Mast cell deficiency improves cognition and enhances disease-associated microglia in 5XFAD mice

• DOI: 10.1016/j.celrep.2023.113141
• Publication Date: 2023-09-19T06:39:51Z
• Authors: Chih-Chung Jerry Lin; Fanny Herisson; Hoang Le; Nader Jaafar; Kashish Chetal; Mary K. Oram; Kelly L. Flynn; Evan P. Gavrilles; Ruslan I. Sadreyev; Felipe L. Schiffino; Rudolph E. Tanzi
• Keywords: Mice; Cognition; QH301-705.5; Alzheimer Disease; CP: Neuroscience; Animals; Immunologic Factors; CP: Immunology; Mice, Transgenic; Microglia; Mast Cells; Biology (General); Article

Emerging evidence suggests that peripheral immune cells contribute to Alzheimer's disease (AD) neuropathogenesis. Among these, mast cells are known for their functions in allergic reactions and neuroinflammation; however, little is known about their role in AD. Here, we crossed 5XFAD mice with mast cell-deficient strains and observed the effects on AD-related neuropathology and cognitive impairment. We found that mast cell depletion improved contextual fear conditioning in 5XFAD mice without affecting cued fear conditioning, anxiety-like behavior, or amyloid burden. Furthermore, mast cell depletion led to an upregulation of transcriptomic signatures for putatively protective disease-associated microglia and resulted in reduced markers indicative of reactive astrocytes. We hypothesize a system of bidirectional communication between dural mast cells and the brain, where mast cells respond to signals from the brain environment by expressing immune-regulatory mediators, impacting cognition and glial cell function. These findings highlight mast cells as potential therapeutic targets for AD.