Use of copper and insulin-resistance to accelerate cognitive deficits and synaptic protein loss in a rat Abeta-infusion Alzheimer's disease model.
The rat amyloid-beta (Abeta) 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 Abeta, is used to attenuate Abeta aggregation within the pump, causing Abeta-dependent toxicity and cognitive deficits within 3 months. Our goal was to identify factors that might accelerate onset of Abeta-dependent deficits to improve efficiency and cost-effectiveness of model. We focused on: 1) optimizing HDL-Abeta 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 Abeta-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 Abeta-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.
Begum
Aynun N
AN
Department of Medicine, University of California, Los Angeles, CA, USA.
Yang
Fusheng
F
Teng
Edmond
E
Hu
Shuxin
S
Jones
Mychica R
MR
Rosario
Emily R
ER
Beech
Walter
W
Hudspeth
Beverly
B
Ubeda
Oliver J
OJ
Cole
Greg M
GM
Frautschy
Sally A
SA
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology / Q000523:psychology*; D003300:Copper / Q000633:toxicity*; D004032:Diet; D005632:Fructose / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009995:Osmosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D005632:Fructose; D003300:Copper