– AD-PLCG2

Alzheimer's disease (AD) has an important genetic component and among the genetic factors characterized, the PLCG2 gene is of major therapeutic interest, because it harbors a reported protective variant with a hypermorphic effect on enzyme function. The pathways and interaction partners of this gene/protein may therefore provide promising candidates for the discovery of new drug targets for AD. Prior research suggests that a decrease in PLCG2 activity may be harmful, and that – even if an increase in PLCG2 expression/activity may be protective – very rare PLCG2 gain-of-function mutations are also responsible for a rare disease (familial autoinflammatory syndrome). It may therefore be more relevant to target a factor upstream or downstream in the pathophysiological pathways dependent on PLCG2, rather than PLCG2 itself. In addition, this gene has been studied mainly in microglia due to its reported specific expression in only this cell type. However, our preliminary results indicate that this gene is also expressed in other cell types, especially in glutamatergic neurons, and we were able to show that PLCG2 is present in synapses and involved in synaptic connectivity. Thus, our preliminary results point out pleiotropic functions of PLCG2 in the brain. In this context, our project will be organized into four work packages to decipher PLCG2-related pathways in different cell types and to potentially characterize potential druggable targets within these pathways: (i) generation of “omics” data from human-induced neurons, microglia cultures, 3D brain tissue and mouse models by presenting different levels of PLCG2 expression and A? exposures; (ii) Determination of PLCG2-related pathways and druggable targets in these pathways through systems biology approaches and clinical individual level data in large population-based cohorts; (iii) Validation of the druggable targets in AD-related phenotypes in human-induced neurons or microglia; (iv) Validation of PLCG2-related pathways and potential drugs in drosophila models. In conclusion, our consortium of partners with highly complementary skills proposes a project to characterize PLCG2-related pathways in human induced neurons/microglia and animal models and the selection of the most promising drug targets within these pathways through comprehensive omics analyses, integrated experimental and computational systems biology approaches, and access to large population-based cohorts to facilitate the translation of genetic findings into disease modulation approaches.