Microbiome Consortium: Interaction of the Microbiome with Astrocytes and Amyloid Pathology

Alzheimer’s disease (AD) is a neurological disease and the most common cause of dementia. Although AD is a leading cause of death in the United States, there are few effective therapeutic options for patients. Proteinaceous aggregates called amyloid beta plaques are found in the brains of AD patients and are likely key initiators of disease progression. Recent studies have shown that the gut microbiome (GMB), which consists of trillions of microorganisms that live in the human digestive tract, is significantly altered in AD patients compared with healthy controls. It has been shown that the GMB regulates amyloid deposition in the brain in AD mouse models. Previous studies indicate that the GMB might be regulating amyloid deposition by its role in activating cells with immune function in the brain. Our recent work has shown that the GMB regulates the structure and functionality of a cell type in the brain called astrocytes, which are crucial for normal brain function. However, in AD and other neurological disorders, astrocytes change their functionality to become inflammatory and release substances that kill other brain cells, modulate amyloid plaques and lead to the progression of AD. In this proposal, we aim to follow up on our previous study to understand which molecular pathways are more fully regulated in astrocytes by the GMB, how these pathways contribute to amyloid pathology and AD progression, and what blood and brain-based intermediate mechanisms regulate the gut–to–astrocyte communication. These results may uncover druggable targets in the GMB-astrocyte pathway axis for AD.