PROJECT SUMMARY MicroRNAs can inhibit gene expression by binding to mRNAs and prevent them from being translated into proteins. MicroRNA levels often differ in diseased cells and in healthy cells, leading to differential expression of certain genes. Controlling microRNA levels therefore offers a promising target for therapeutic intervention. MicroRNA-218 (miR-218) is over-expressed in cells obtained from Alzheimer's disease (AD) patients. Interestingly, we found that miR-218 can be degraded by its target mRNA (TRIM9), which is down- regulated in Lewy body dementia, an AD-related dementia. This is surprising because microRNAs usually control the levels of their targets, but not the other way around. This is also exciting because it is one of the few examples representing a recently discovered gene regulation mode carried out by the mRNAs and opens up strategies for AD intervention. In this administrative supplement, we first aim to understand how TRIM9 mRNA triggers miR-218 degradation. Our second aim is to develop an innovative biochemical and computational protocol to globally identify sequences in different target mRNAs that can induce miRNA degradation in AD patient- derived cells. Collectively, our efforts will examine a new mechanism of gene regulation in AD and related dementia, in which mRNAs counteract microRNAs. Given that we have discovered a potentially widespread occurrence of the mRNA-induced microRNA degradation pathway, identifying the mRNAs that can degrade miRNAs would help develop new therapies to combat AD and other types of neurological diseases.