Changes in Cognition and Amyloid-β Processing with Long Term Cholesterol Reduction using Atorvastatin in Aged Dogs

Article type: Research Article

Authors: Murphy, M. Paul^{a; b; *} | Morales, Jacqueline^e | Beckett, Tina L.^a | Astarita, Giuseppe^e | Piomelli, Daniele^e | Weidner, Adam^{a; b} | Studzinski, Christa M.^a | Dowling, Amy L.S.^a | Wang, Xiaohong^a | LeVine, III, Harry^{a; b} | Kryscio, Richard J.^{a; c} | Lin, Yushun^{a; c} | Barrett, Edward^f | Head, Elizabeth^{a; d; *}

Affiliations: [a] Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA | [b] Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA | [c] Department of Statistics, University of Kentucky, Lexington, KY, USA | [d] Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY, USA | [e] University of California Irvine, Irvine, CA, USA | [f] Lovelace Respiratory Research Institute, Albuquerque, NM, USA

Correspondence: [*] Correspondence to: Elizabeth Head, M.A., Ph.D., Department of Molecular and Biomedical Pharmacology, Sanders-Brown Center on Aging, 203 Sanders-Brown Building, 800 South Limestone St., Lexington, KY, 40536, USA. Tel.: +1 859 257 1412 ext 481; Fax: +1 859 323 2866; E-mail: [email protected]. Or M. Paul Murphy, M.A., Ph.D., Department of Molecular and Cellular Biochemistry, University of Kentucky, 211 Sanders-Brown Center on Aging, 800 S. Limestone, Lexington, KY, 40536-0230, USA. Tel.: +1 859 257 1412 x490; Fax: +1 859 257 9479; E-mail: [email protected].

Note: [] Handling Associate Editor: Gary Arendash

Abstract: Human studies suggest either a protective role or no benefit of statins against the development of Alzheimer's disease (AD). We tested the hypothesis that statin-mediated cholesterol reduction in aged dogs, which have cognitive impairments and amyloid-β (Aβ) pathology, would improve cognition and reduce neuropathology. In a study of 12 animals, we treated dogs with 80 mg/day of atorvastatin for 14.5 months. We did not observe improvements in discrimination learning; however, there were transient impairments in reversal learning, suggesting frontal dysfunction. Spatial memory function did not change with treatment. Peripheral levels of cholesterol, LDLs, triglycerides, and HDL were significantly reduced in treated dogs. Aβ in cerebrospinal fluid and brain remained unaffected. However, β-secretase-1 (BACE1) protein levels and activity decreased and correlated with reduced brain cholesterol. Finally, lipidomic analysis revealed a significant decrease in the ratio of omega-6 to omega-3 essential fatty in temporal cortex of treated aged dogs. Aged beagles are a unique model that may provide novel insights and translational data that can predict outcomes of statin use in human clinical trials. Treatment with atorvastatin may be beneficial for brain aging by reducing BACE1 protein and omega6:omega3 ratio, however, the potential adverse cognitive outcomes reported here should be more carefully explored given their relevance to human clinical outcomes.

Keywords: Amyloid-β protein precursor (AβPP), β-secretase (BACE1), canine, cholesterol, dog, LRP-1, statin

DOI: 10.3233/JAD-2010-100639

Journal: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 135-150, 2010