P3‐069: HUMAN WILD TYPE Aβ KNOCK‐IN MICE AS A BASIS TO STUDY SPORADIC ALZHEIMER'S DISEASE

Abstract

Over the past two-decade researchers have focused their efforts on developing animal models to dissect the molecular mechanisms underlying AD, and to assist with the identification and development of potential therapies. Although these models have provided useful insights into the mechanisms of disease, the initial optimism for hastening drug development was perhaps premature, as successes in treating AD in mouse models have not been translated into the clinic. The discordance between preclinical efficacy in animal models and the lack of success during transition into clinical testing could be due to the significant overexpression of familial AD (FAD)-associated mutated proteins and the dependence of artificial transcriptional regulatory elements, among several other limitations. Therefore, new models are urgently needed to better understand pathophysiological events that occur in the sporadic form of the disease. We used a combination of genetic, biochemical, histological and behavioral approaches to generate and characterize a wildtype human Aβ knock-in mice. Our model, termed hAβ-KI, expresses wild-type human Aβ under the control of the endogenous mouse APP gene. The hAβ-KI mouse line develops age dependent increase in sparse Ab aggregates, cognitive and electrophysiological deficits. This knock-in model represents an important first step towards the development of next-generation animal models that hopefully will provide better predictive outcomes for human patients, which can turn into safe and effective clinical applications.