Dylan Freedman

Alzheimer’s Disease (AD) is the most common type of dementia that begins with mild memory loss and deteriorates over time. In the brain, AD disrupts processes vital to neurons –including communication, metabolism, and repair– leading the neurons to ultimately die. AD is associated with both tau and neuroinflammation pathologies. Tau, a protein inside neurons that helps regulate their function in the brain, accumulates to form “tau tangles” in AD that block neurons from performing their functions. This disruption contributes to the cognitive decline in AD. Neuroinflammation, the activation of the brain’s immune system in response to an inflammatory challenge, is also closely associated with AD. An overactivation of microglia, immune cells that normally clear waste out of a healthy brain, can cause neuroinflammation in the AD brain. Microglia can function due to receptors on cells known as myeloid cells 2 (TREM2). Soluble TREM2 (sTREM2) is the split fragments of TREM2 that can be found in the extracellular space of the brain. A common mutation of sTREM2 is called R47H-sTREM2, which is known to disrupt the process of microglial activation. 

We know sTREM2 plays an important role in regulating microglial function, and levels in the brain vary depending on the stage of AD. However, there is conflicting data on how an increase in sTREM2, as compared to an increase in R47H-sTREM2, impacts the levels of tau in the AD brain. My study aims to address the following two questions: 1) What is the relationship between sTREM2 and tau in the AD brain? 2) How do the effects and amount of tau tangles of sTREM2 compare to those of R47H sTREM2? 

To answer these questions, I will be working with a model known as a human neuron-induced pluripotent stem cell and inducing increased sTREM2 in my first model and increased R47H-sTREM2 in my second model. Then, I will compare the levels of tau in both models and a control model using immunofluorescence staining. The implications of my study include learning more about the AD brain as well as coming up with possible targets for treatment.