Mast cell deficiency improves cognition and enhances disease-associated microglia in 5XFAD mice
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
Affiliations
Chih-Chung Jerry Lin
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Fanny Herisson
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Hoang Le
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Nader Jaafar
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Kashish Chetal
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
Mary K. Oram
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Kelly L. Flynn
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Evan P. Gavrilles
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Ruslan I. Sadreyev
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Felipe L. Schiffino
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Rudolph E. Tanzi
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Charlestown, MA 02129, USA; Corresponding author
Summary: 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.
