Project Summary

Growing evidence suggests a role of the gut microbiota in controlling the activity of CNS innate immune
cells, especially microglia . In the first funding period we observed that host microbiota controls aging
of microglia and phagocytic clearance of β-amyloid (Aβ) deposits in the 5xFAD mouse model of Alzheimer’s
disease (AD). In young germ-free (GF) mice, microglia displayed several defects in metabolism, including
changes in mitochondrial mass, mitochondrial membrane potential and disruption of oxidative
phosphorylation. This was connected to a decrease in AD pathology in GF mice. However, we also found
diminished signs of microglial aging in GF mice. In the second funding period, we propose to investigate the
role of the microbiota in controlling the function of CNS-associated macrophages (CAMs), including
meningeal (mMɸ), perivascular (pMɸ) and choroid plexus macrophages (cpMɸ) . Building on our previous
work on the role of microglia in the context of aging and Alzheimer’s disease (AD) , as well as
on the regional specification of microglia, we will now (i) investigate the role of the microbiota in
controlling CAMs under homeostatic conditions, during aging and AD, (ii) characterize metabolic parameters
in CAMs of specific pathogen-free (SPF) and GF mice during steady-state, aging and AD, and (iii) determine
how localization influences the phenotype and function of CAMs.