The iMIND project is structured to investigate the contribution of neuroinflammation in Alzheimer’s disease (AD) by employing a novel, human-derived, pathology-relevant cellular model. AD is an irreversible neurodegenerative condition affecting 50 million people worldwide. The current figure indicates that AD is becoming a severe threat to the health system's stability. However, no disease-modifying strategies are available despite major research and clinical efforts. Neuroinflammation is emerging as a key component of the disease, affecting its onset and progression. Recent analyses have identified over 20 genes that influence the risk of developing AD and, of note, most of these genes are primarily expressed in microglia, the innate immune cells of the brain and critical modulators of neuroinflammatory processes.
The original proposal was set to investigate a rare protective mutation (P522A) in the PLCG2 (Phospholipase C Gamma 2) gene associated with AD in a model of microglia derived from human pluripotent stem cells (iPSC). Unfortunately, the early phases of the fellowship have been significantly impacted by the COVID-19 pandemic and the stringent plans set in place to limit its spread. Therefore, a contingency plan was drafted to limit the disruption of research activities. The revised proposal focused on the investigation and the functional characterization of the TREM2 gene in human microglia. Like PLCG2, the TREM2 gene is primarily expressed in microglia but, unlike PLCG2, rare loss-of-function TREM2 variants increase the risk of developing AD. We have previously shown that TREM2 knock-out (TREM2 KO) alters gene expression and functional responses in human AD models. However, the molecular mechanisms linking deficits in TREM2 signaling to the functional alterations observed in AD are still poorly understood. The key objectives of the iMIND project are as follow: 1) to gain expertise in the generation of microglia derived from wild-type and TREM2 KO mutant iPSC, 2) to investigate the molecular and functional responses of mutant microglia to AD-related stimuli, 3) to investigate functional effects of TREM2 deficits on calcium (Ca2+) signaling and cell motility. Additional objectives, specifically investigated during the return phase of the fellowship, are as follow: 1) to detect the specific source of Ca2+ that contributes to the spontaneous transients and 2) to investigate the contribution of Ca2+ signaling on directed cell migration in human microglia.
Collectively, the project identified novel therapeutic targets, explored new grounds in the molecular underpinnings of AD, and elucidated key, unexpected mechanisms of microglia functioning in physiological and pathological settings.
