Neuroinflammation is a well-established feature of Alzheimer’s disease (AD), driven primarily by the chronic activation of astrocytes and microglia. Although our understanding of the roles microglia play in AD has grown considerably over the past decade, our knowledge of how astrocytes contribute is still relatively limited. Astrocytes support brain health through several important functions: they mount inflammatory responses, clear cellular debris, are integral to the blood-brain barrier, supply nutrients to other brain cells, and maintain connections between neurons (synapses). Specialized proteins on their outer surface, known as cell surface proteins (CSPs), enable them to accomplish these tasks in a variety of ways, including recognizing chemical signals from other cells.
Drs. Zheng and Peng propose that identifying which astrocyte CSPs change the most in response to Alzheimer’s pathology will indicate how these cells function detrimentally in the disease. Their project goal is to identify, using mouse models, which CSPs are altered in the presence of amyloid plaques and tau tangles, and then determine the function of the most altered CSPs through cell culture experiments. CSPs are logistically compelling therapeutic targets since they sit on the outside of cells rather than within them, so astrocyte CSPs identified in this project for their altered function in AD could be targets for small-molecule drugs.
They proposed two aims toward this goal. In the first aim, they are identifying astrocyte CSP changes in amyloid (5xFAD) and tau (PS19) mouse models across different ages and then determining whether these CSPs are also produced by human astrocytes. In the second aim, they are evaluating how the top CSP candidates from the first aim affect two astrocytic functions known to go awry in AD: clearing cellular debris (phagocytosis) and maintaining neuronal synapses. They are experimentally modifying the levels of specific CSPs in human astrocyte cultures and measuring the impact on amyloid and tau levels, as well as synaptic debris uptake. The team is also culturing these astrocytes with neurons to determine how changes in astrocytic CSP levels affect the structure and function of neuronal synapses. Together, these experiments aim to decode the function of CSPs on astrocytes, with the expectation that they will highlight specific pathways impacted by Alzheimer’s, which could lead to novel targets for drug discovery.
The team made significant strides in the first funding period. They identified a robust initial set of CSPs for further investigation after analyzing and comparing data from amyloid and tau mice at multiple time points. Although tau data are still being analyzed, results from the amyloid mice suggest that the cell surface protein CD44 is associated with increased amyloid pathology. Reducing CD44 decreased amyloid pathology and lowered astrocyte inflammation. Preliminary results suggest that CD44 may regulate the formation of lipid droplets. Lipid droplets are normal structures for energy storage within astrocytes, but increases in their number and size are associated with higher levels of inflammation and with AD. Drs. Zheng and Peng believe CD44 could be a promising target for therapeutic intervention and are performing additional experiments. Alongside these experiments, Drs. Zheng and Peng will complete the tau CSP analyses and compare CSPs across timepoints to assess the impact of age in the second funding period.
