Premium
P3‐171: MicroRNA related cofilin abnormality and the pathological consequences in a transgenic mouse model of Alzheimer's disease
Author(s) -
Yao Jiaqi,
Beal Flint,
Lin Michael
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1612
Subject(s) - cofilin , microrna , biology , microbiology and biotechnology , genetically modified mouse , transgene , untranslated region , messenger rna , genetics , gene , actin cytoskeleton , cell , cytoskeleton
Background: Rod-like structures composed of actin and the actin-binding protein cofilin are found in Alzheimer’s disease (AD) patients. Recent studies in cells demonstrate that abnormal actin-cofilin rods form in response to various stressors. However, the mechanisms of rod formation are largely unknown. We hypothesize that microRNA regulated cofilin expression plays an important role in cofilin rod formation in AD. Methods: We used a wide range of biochemical, molecular and cellular methods to test our hypothesis. Results: We have shown that cofilin expression levels are increased in a transgenic mouse model of AD (Tg19959), and that rod-like inclusions, including cofilin and actin, develop in brain tissue and in neurons from these mice. Although cofilin protein levels are increased, cofilin mRNA levels are not, suggesting that the increase in cofilin protein levels maybe due to post-transcriptional regulation. We hypothesize that microRNAs regulations involved. Based on bioinformatic analysis, miR-103/ 107 are predicted to interact with the 3’UTR of cofilin mRNA. To confirm a functional interaction between miR-103/107 and the predicted target region in the cofilin 3’UTR, we construct a miR luciferase reporter. Our luciferase assay results suggest that miR-103/107 bind the putative target sequence in the cofilin 3’UTR and functionally repress translation of the upstream gene. Conversely, when endogenous miR-103 levels are reduced by anti-sense oligos, cofilin protein levels increased, as seen by Western blotting. Using quantitative RT-PCR, we show that decreased miR-103 and miR-107 in Tg19959 mouse brain compared to wild-type littermates. We also observe over expression of activated cofilin protein is sufficient to induce rod formation in primary neurons. In addition, our image data have shown shortened neurites and abnormal mitochondria in neurons containing cofilin rods. Conclusions: Taken together, our data indicates the deficiency of miR-103 and 107 increase cofilin protein level, resulting in formation of rod structure in a transgenic mouse model of AD. The rod formation has pathological consequences including neurite development, mitochondrial morphology and dynamics. These are the first observations that miRNAs involved protein regulationmay contribute to formation of abnormal cytoskeletal aggregates in AD pathogenesis. Furthermore, these studies will give us fresh insights into AD pathogenesis and provide new therapeutic targets.