Role of microRNA in regulating Fe, Amyloid, and Tau (FeAT) in Alzheimer's disease

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder; available therapies only modestly improve symptoms. Our goal is to identify neurobiological mechanisms leading to neurodegeneration in AD. MicroRNAs (miRNA) are endogenous noncoding RNA molecules that typically silence translation. Little research exists on roles of miRNAs that target gene products implicated in AD as participants in neurobiology. We recently discovered a miRNA (miR346) that stimulates translation of amyloid-β precursor protein (APP) as part of iron (Fe) homeostasis. This miRNA binds a site that overlaps an iron responsive element (IRE) in APP. miR346 also has a predicted site in the tau 3’-UTR, and tau facilitates APP activity in Fe homeostasis. Also, we have identified miR298 reducing levels of APP and a specific tau protein moiety. The proposal objective is to test “balancing feat” among miR346, miR298, Fe, and cellular inflammation networks via APP and tau (FeAT). Our central hy- pothesis is 1) miR346 plays a vital role in maintaining Fe homeostasis; 2) Manipulating miRNA could redirect Fe metabolism to prevent or treat AD and other neurodegenerative disorders. SA1: Test hypothesis—miR346 and 298 interact with APP and tau mRNA untranslated region (UTR) se- quences. Rationale: Fe dyshomeostasis is implicated in AD. APP and tau play roles in Fe metabolism. A co- regulator of both that also takes part in Fe metabolism could be a vital tool for preventing AD-related neurotoxi- city. Impact: Studies reveal miR346 and miR298 coregulate APP and tau. SA2: miR346 and 298 regulation of APP and tau both leads to and responds to Fe dyshomeostasis. Rationale: We intend to establish specific mechanisms of miR346 and miR298 activity within Fe metabolism. miR298 will be indirectly involved in response to Fe levels. Identifying the role of miRNA-mediated regulation within this network should elucidate miRNA-dependent mechanisms for pharmacological manipulation. Impact: These studies are likely to reveal novel biological mechanisms for miRNA function and FeAT trio regulation. SA3: Test hypothesis—miR346 and 298 are dysregulated in AD in stage and brain region specific man- ners. Rationale: We will identify partners of FeAT with miR346 and miR298 in well-characterized clinical sam- ples. We expect regulation to vary in anatomical- and pathology-dependent patterns. Impact: These studies in AD patients will further establish the miRNAs as therapeutic targets. SA4: Translate miR346 and miR298 manipulation on Fe homeostasis, APP and tau, and critical pro- cessing enzymes in transgenic AD model mice. Rationale: We intend to ascertain how or if AD pathology affects the interaction and how the interaction affects AD pathology. We will pay particular attention to differences in response to miRNAs or blockade in wild type vs. transgenic mice. Impact: Determining how manipulation of miR346 in both normal and induced pathology systems will alter pertinent protein levels with an eye toward reducing pathology via miR346 control.