Nasal administration of anti-CD3 monoclonal antibody improves cognition in mouse models of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder in which microglial cells change from a homeostatic (M0) to a neurodegenerative (MgnD) phenotype and become activated, contributing to neuroinflammation and cognition decline. We have shown in several mouse models of central nervous system (CNS) inflammation that nasal administration of anti-CD3 monoclonal antibody localizes to the cervical lymph nodes where it induces IL-10-producing Treg cells that migrate to the CNS to control inflammation by switching microglia from MGnD to M0 phenotype. Here, we investigated whether nasal anti-CD3 would improve cognition in APP-PS1 and 3xTg mice, which develop impaired cognition. Nasal anti-CD3 or isotype control were administered at a dose of 1mcg/mouse, 3x/week for 2 months (APP-PS1) or 5 months (3xTg) and then tested for cognition using the Y-maze and the Morris water maze. Mice were then euthanized, and brains removed for microglial cell sorting and RNA-sequencing. We found that nasal anti-CD3 improved short-term memory in APP-PS1 mice and both short- and long-term memory in 3xTg mice. Improvement in cognition was associated with a downregulation of microglial genes associated with neurodegeneration and an upregulation of microglial genes associated with homeostasis. Thus, nasal anti-CD3 may constitute a novel microglial modulating immunotherapy to treat AD.