Targeting microglial cell iron-handling in Alzheimer’s Disease

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Project Summary Alzheimer’s Disease (AD) is the most common cause of dementia, and its incidence continues to rise. This neurodegenerative disease is associated with the accumulation of extracellular amyloid beta (Aβ plaques) and intraneuronal tau tangles, which contribute to a progressive cascade of changes leading to neuronal loss, brain atrophy, and cognitive decline. However, not all individuals who exhibit AD-associated alterations (i.e., Aβ plaques) develop clinical dementia, suggesting other convergent pathologies that synergize to help drive the disease. Increasing evidence demonstrates the significant presence of neuroinflammation and microglial activation in the brains of AD patients. We and others have specifically shown enhanced iron load in these AD- associated microglia, and increased brain iron content is associated with greater Aβ plaque deposition and worsened cognitive decline. Interestingly, my preliminary in vitro studies suggest that microglia specifically shift their iron-handling function in age and during Aβ-induced inflammation. These cells preferentially upregulate the ferrous iron importer, divalent metal transporter 1 (DMT1) in response to Aβ, allowing the import of highly reactive iron which could worsen inflammation if in excess. However, much of the prominent associations between cellular iron load and microglial inflammation in vivo have been shown in late disease stages in humans and animal models, and it is not known whether early alterations in microglial iron homeostasis contribute to downstream inflammation and disease dysfunction. Thus, this project aims to target a critical iron-handling function of microglial cells at an early pre-symptomatic stage of AD to determine how microglial iron handling and linked inflammatory status contribute to disease progression. To do this, I will utilize a novel transgenic mouse model with altered microglial iron-handling on the background of an AD mouse line. Following inhibition of microglial DMT1 – the key iron importer in our AD mouse model –, I will assess cognition and memory performance, markers of neuroinflammation, and brain iron and Aβ plaque load. Behavioral assays, immunohistochemical approaches, and unbiased gene expression analyses will be performed to assess the effect of manipulating microglial iron-handling on markers related to AD progression. Ultimately, this project seeks to address a critical gap in the field’s understanding of early microglial cell dysfunction in AD. I hypothesize that inhibiting microglial DMT1 early during the progression of disease will disallow excessive and chronic Aβ-induced iron import, and thus reduce downstream inflammation and improve markers of AD. In addition to the scientific goals of the project, the training received while conducting this work will support my long-term goal of becoming an independent academic researcher and mentor. Specifically, the training plan set forth places emphasis on fostering the technical, analytical, and communication skills needed to achieve a successful career in academia. The interdisciplinary, collaborative, and supportive environment at Vanderbilt University provides a strong foundation for this project to succeed.