Effect of Adeno‐associated Viral Vector Mediated APOE Protective Variants Expression on Tau Pathology in a Tau Mouse Model

Background Alzheimer’s disease (AD) is characterized by two main pathological hallmarks in the brain, namely, the presence of amyloid plaques and neurofibrillary tangles. However, the underlying mechanisms of AD pathogenesis are still largely unknown. Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late‐onset AD, with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring protection relative to the common APOE*ε3 allele. Previous studies have shown that the presence of APOE*ε4 exacerbates tau pathology in AD patients as well as AD mouse models. uniQure is developing an AAV gene therapy approach which will simultaneously silence the risk‐increasing APOE allele and overexpress the protective APOE variant. Here, our goal is to investigate the effect of AAV‐mediated APOE protective variants expression on tau pathology in a tau mouse model. Method Protective APOE‐variants were tested by intra‐striatal delivery of AAV vectors in a humanized tau mouse model. Vehicle or empty AAVs were injected in two separate control groups. Vector DNA, APOE mRNA and human APOE protein levels were measured in different brain areas of these mice. In addition, human tau protein levels were measured. Result We successfully expressed protective variants of APOE in a tau mouse model and measured human APOE protein levels in different brain areas. Furthermore, phosphorylated tau protein levels were significantly lower in AAV‐APOE‐protective variants treated tau mice compared to control groups mice indicating reduction in tau pathology in the hippocampus after protective APOE variants expression. Conclusion AAV‐mediated overexpression of protective APOE variants results in reduction of tau pathology in mice. Overexpression of protective APOE variants or in combination with a silencing approach using a new generation of therapeutic microRNAs (miRNAs) from our miQURE ® platform could be an attractive treatment approach for AD.