O1‐01‐04: HAβ‐KI: A KNOCK‐IN MOUSE MODEL FOR 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. To date, 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 the 98% of patients that lack the known mutations that cause familial AD (FAD). Here, we introduce a novel animal model of sporadic AD (hAß-KI), in which the mouse Aβ encoding DNA sequence was replaced with the human Aβ sequence (which is known to more readily aggregate than the mouse Aß). We used a combination of genetic, biochemical, histological and behavioral approaches to generate and characterize this innovative AD model. DNA sequence analysis demonstrated that hAb-KI express humanized Ab and that expression of amyloid precursor protein (APP) was similar between wild type and hAb-KI mice. hAb-KI present with diffuse Ab aggregates from 18 months of age and no Congophilic or ThioS aggregates were observed. Cognitive deficits begin at 10 months in hAb-KI. Moreover, seeding experiments in which 8-month-old hAb-KI were inoculated with brain extract from AD patients with high pathology demonstrated a significant increase of plaque load. A highly innovative aspect of this study 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 without the addition of any FAD mutations or overexpression of APP or its metabolites. This mouse model should enable a 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.