The Age-dependent Elevation of miR-335-3p Leads to Reduced Cholesterol and Impaired Memory in Brain

• Published in: Neuroscience Vol. 390; pp. 160 - 173
• Main Authors: Raihan, Obayed, Brishti, Afrina, Molla, Md Rasel, Li, Wenbo, Zhang, Qilun, Xu, Peng, Khan, Muhammad Imran, Zhang, Juan, Liu, Qiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 15-10-2018
• Subjects: Aging; Animals; astrocytes; Astrocytes - metabolism; cholesterol; Cholesterol - metabolism; Coculture Techniques; Disks Large Homolog 4 Protein - metabolism; Gene Expression Regulation; HEK293 Cells; Hippocampus - metabolism; Humans; Male; Memory; Mice; Mice, Inbred C57BL; MicroRNAs - metabolism; miRNA; Neurons - metabolism; Signal Transduction; PSD95; memory; HMGCS1; miRNA; cholesterol; HMGCR; astrocytes; aging; GFAP
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2018.08.003

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•MiR-335-3p is enriched in aged cultured astrocytes and hippocampal brain of aged mice.•MiR-335-3p reduces cellular cholesterol by suppressing HMGCS1 and HMGCR, key enzymes in cholesterol biosynthesis pathway.•MiR-335-3p deficiency leads to rescued PSD95 level and cognitive impairment in aged mice, in a cholesterol-dependent manner.
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.