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

• Published in: Cell reports (Cambridge) Vol. 42; no. 9; p. 113141
• Main Authors: Lin, Chih-Chung Jerry, Herisson, Fanny, Le, Hoang, Jaafar, Nader, Chetal, Kashish, Oram, Mary K., Flynn, Kelly L., Gavrilles, Evan P., Sadreyev, Ruslan I., Schiffino, Felipe L., Tanzi, Rudolph E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.09.2023; Elsevier
• Subjects: 5XFAD; Alzheimer Disease - pathology; Alzheimer's disease; Animals; astrocyte; behavior; Cognition; CP: Immunology; CP: Neuroscience; Immunologic Factors; mast cell; Mast Cells - pathology; meninges; Mice; Mice, Transgenic; microglia; Microglia - pathology; neuroimmune interaction; CP: Immunology; 5XFAD; CP: Neuroscience; neuroimmune interaction; mast cell; behavior; Alzheimer's disease; microglia; astrocyte; meninges
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113141

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. [Display omitted] •Mast cell depletion restores cognition in 5XFAD mice without altering β-amyloid•Mast cell deficiency elevates levels of disease-associated microglia in 5XFAD mice•Absence of mast cells reduces markers indicative of reactive astrocytes Lin et al. show that depletion of mast cells restores cognitive function (contextual fear conditioning), increases disease-associated microglia gene expression, reduces GFAP levels, and alters astrocytic morphology. These data implicate mast cells as potential targets for treating AD.