1. The Age-dependent Elevation of miR-335-3p Leads to Reduced Cholesterol and Impaired Memory in Brain
- Author
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Wenbo Li, Qiang Liu, Muhammad Imran Khan, Peng Xu, Qilun Zhang, Rasel Molla, Juan Zhang, Obayed Raihan, and Afrina Brishti
- Subjects
Male ,0301 basic medicine ,Aging ,medicine.medical_specialty ,Age dependent ,Reductase ,Hippocampal formation ,Hippocampus ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Memory ,Internal medicine ,microRNA ,medicine ,Animals ,Humans ,Neurons ,chemistry.chemical_classification ,Cholesterol ,General Neuroscience ,Impaired memory ,Coculture Techniques ,Mice, Inbred C57BL ,MicroRNAs ,HEK293 Cells ,030104 developmental biology ,Enzyme ,Endocrinology ,Gene Expression Regulation ,chemistry ,Astrocytes ,lipids (amino acids, peptides, and proteins) ,Disks Large Homolog 4 Protein ,Postsynaptic density ,Signal Transduction - Abstract
MiR-335-3p, a neuron-enriched microRNA, has been reported to be involved in aging and age-related neurological diseases. However, the role of miR-335-3p in cholesterol metabolism of astrocytes, and whether it affects neuronal functions, particularly during aging process, largely remains unknown. In this study, we uncover that miR-335-3p is significantly increased in aged cultured astrocytes and aged hippocampal brains, accompanied by decreased cellular cholesterol and diminished expression of HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) and 3-hydroxy-3-methylglutaryl-CoA synthase-1 (HMGCS1), both step-limiting enzymes in cholesterol synthesis pathway. We also demonstrate that miR-335-3p suppresses HMGCS1 post-transcriptionally by directly binding to its 3'UTR, and HMGCR through binding mediated by SFRS2. More importantly, aged mice with miR-335-3p deficiency in hippocampal brains exhibit improved learning and memory, accompanied by enhanced levels of postsynaptic density protein 95 (PSD95). We further reveal that the level change of PSD95 is resulted from altered cholesterol metabolism. Our findings provide a novel insight into the regulatory role of miR-335-3p in cholesterol metabolism in astrocytes, and consequently cognitive functions during aging.
- Published
- 2018
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