miR-106b aberrantly expressed in a double transgenic mouse model for Alzheimer's disease targets TGF-β type II receptor

MicroRNAs (miRNAs) are abundantly expressed in the brain and play an important role in disorders of the brain, including Alzheimer's diseases (AD). Growing body of evidence suggests that the TGF-beta signaling pathway plays a key role in the pathogenesis of AD. However, it is unclear whether miRNAs involved in AD pathogenesis by regulating TGF-beta signaling. Here we found that miR-106b and TGF-beta type II receptor (T beta R II) were aberrantly expressed in APPswe/PS Delta E9 mice (a double transgenic mouse model for AD). Sequence analysis revealed two putative binding sites for miR-106b in the 3' UTR of the T beta R II mRNA. Our results showed that the expression of miR-106b was inversely correlated with T beta R II protein levels and miR-106b can directly inhibit the T beta R II translation in vitro. After induced neurodifferentiation with all-trans retinoic acid, we observed significant neurodegeneration in SH-SYSY cells stably transfected with miR-106b. Western blot analysis revealed unchanged total Smad2/3 protein levels, but reduced phospho-Smad2/3 (p-Smad2/3) and increased Smad6/7 protein levels in the miR-106b stably transfected cell line. Exposure of SH-SY5Y cells to A beta 42 oligomers led to the expression of miR-106b was first increased and then decreased and T beta R II levels reduced. Our in vitro results suggested that A beta 42 oligomer-induced miR-106b leads to impairment in TGF-beta signaling through T beta R II, concomitant with retinoic acid-induced neurodegeneration in SH-SYSY cells. These results show that T beta R II is a functional target of miR-106b and that miR-106b may influence TGF-beta signaling, thereby contributing to the pathogenesis of AD. (C) 2010 Elsevier B.V. All rights reserved.