Abstract
Alzheimer's disease (AD) is a serious neurodegenerative disease, and microRNAs (miRNAs) have been linked to its pathogenesis. miR-603, a novel primate-specific miRNA and an intronic miRNA of a human brain highly expressed gene KIAA1217, is implicated in the risk and pathogenesis of AD. The rs11014002 single nucleotide polymorphism (SNP) (C/U), which locates in miR-603 precursor (pre-miR-603), exhibits a protective effect towards AD risk. Additionally, the rs11014002 SNP promotes the biogenesis of mature miR-603. miR-603 downregulates LRPAP1 mRNA and protein levels through directly binding the 3' untranslated region (3'UTR) of LRPAP1. Moreover, miR-603 increases LRP1 protein expression. LRPAP1 and LRP1, playing opposite roles, are involved in Aβ clearance and pathogenesis of AD. Strikingly, miR-603 exhibits a relatively higher expression and there is a loss of a negative correlation between miR-603 and LRPAP1/RND1 mRNA levels in the hippocampi of patients with AD. In addition, miR-603 directly downregulates a key neuronal apoptotic component-E2F1, and prevents HeLa cells from undergoing H2O2-induced apoptosis. This work suggests that miR-603 may be a novel AD-relevant miRNA and that its rs11014002 SNP may serve as a protective factor against AD.
Highlights
Alzheimer’s disease (AD) is characterized by a progressive loss of episodic memory and other cognitive functions and is a type of neurodegenerative disorder
By analyzing the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, we found that a single nucleotide polymorphism (SNP), rs11014002, in miR-603 precursor that is associated with a reduced risk of AD and probable later onset of mild cognitive impairment (MCI)
These results suggest that miR-603 may be involved in AD pathogenesis and that the rs11014002 SNP may serve as a protective factor against AD
Summary
Alzheimer’s disease (AD) is characterized by a progressive loss of episodic memory and other cognitive functions and is a type of neurodegenerative disorder. AD has been defined by its pathological signature, which includes β-amyloid deposits in the form of extracellular amyloid β (Aβ) plaques and hyperphosphorylated Tau aggregates in the form of intracellular neurofibrillary tangles (NFTs) [1]. Numerous studies have indicated that miRNAs are implicated in a diverse array of brain functions, including development, cognition, and synaptic plasticity [4]. Several miRNAs have been found to be related to AD pathogenesis [5] and to affect the expression or function of AD-relevant molecules such as amyloid precursor protein (APP) [6], β-site amyloid precursor protein cleaving enzyme 1 (BACE1) [7, 8] or Tau [9],[10]
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