Late onset Alzheimer’s Disease (LOAD) is one of the most common forms of dementia.

The endocytic pathway plays an important role in the mechanisms underlying AD pathology. The early endosome is a major site of APP generation, and dysfunction in this pathway is associated with AD both through genetics and pathology studies [1]. GWAS have revealed numerous risk genes in LOAD that are involved in endocytosis, including PICALM. APOE is strongly associated with developing LOAD, specifically APOE4, a known risk gene, has been known to induce Aβ toxicity whereas PICALM encodes is involved in clathrin-mediated endocytosis, which facilitates the clearance of Aβ [2,3].

Studies show the upregulation of PICALM can rescue phenotypes caused by the APOE 4/4 genotype, including Aβ clearance [4]. PICALM expression has also been seen to be reduced in AD microglia [5]. It is hypothesized that the APOE4-PICALM interaction could drive endocytic disease mechanisms, and that the upregulation of PICALM could rescue the APOE4 induced phenotype in microglia. The aims of my research

are to investigate whether the combination of APOE and PICALM will drive endocytic and lipid handling disease mechanisms that impact microglial function.

To investigate the APOE4-PICALM interaction, we have generated hiPSC cell lines using CRISPR/Cas9 gene editing to produce APOE3+/+, PICALM+/- and APOE4+/+, PICALM+/- to study the combinational effect of APOE and PICALM .The first microglial differentiation is currently on-going, and we are planning to investigate endocytic pathways, phagocytic activity, lipid accumulation and wider microglial phenotypes.