Use of Copper and Insulin-Resistance to Accelerate Cognitive Deficits and Synaptic Protein Loss in a Rat Aβ-Infusion Alzheimer's Disease Model

Abstract

The rat amyloid-β (Aβ) intracerebroventricular infusion can model aspects of Alzheimer's disease (AD) and has predicted efficacy of therapies such as ibuprofen and curcumin in transgenic mouse models. High density lipoprotein (HDL), a normal plasma carrier of Aβ, is used to attenuate Aβ aggregation within the pump, causing Aβ-dependent toxicity and cognitive deficits within 3 months. Our goal was to identify factors that might accelerate onset of Aβ-dependent deficits to improve efficiency and cost-effectiveness of model. We focused on: 1) optimizing HDL-Aβ preparation for maximal toxicity; 2) evaluating the role of copper, a factor typically in water that can impact oligomer stability; and 3) determining impact of insulin resistance (type II diabetes), a risk factor for AD. In vitro studies were performed to determine doses of copper and methods of Aβ-HDL preparation that maximized toxicity. These preparations when infused resulted in earlier onset of cognitive deficits within 6 weeks post-infusion. Induction of insulin resistance did not exacerbate Aβ-dependent cognitive deficits, but did exacerbate synaptic protein loss. In summary, the newly described in vivo infusion model may be useful cost-effective method for screening for new therapeutic drugs for AD.