched cognitively normal controls. Three miRNAs, hsa-miR-501–3p, hsa-let-7f-5p, and hsa-miR-26b-5p, were significantly deregulated in AD patients compared with controls. Among them the most significant serum hsa-miR-501–3p levels were downregulated in AD patients, and its lower levels significantly correlated with lower MMSE scores. Contrary to the serum levels, hsa-miR-501–3p was remarkably upregulated in AD autopsy brains as the lesion advanced. The hsa-miR-501–3p overexpression in cultured cells, which mimicked the hsa-miR-501–3p upregulation in the AD brains, induced significant downregulation of 128 genes that overrepresented the Gene Ontology terms such as DNA replication and the mitotic cell cycle. Our results suggest that hsa-miR-501–3p is a novel serum biomarker that presumably corresponds to pathological events occurring in AD brains.