Treatment of Alzheimer’s disease by modulation of microglial neuroinflammation by nasal anti‐CD3 mAb

Abstract

AbstractBackgroundNeuroinflammation and microglial activation play a role in AD as shown pathologically and by microglial PET imaging (Zhou et al, Front Immunol 2021). We found that nasal anti‐CD3 mAb induced IL‐10‐secreting T cells in the cervical lymph node that migrate to the brain, suppress microglial inflammation and ameliorate disease in a model of progressive MS (Mayo et a,l Brain 2016). In humans we found that nasal anti‐CD3 (Foralumab) decreased inflammation and accelerated resolution of lung inflammation in patients with mild COVID‐19 (Moreira et al, Front Immunol 2021) and modulated microglial activation in progressive MS as measured by microglial PET imaging (Chitnis et al, unpublished). We thus tested nasal anti‐CD3 in animal models of AD.MethodWe treated AD mice (3xTg and APP/PS1) with nasal anti‐CD3, isotype control antibody or PBS 3x/week for 6 months (3xTg) or 3x/week for 2 months (APP/PS1) and investigated cognitive behavior (Morris water maze and Y‐maze), microglia gene profile using a Nanostring myeloid codeset and T cell infiltration in the brain by immunofluorescence.ResultWe found that microglia lose their homeostatic (M0) signature and acquire a neurodegenerative (MGnD) signature in animal models of AD. In 3xTg mice, we found that nasal anti‐CD3 restored the M0 signature by increasing the expression of Cx3cr1, Mafb, and Jun, and lessened the MGnD signature by decreasing the expression of Trem2, Nos2 and Ccl5. Nasal anti‐CD3 improved cognition in 3xTg mice as measured by the Y‐maze and Morris water maze tests and in APP/PS1 mice as measured by the Y‐maze test. Nasal anti‐CD3 induced migration of T cells to the brain which interacted with microglia.ConclusionNasal anti‐CD3 restores the microglial M0 signature and improves behavior in animal models of AD. Based on these results and the successful administration of nasal anti‐CD3 to subjects with progressive MS and COVID‐19, phase 1 trials of nasal Foralumab are planned in subjects with mild AD to assess safety, clinical effects and microglial activation as measured by microglial PET imaging. Nasal anti‐CD3 is a novel approach to treat AD by targeting microglial inflammation.