The role of miR-34a in inflammation in Alzheimer's disease.

Abstract

A plethora of evidence support that central and systemic inflammation promotes AD progression. Amyloid plaques are closely accompanied with neuroinflammation characterized by activated microglia and reactive astrocytes. However, the precise molecular mechanisms by which inflammation contributes to development of AD remain to be elucidated. MicroRNA-34a (miR-34a) can regulate inflammatory states in animal models of diabetes and atherosclerosis by modulating M1/M2 polarization of macrophages in adipose tissues and arterial wall, respectively. MiR-34a increases during aging and in AD. In this study, we produced miR-34a-deficient Tg-SwDI to investigate an underlying mechanism by which miR-34a may contribute to the AD pathogenesis including neuroinflammation. Twelve-month-old miR-34a sufficient (miR-34a+/+) and deficient (miR-34a-/-) Tg-SwDI mice were used for a battery of behavioral tests. At age 13 months, the mice were euthanized and neuroinflammation and brain Aβ levels were determined by immunohistochemistry and ELISA, respectively. To investigate the effect of miR-34a deficiency on the hippocampal transcriptomics, we isolated RNAs from the hippocampus of miR-34a-/- and miR-34a+/+ Tg-SwDI mice and performed RNA-seq. Expression dataset was subjected to Gene Set Enrichment Analysis (GSEA) based on the latest MSigDB database (c5.all.v7.4). In the probe trial of Morris water maze, the percentages of time spent in the correct quadrant for miR-34a-/- Tg-SwDI mice are greater than those for miR-34a+/+ Tg-SwDI mice for male and female mice (P<0.05). We found that miR-34a-/- increased CSF Aβ40 levels in male Tg-SwDI mice (P<0.001) and induced an increasing trend in female Tg-SwDI mice (P=0.057). miR-34a -/- induced an increasing trend of soluble Aβ40 in the cortex in male Tg-SwDI mice (P=0.06) and increased in the cortex in female Tg-SwDI mice (P< 0.001). MiR-34a-/- had no effect on insoluble Aβ40 and Aβ42 levels in the cortex in male Tg-SwDI mice but increased their levels in female Tg-SwDI mice (P<0.001). In addition, miR-34a-/- increased activated microglia and reactive astrocytes by Iba1 and GFAP immunohistochemistry, respectively. Finally, Go analysis-based GSEA of RNA-seq revealed upregulation of a battery of immune/inflammatory pathways. Our results indicate that miR-34a-/- increases the brain Aβ load, activated microglia and reactive astrocytes in Tg-SwDI mice. However, miR-34a-/- improves special memory.