Project description
Microglial proteins and Alzheimer's disease
As the global population ages, diseases associated with ageing increase in prevalence. Among them is the incurable Alzheimer's disease (AD), a debilitating neurodegenerative condition causing loss of memory and cognition. Recently, researchers identified a protective mutation in a gene associated with AD. The gene codes a protein abundant in microglia, cells that engulf and digest cellular debris and dead cells in the brain and spinal cord, playing an important role in immunity. iMIND is creating human microglial cell lines from both healthy and AD-derived stem cells. These will be edited to express the mutation. Studies may elucidate novel molecular mechanisms of AD and point to therapies.
Objective
Alzheimer’s disease (AD) is an irreversible neurodegenerative condition affecting 50 million people worldwide. To date, no disease modifying therapy for AD is available. Neuroinflammation is emerging as an important component of the disease. A recent GWAS analysis identified a rare protective coding mutation (P522A) in the PLCG2 (Phospholipase C Gamma 2) gene that is associated with AD. Interestingly, the gene encodes a transmembrane signaling enzyme that is highly enriched in microglia. The major aim of the proposal revolves around the functional characterization of the P522A mutation in microglia. To that aim, using an array of biochemical, imaging, functional, and transcriptomic assays, we will investigate human microglia generated from control- and AD patient-derived induced pluripotent stem cells (iPSCs). iPSCs will be gene-edited to generate P522A mutated isogenic cell lines. The proposal aims at identifying novel therapeutic targets and, in line with the objectives of the H2020 Framework Programme, explores new grounds in the molecular underpinnings of AD. The use of cutting-edge and innovative approaches (CRISPR/Cas9 gene editing, iPSC reprogramming, RNA-Seq analysis, high-throughput screening, and subcellular calcium imaging) provides a novel experimental model that is closer to the pathological processes of the AD brain and bypasses the limitations and shortcomings of preclinical AD animal models.
Fields of science
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural scienceschemical sciencesinorganic chemistryalkaline earth metals
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsmutation
Keywords
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
66013 Chieti
Italy