Alzheimer’s disease is the health challenge of our generation. The majority of AD cases are late onset and result from the interaction of multiple genetic and nongenetic risk factors, of which the most important is aging. Genetic studies implicate the brain’s resident immune cells, microglia, in the pathogenesis of late-onset AD, while other evidence ties immune mechanisms not only to AD, but also to other neurodegenerative disorders. In fact, more than half the risk genes associated with late-onset AD are selectively expressed in microglia, yet we know shockingly little about their biology or how they contribute to AD pathogenesis. Under normal conditions, microglia actively survey the brain; they are highly sensitive to changes caused by injury, infection or other abnormalities. In this role they can be beneficial by removing toxic proteins and cellular debris, but in disease they also can promote detrimental neuroinflammation leading to inappropriate synapse loss—one of the earliest changes in the AD brain and the strongest correlate of cognitive decline.
Given the complexity and diversity of microglia in health and disease, there is a critical need for biomarkers that distinguish “beneficial” from “detrimental” microglial states over the course of AD. For the first time, it is possible to isolate individual cells from banked post-mortem brains, and analyze changes in gene expression and cell state at single cell resolution. Using these and other emerging technologies, we will help build the first comprehensive map of immune and neural cell state changes in AD and normal aging. We will examine the microglial response in the human AD brain at the single cell level, and ask how microglia transcriptional changes relate to other neural cells (neurons, astrocytes) in vulnerable brain regions. In parallel, we will profile the glial response in an established mouse model of AD and test whether inhibition of the classical complement cascade, a pathway that mediates synaptic loss and glial activation, ameliorates pathogenic inflammation and neuropathology. Results from these studies will further our knowledge of the neuroinflammatory response in AD and may lead to the identification of new biomarkers and therapeutic targets or pathways.