Gene Transfer Induced Hypercholesterolemia in Amyloid Mice

Article type: Short Communication

Authors: Grames, Mychal S.^a | Dayton, Robert D.^a | Lu, Xiaohong^a | Schilke, Robert M.^b | Alexander, J. Steven^c | Orr, A. Wayne^d | Barmada, Sami J.^e | Woolard, Matthew D.^b | Klein, Ronald L.^{a; *}

Affiliations: [a] Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center, Shreveport, LA, USA | [b] Department of Microbiology and Immunology, LSU Health Sciences Center, Shreveport, LA, USA | [c] Department of Physiology, LSU Health Sciences Center, Shreveport, LA, USA | [d] Department of Pathology, LSU Health Sciences Center, Shreveport, LA, USA | [e] Department of Neurology, University of Michigan, Ann Arbor, MI, USA

Correspondence: [*] Correspondence to: Ronald Klein, PhD, Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. Tel.: +1 318 675 7830; E-mail: Klein@lsuhsc.edu.

Abstract: A risk factor for cardiovascular disease (CVD), mutant PCSK9, was expressed in APP/PS1 mice to study the CVD-Alzheimer’s disease inter-relationship. Cholesterol levels were elevated by 5-6-fold from 3 to 13 weeks after PCSK9 gene transfer. We tested whether hypercholesterolemia would increase amyloid-β plaques at a relatively early stage of plaque deposition. Plaque burden was increased in the hippocampus of PCSK9 treated mice though the increase was modest compared to the large elevation in cholesterol. Elevating cholesterol via gene transfer could be valuable in a variety of disease models compared to making crosses with germ-line transgenic mouse models of CVD.

Keywords: Adeno-associated virus, Alzheimer’s disease, amyloid-β plaques, cardiovascular disease, gene transfer, hypercholesterolemia, PCSK9

DOI: 10.3233/JAD-180494

Journal: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1079-1086, 2018