PROJECT SUMMARY Alzheimer’s disease (AD) is the most common type of dementia, afflicting approximately 5.7 million people, or 60–80% of cases of dementia in the United States, and is predicted to triple to 16 million by the year 2050. Diagnosis is made after the age of 65 in 90-95% of patients, with the remaining 5-10% considered early-onset. Symptoms usually begin with difficulty learning new facts or recalling recent memories. In the middle stage of AD progression, language becomes more difficult, memory continues to deteriorate with long-term memory now also being affected, patients may not recognize close relatives, and will need assistance with most activities of daily living. During the late stage of AD, language is eventually lost, muscle atrophies to the degree that patients cannot get out of bed or feed themselves, and pneumonia or infection of pressure ulcers usually leads to death. Thus, AD is clearly a significant health problem. The biochemical basis for AD pathophysiology is thought to be the aggregation of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. These markers correlate with the severity of clinical signs and symptoms of the disease, and it is thought that they may be directly neurotoxic. However, a more recent paradigm is that these aggregates of misfolded proteins may lead to a state of chronic neuroinflammation, and that this inflammatory state is responsible for loss of neuronal function and neuron death. This inflammatory state is achieved through activation of the innate microglia, as well as the relatively understudied (in this context) activation of adaptive T lymphocytes. Regulatory T cells (Tregs) are a subset of T cells that dampen immune responses and promote tissue repair after injury in various tissues including the brain. Recently, regulatory T cells have been suggested to play an important role in AD. However, important gaps in our understanding of Tregs in AD remain: What types of Tregs are found in the brain in AD mice relative to wildtype mice? and, What role do Tregs play in the progression of AD? I will address this knowledge gap in two specific aims. In Aim 1, I will characterize the types of Tregs and their spatial localization in the aging WT and AD brains, while in Aim 2 I will establish the effect of increasing or decreasing Treg numbers or function. My hypothesis is that brain-specific Tregs play a critical role in preventing or delaying AD progression, and that increasing their number and function will lead to improved outcomes in AD. Successful completion of the aims of this grant will provide insight into the role of Tregs in AD. These studies will enhance my training in computational and hypothesis generating experiments (Aim 1), as well as hypothesis driven functional studies (Aim 2).