Primate-specific miR-603 is implicated in the risk and pathogenesis of Alzheimer's disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder.
• MicroRNAs (miRNAs) are increasingly recognized for their role in AD pathogenesis.
• miR-603, a primate-specific miRNA, is implicated in AD risk and development.

Purpose of the Study:

• To investigate the role of miR-603 in Alzheimer's disease.
• To examine the impact of the rs11014002 single nucleotide polymorphism (SNP) on miR-603 biogenesis and AD risk.
• To elucidate the molecular targets and pathways regulated by miR-603 relevant to AD.

Main Methods:

• Analysis of miR-603 precursor (pre-miR-603) and the rs11014002 SNP.
• Assessment of miR-603's effect on the biogenesis of mature miR-603.
• Luciferase reporter assays to confirm direct binding of miR-603 to LRPAP1 3'UTR.
• Western blot analysis to measure LRPAP1 and LRP1 protein levels.
• Correlation analysis of miR-603 expression with LRPAP1/RND1 mRNA in AD patient hippocampi.
• Investigation of miR-603's effect on E2F1 expression and apoptosis in HeLa cells.

Main Results:

• The rs11014002 SNP in pre-miR-603 enhances mature miR-603 biogenesis and is associated with reduced AD risk.
• miR-603 directly downregulates LRPAP1 mRNA and protein levels.
• miR-603 increases LRP1 protein expression, while LRPAP1 and LRP1 play opposing roles in AD pathogenesis.
• Elevated miR-603 expression and a loss of negative correlation with LRPAP1/RND1 mRNA were observed in AD patient hippocampi.
• miR-603 downregulates E2F1 and protects against apoptosis.

Conclusions:

• miR-603 is a novel miRNA implicated in Alzheimer's disease pathogenesis.
• The rs11014002 SNP acts as a protective factor against AD by modulating miR-603 levels.
• miR-603 influences AD pathology through the regulation of LRPAP1, LRP1, and neuronal apoptosis.