the Role of Human Microglia in the Transition Between Parenchymal and Vascular Amyloid Beta Pathology


Alzheimer’s disease (AD) is the leading cause of age-related dementia, affecting more than 5 million people in the United States alone. Unfortunately, current therapies are largely palliative, and thus there is an urgent need to improve our understanding of the mechanisms that drive the development and progression of AD. Recent genetic studies have provided strong evidence that microglia, the primary immune cell of the brain, play a critical role in this disease. Yet precisely how microglia influence the accumulation of amyloid beta, the pathology that underlies the initial development of AD, remains unclear. In recent studies, we have found that microglia help to determine whether amyloid beta accumulates within the extracellular space as amyloid plaques, or within the blood vessels of the brain as cerebral amyloid angiopathy (CAA). This distinct localization appears to be very important in the progression of AD, as CAA occurs in greater than 80% of AD patients and is associated with a more rapid decline in cognitive function and earlier mortality. To further understand how microglia influence CAA, we will collaborate closely with the other members of the CureAlz Neuroimmune Consortium to examine the impact of genetic changes in human microglia on multiple aspects of AD neuropathology. Using both mouse models and stem cell-derived human microglia, we will determine how two key AD risk genes—APOE and TREM2—influence the development of AD pathology, and neuronal and cognitive function. Our studies will, therefore, provide crucial insight into the functional genetics that underlie AD, and hopefully uncover important new information that can be used to guide the development of therapies.

Funding to Date



Studies of Innate Immune Pathology, Translational


Mathew Blurton-Jones, Ph.D.