2020, 2022
2022
Genetic and neuropathological studies have strongly implicated microglia in the development and progression of Alzheimer’s disease (AD). Yet precisely how AD risk genes alter microglial function to impact amyloid beta pathology remains unclear. One popular hypothesis is that microglial risk genes reduce amyloid beta clearance from the brain by impairing phagocytosis. However, recent studies have surprisingly shown that pharmacological depletion of microglia reduces amyloid beta plaque load. In preliminary studies, we have similarly found that a genetic loss of microglia reduces parenchymal amyloid beta plaques, which in turn is accompanied by a dramatic increase in cerebral amyloid angiopathy (CAA). As CAA occurs in 80% to 90% of patients with AD, and is associated with a poorer prognosis, it is critical to understand how microglia impact the development of this often-overlooked AD pathology. In this CureAlz proposal, we will test the hypothesis that microglial TREM2 and Apolipoprotein E (APOE) drive the compaction of parenchymal amyloid plaques, which inversely reduces the development of CAA. In Specific Aim 1, we will collaborate with each of the members of the CureAlz Neuroimmune Consortium to examine the impact of murine microglial deletion on amyloid beta pathology, neuronal and glial transcriptomes (Stevens, Glass, Liddelow Labs), synaptic and cognitive function (Stevens and Datta Labs) and inflammatory state (Hooker Lab). In Specific Aim 2, we will take advantage of isogenic APOE and TREM2 knockout induced pluripotent stem cells and a chimeric mouse model of AD to specifically determine whether human APOE or TREM2 impacts these same transcriptional, functional and neuropathological endpoints. Results from these studies will greatly improve our understanding of how microglia influence the development of AD, and provide important new insight into the potential impact of human microglia on the development and progression of CAA.
2020
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.
Mathew Blurton-Jones, Ph.D.
