Abstract Body

Cholinergic deficiency is a characteristic of many neurodegenerative disorders including Alzheimer’s disease (AD). Decreased levels of the vesicular acetylcholine transporter (VAChT) have been detected in AD patients and imaging data suggest that VAChT levels can predict human pathology. However, whether changes in VAChT are associated with plaque formation is unknown. To test for a causal relationship between VAChT levels and Ab plaques, we crossed a humanized APP knock-in (KI) mouse, carrying 2 AD-associated familial mutations, with mice lacking VAChT in forebrain neurons. We found that mice with elimination of forebrain VAChT presented with increased plaque area and Abeta levels. In contrast, in mice in which VAChT is overexpressed, we found a decrease in plaque area and Abeta levels in younger double mutant mice when compared to APP KI mice. In both these lines, potential changes in microglia-associated with plaques was observed. To further understand how cholinergic signaling in microglia may influence neuroinflammation, we generated mice expressing hM3Dq (a muscarinic M3 DREADD) exclusively in microglia. Our results suggest that chronic activation of muscarinic Gq signalling in microglia can trigger an inflammatory-like response that preconditions microglia to decrease their response to further immunological challenges. Our results suggest that VAChT levels are casually linked to plaque formation in humanized APP KI mice and that muscarinic signalling in microglia can trigger microglial immunological memory in vivo, which may be applicable for manipulation of neuroinflammation in neurodegenerative diseases.