Administrative Supplement Summary/Abstract: Alzheimer's disease (AD) is the most common form of dementia and one of the leading causes of morbidity and mortality worldwide. AD has a profound economic and social burden impacting the well-being of individuals, families, and a significant percentage of the world's population. It is one of the most pressing problems facing public health today. Thus, there is urgency to understand disease mechanisms to develop novel therapeutic strategies to combat this devastating disease. Neuroinflammation in the form of microglia activation and oxidative stress are hallmark features of AD. Our laboratory has had a long-standing history in the validation and application of Translocator Protein 18 kDa (TSPO) as a biomarker of neuroinflammation. TSPO is expressed in microglia and our work (in the parent grant) is focused in understanding the function(s) of TSPO in microglia. We have discovered an association between TSPO and NADPH Oxidase (NOX2) in microglia suggesting that TSPO may modulate NOX2 subunit(s) gene expression altering reactive oxygen species (ROS) production and oxidative stress in the brain. TSPO levels and NOX2 activity are both significantly increased in the brains of AD subjects and in animal models of AD. Since they are both highly expressed in AD-associated microglia, their interaction may be important in ROS production and oxidative stress leading to the aggregation of β-amyloid, neuronal loss, and cognitive deficits. We hypothesize that disruption of the TSPO-NOX2 interaction in microglia may arrest AD progression. Our working hypothesis is that 5XFAD mice (animal model of AD) that are deficient in TSPO will have a lower level of AD pathology and cognitive function deficits when compared to sex- and age-matched 5XFAD mice that are wildtype for TSPO. To this goal, in specific aim 1, we propose to use 5XFAD mice and our global TSPO knockout mice to generate 5XFAD mice with different levels of TSPO gene expression. We propose to generate 5XFAD mice that are wiltype, heterozygous, and deficient for TSPO. The goal of specific aim 2 is to use these mice to obtain preliminary data on the impact of TSPO gene dosage on the cognitive function deficits and hallmark AD pathology in 5XFAD mice. We will use the Barnes maze (spatial learning task) as one measure of cognitive function and will assess β-amyloid plaque load, and microglia and astrocyte activation using immunohistochemistry methods. The proposed studies resulting from this administrative supplement will leverage the ongoing studies in the parent grant on the association of TSPO and NOX2 in microglia and will extend them to their potential role in the neuroinflammation and neurodegeneration associated with AD. The data generated will serve to provide preliminary evidence for a larger and more comprehensive NIH proposal on the role of TSPO and NOX2 in the initiation and progression of the hallmark pathology and cognitive deficits in AD using a life c...