Understanding and Mimicking the Biological Effects of the Phospholipase C-gamma-2 P522R Variant That Protects Against Alzheimer’s Disease

The cause of Alzheimer’s disease remains unknown. However, thanks to the progress of genomic-wide association analysis, where genetic sequences are studied in big populations and related to the incidence of diseases, new genetic risk factors and genetic protective factors have been identified. Among those, it recently was shown that a variant in the gene coding for the protein called Phospholipase C-gamma-2 (PLCγ2) was associated with a diminished risk of developing late-onset Alzheimer’s disease, the most common form of age-related neurodegenerative disorder. Interestingly, this variant of PLCγ2 also was associated with longevity. However, the mechanism of protection remains unknown, limiting our capacity to find drugs able to mimic this effect.

In this project, using the gene editing technology CRISPR/Cas9, we have generated a set of induced human pluripotent stem cell (iPSC) lines that possess identical genes but differ in the PLCγ2 gene, including the protective variant. From these cell lines, we will generate different human cell types, such as neurons and microglia, the immune cells from the brain, that are the ones that produce the PLCγ2 protein. We then will be able to study the response to different stimuli in cell cultures and identify a distinctive effect from this variant. We will use this knowledge to design an assay to search for drugs that reproduce this protective effect and may be therefore potential treatments for Alzheimer’s disease.