The effect of acetyl-L-carnitine and R-α-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer's disease

Shenk, Justin C.; Liu, Jiankang; Fischbach, Kathryn; Xu, Kui; Puchowicz, Michel; Obrenovich, Mark E.; Gasimov, Eldar; Alvarez, Ludis Morales; Ames, Bruce N.; LaManna, Joseph C.; Aliev, Gjumrakch

doi:10.1016/j.jns.2009.03.002

« Previous Next »Journal of the Neurological Sciences
Volume 283, Issue 1 , Pages 199-206, 15 August 2009

The effect of acetyl-L-carnitine and R-α-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer's disease

Justin C. Shenk
- Department of Biology and Electron Microscopy Research Center, University of Texas at San Antonio, San Antonio, TX, 78249, USA
Jiankang Liu
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
Kathryn Fischbach
- Department of Biology and Electron Microscopy Research Center, University of Texas at San Antonio, San Antonio, TX, 78249, USA
Kui Xu
- Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA
Michel Puchowicz
- Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA
Mark E. Obrenovich
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA
Eldar Gasimov
- Department of Cytology, Histology and Embryology, Baku Medical University, Baku, AZ10-25, Azerbaijan
Ludis Morales Alvarez
- Department of Nutrition and Biochemistry, University of Javeriana, Bogota, Colombia
Bruce N. Ames
- Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA
Joseph C. LaManna
- Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA
Gjumrakch Aliev
- Department of Biology and Electron Microscopy Research Center, University of Texas at San Antonio, San Antonio, TX, 78249, USA
- Corresponding author. Department of Biology, College of Sciences & Electron Microscopy Research Center, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-1664, USA. Tel.: +1 440 263 7461.

published online 02 April 2009.

Abstract

We measured age-dependent effects of human ApoE4 on cerebral blood flow (CBF) using ApoE4 transgenic mice compared to age-matched wild-type (WT) mice by use of [¹⁴C] iodoantipyrene autoradiography. ApoE4 associated factors reduce CBF gradually to create brain hypoperfusion when compared to WT, and the differences in CBF are greatest as animals age from 6-weeks to 12-months. Transmission electron microscopy with colloidal gold immunocytochemistry showed structural damage in young and aged microvessel endothelium of ApoE4 animals extended to the cytoplasm of perivascular cells, perivascular nerve terminals and hippocampal neurons and glial cells. These abnormalities coexist with mitochondrial structural alteration and mitochondrial DNA overproliferation and/or deletion in all brain cellular compartments. Spatial memory and temporal memory tests showed a trend in improving cognitive function in ApoE4 mice fed selective mitochondrial antioxidants acetyl-l-carnitine and R-α-lipoic acid. Our findings indicate that ApoE4 genotype-induced mitochondrial changes and associated structural damage may explain age-dependent pathology seen in AD, indicating potential for novel treatment strategies in the near future.

Keywords: ApoE4, Alzheimer's disease, Cerebral blood flow, Electron microscopy, Vascular and mitochondrial damage, Mitochondrial antioxidant and cognitive performance