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

Issue title: Animal Models of Alzheimer's Disease: Therapeutic Implications

Guest editors: Diana Woodruff-Pak

Article type: Research Article

Authors: Begum, Aynun N.^{a; c} | Yang, Fusheng^{a; c} | Teng, Edmond^{b; d} | Hu, Shuxin^{a; c} | Jones, Mychica R.^{a; c} | Rosario, Emily R.^{a; c} | Beech, Walter^{a; c} | Hudspeth, Beverly^{a; c} | Ubeda, Oliver J.^{a; c} | Cole, Greg M.^{a; b; c} | Frautschy, Sally A.^{a; b; c; *}

Affiliations: [a] Department of Medicine, University of California, Los Angeles, CA, USA | [b] Department of Neurology, University of California, Los Angeles, CA, USA | [c] Geriatric Research Education Clinical Center (GRECC), North Hills, CA, USA | [d] Greater Los Angeles Veterans Affairs Healthcare System, Neurobehavior Unit, Los Angeles, CA, USA

Correspondence: [*] Corresponding author: Dr. Sally A. Frautschy, Greater Los Angeles VA Healthcare System, Sepulveda Ambulatory Care Center, Research 151, 16111 Plummer Street, North Hills, CA 91343, USA. Tel.: +1 818 895 5892; Fax: +1 818 895 5835; E-mail: [email protected].

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.

Keywords: Alzheimer's disease, amyloid-β, copper, cognitive deficit, high density lipoprotein, insulin resistance

DOI: 10.3233/JAD-2008-15409

Journal: Journal of Alzheimer's Disease, vol. 15, no. 4, pp. 625-640, 2008