Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD.
The posterior cingulate cortex (PCC) is the brain region displaying the earliest sign of energy hypometabolism in patients with amnestic mild cognitive impairment (MCI) who develop Alzheimer's disease (AD). In particular, the activity of the mitochondrial respiratory enzyme cytochrome oxidase (C.O.) is selectively inhibited within the PCC in AD. The present study is the first experimental analysis designed to model in animals the localized cortical C.O. inhibition found as the earliest metabolic sign of early-stage AD in human neuroimaging studies. Rats were used to model local inhibition of C.O. by direct injection of the C.O. inhibitor sodium azide into the PCC. Learning and memory were examined in a spatial holeboard task and brains were analyzed using quantitative histochemical, morphological and biochemical techniques. Behavioral results showed that sodium azide-treated rats were impaired in their memory of the baited pattern in probe trials as compared to their training scores before treatment, without non-specific behavioral differences. Brain analyses showed that C.O. inhibition was specific to the PCC, and sodium azide increased lipid peroxidation, gliosis and neuron loss, and lead to a network functional disconnection between the PCC and interconnected hippocampal regions. It was concluded that impaired memory by local C.O. inhibition in the PCC may serve to model in animals a metabolic lesion similar to that found in patients with amnestic MCI and early-stage AD. This model may be useful as an in vivo testing platform to investigate neuroprotective strategies to prevent or reduce the amnestic effects produced by posterior cingulate energy hypometabolism.
Riha
P D
PD
Department of Psychology, University of Texas, 1 University Station A8000, Austin, TX 78712, USA.
Rojas
J C
JC
Colorado
R A
RA
Gonzalez-Lima
F
F
D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D000647:Amnesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D002452:Cell Count; D004193:Discrimination Learning / Q000502:physiology; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006179:Gyrus Cinguli / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D009812:Odorants; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D019810:Sodium Azide / Q000494:pharmacology; D013028:Space Perception / Q000502:physiology
D004791:Enzyme Inhibitors; D019810:Sodium Azide; D003576:Electron Transport Complex IV