APPKI-HaβWT: A NOVEL TRANSGENIC MOUSE TO MODEL SPORADIC ALZHEIMER’S DISEASE

Abstract

The majority of Alzheimer's disease (AD) cases are sporadic, which means that the disease originates spontaneously, without any known cause. Today, no lab has succeeded in developing a model for sporadic AD, which represents one of the consequential hurdles remaining in the field. Thus, it is critical to study and elucidate factors and conditions that trigger the diseases in 98% of the patients. Here, I introduce the first animal model of sporadic AD, to which the consequential step involves the deletion of the mouse Aβ sequence and replacing it with the human Aβ sequence. We used a combination biochemical, histological and behavioral approaches to characterize this innovative AD model. DNA sequence analysis demonstrated that APPKI-hAβwt express humanized Ab and amyloid precursor protein (APP) were similar between non-transgenic and APPKI-hAβwt mice. APPKI-hAβwt express diffuse Aβ aggregates from 10 month of age and no Congofilic or ThioS aggregates were observed. In addition, cognitive deficits begin at 10 months in APPKI-hAβwt. A highly innovative aspect of this proposal is that we generated the first Knock-in mice that express human non-mutated Aβ in the fully natural context of the endogenous mouse APP gene and it does so without the addition of any FAD mutations, or overexpression of APP or its metabolites. This highly innovative mouse model pledge a much more physiologically relevant understanding of the underlying mechanisms driving AD pathology, by more closely recapitulating the pathological cascade of events that occurs in the majority of human AD patients.