Amyloid-β Peptide and Oligomers in the Brain and Cerebrospinal Fluid of Aged Canines

Article type: Research Article

Authors: Head, Elizabeth^{a; *} | Pop, Viorela^b | Sarsoza, Floyd^c | Kayed, Rakez^d | Beckett, Tina L.^e | Studzinski, Christa M.^f | Tomic, Jennifer L.^g | Glabe, Charles G.^g | Murphy, M. Paul^{h; *}

Affiliations: [a] Department of Molecular and Biomedical Pharmacology and the Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA | [b] Department of Pediatrics, Loma Linda University, Loma Linda, CA, USA | [c] Department of Neuroscience, University of California, San Diego, CA, USA | [d] University of Texas Medical Branch, Department of Neurology, Galveston, TX, USA | [e] Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA | [f] Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada | [g] Department of Molecular Biology and Biochemistry and the Institute for Brain Aging and Dementia, University of California at Irvine, Irvine, CA, USA | [h] Department of Molecular and Cellular Biochemistry and the Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

Correspondence: [*] Correspondences to: M. Paul Murphy, M.A., Ph.D., Department of Molecular and Cellular Biochemistry, University of Kentucky, 800 S. Limestone, 211 Sanders-Brown Building, Lexington, KY 40536-0230, USA. Tel.: +1 859 257 1412 x490; Fax: +1 59 257 9479; E-mail: [email protected]. Elizabeth Head, M.A., Ph.D., Department of Molecular and Biomedical Pharmacology, University of Kentucky, 800 S. Limestone, 203 Sanders-Brown Building, Lexington, KY 40536-0230, USA. Tel.: +1 859 257 1412 x481; Fax: +1 859 323 2866; E-mail: [email protected].

Note: [] Handling Associate Editor: Peter Nelson

Abstract: The study of Alzheimer's disease (AD) pathogenesis requires the use of animal models that develop some amount of amyloid pathology in the brain. Aged canines (beagles) naturally accumulate human-type amyloid-β peptide (Aβ) and develop parallel declines in cognitive function. However, the type and quantity of biochemically extracted Aβ in brain and cerebrospinal fluid (CSF), its link to aging, and similarity to human aging has not been examined systematically. Thirty beagles, aged 4.5–15.7 years, were studied. Aβ40 and Aβ42 were measured in CSF by ELISA, and from SDS and formic acid extracted prefrontal cortex. A sample of the contralateral hemisphere, used to assess immunohistochemical amyloid load, was used for comparison. In the brain, increases in Aβ42 were detected at a younger age, prior to increases in Aβ40, and were correlated with an increased amyloid load. In the CSF, Aβ42 decreased with age while Aβ40 levels remained constant. The CSF Aβ42/40 ratio was also a good predictor of the amount of Aβ in the brain. The amount of soluble oligomers in CSF was inversely related to brain extractable Aβ, whereas oligomers in the brain were correlated with SDS soluble Aβ42. These findings indicate that the Aβ in the brain of the aged canine exhibits patterns that mirror Aβ deposited in the human brain. These parallels support the idea that the aged canine is a useful intermediate between transgenic mice and humans for studying the development of amyloid pathology and is a potentially useful model for the refinement of therapeutic interventions.

Keywords: Alzheimer's disease, amyloid-β peptide, amyloid-β protein precursor, beagle, cerebrospinal fluid, dog, oligomer

DOI: 10.3233/JAD-2010-1397

Journal: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 637-646, 2010