A Novel APP p.V742L variant in a patient with ischemic small vessel disease enhances FE65 signalling

Pathogenic variants in the amyloid precursor protein gene (APP) have been linked to Alzheimer's disease and intracerebral haemorrhage resulting from cerebral amyloid angiopathy. In these disorders, variants are generally located within or surrounding the amyloid-beta domain of APP and mostly increase the production or aggregation properties of the toxic amyloid-beta peptide. Here, we report a novel APP p.V742L variant in the APP intracellular domain (AICD) in a patient with a clinical and neuroradiological ischemic small vessel disease phenotype and a positive family history. We investigate the functional consequences of the variant on AICD function. We obtained patient fibroblasts through a skin biopsy and applied immunocytochemistry to examine the subcellular localization of APP. Subsequently, 3' mRNA sequencing was deployed to investigate changes in gene expression. Finally, the effect of the variant on the binding of FE65 to AICD was investigated using co-immunoprecipitation followed by western blot. Localization of APP p.V742L to lysosomes was increased, without affecting lysosomal motility. Transcriptome analysis showed altered expression of AICD target genes as well as dysregulation of genes relevant to the ischemic stroke phenotype. Finally, APP p.V742L was associated with an increased interaction with FE65, its most important intracellular binding partner. Taken together, our data demonstrate that the APP p.V742L variant enhances the interaction of the AICD with FE65, resulting in dysregulation of gene transcription. This study illustrates the diverse roles of APP in brain disorders, and suggests ischemic small vessel disease as a novel APP-associated phenotype.