iPS-derived MIcroglia and Neuroinflammation in Dementia (iMIND)

Title iPS-derived MIcroglia and Neuroinflammation in Dementia (iMIND)
Start date 2020-02-20
End date 2023-02-19
Sponsor University of California Irvine

Project Description

The World Alzheimer Report 2015 estimates over 9.9 million new cases of dementia each year worldwide, one new case every 3.2 seconds. Dementia is becoming a severe threat to health system stability and, despite major research and clinical efforts, no disease-modifying strategies are available. Many studies have been centered on the pathogenic role of β-amyloid (Aβ) dysmetabolism, but therapeutic approaches targeting Aβ have so far failed. There is an urgent need to explore alternative pathogenic pathways as well as to employ experimental settings that are closer to the disease. Microglia is the primary innate immune cell of the brain, and its activity has recently emerged as a critical modulator of the disorder. Interestingly, genome-wide association studies (GWAS) have identified polymorphisms in over 20 genes that influence the risk of developing AD and most of these genes are selectively expressed in microglia. Recent evidence indicates a protective role for P522A, a mutation of the PLCG2 (Phospholipase C Gamma 2) gene. The gene encodes for a transmembrane signaling enzyme that is highly enriched in microglia and modulates the generation of inositol 1,4,5-trisphosphate (IP3), a second messenger controlling calcium (Ca) release from intracellular stores. Although rare (<1% of healthy controls and about 0.6% of AD cases harbor this mutation), the P522A frequency is comparable to the, widely studied, TREM2 R47H AD-linked mutation. The use of preclinical AD models has been the object of a critical reappraisal as AD-engineered animals show several shortcomings and poor translation value, thereby highlighting the urgent need to investigate human models. iMGL cells are highly similar to brain-derived microglia. iMGL has similar transcriptomic and functional features, show phagocytosis of Aβ, tau, and synapses as well as chemoattractant migration, cytokine/chemokine production, and in vivo engraftment. The model is highly scalable for the development of the proposal. Overall, the project is set to identify novel therapeutic targets and, in line with the Health, Demographic Change and Wellbeing panel of the H2020 Framework Programme, explores new grounds in the molecular underpinnings of AD. Throughout the project, we will investigate transcriptomic, molecular, and functional changes modulated by the protective activity of the PLCG2 P522A mutation in human iPSC-generated microglia derived from control and AD individuals, an experimental setting that is very close to the AD battleground.