Identification of N-Terminally Truncated Pyroglutamate Amyloid-β in Cholesterol-Enriched Diet-Fed Rabbit and AD Brain

Article type: Research Article

Authors: Perez-Garmendia, Roxanna^a | Hernandez-Zimbron, Luis Fernando^a | Morales, Miguel Angel^a | Luna-Muñoz, José^b | Mena, Raul^c | Nava-Catorce, Miriam^a | Acero, Gonzalo^a | Vasilevko, Vitaly^d | Viramontes-Pintos, Amparo^b | Cribbs, David H.^{d; e} | Gevorkian, Goar^{a; *}

Affiliations: [a] Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Cuidad Universitaria, Mexico, DF, Mexico | [b] Brain Bank, National Laboratory of Experimental Services, CINVESTAV-IPN, Mexico, DF, Mexico | [c] Department of Neurosciences, CINVESTAV-IPN, Mexico, DF, Mexico | [d] Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA | [e] Department of Neurology, University of California Irvine, Irvine, CA, USA

Correspondence: [*] Correspondence to: Goar Gevorkian, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico (UNAM), Apartado Postal 70228, Cuidad Universitaria, Mexico DF, CP 04510, Mexico. Tel.: +52 55 56223151; Fax: +52 55 56223369; E-mail: gokar@unam.mx.

Abstract: The main amyloid-β peptide (Aβ) variants detected in the human brain are Aβ1-40 and Aβ1-42; however, a significant proportion of Aβ in Alzheimer's disease (AD) brain also consists of N-terminal truncated/modified species. AβN3(pE), Aβ peptide bearing amino-terminal pyroglutamate at position 3, has been demonstrated to be a major N-truncated/modified constituent of intracellular, extracellular, and vascular Aβ deposits in AD and Down syndrome brain tissue. It has been previously demonstrated that rabbits fed a diet enriched in cholesterol and given water containing trace copper levels developed AD-like pathology including intraneuronal and extracellular Aβ accumulation, tau hyperphosphorylation, vascular inflammation, astrocytosis, microgliosis, reduced levels of acetylcholine, as well as learning deficits and thus, may be used as a non-transgenic animal model of sporadic AD. In the present study, we have demonstrated for the first time the presence of AβN3(pE) in blood vessels in cholesterol-enriched diet-fed rabbit brain. In addition, we detected AβN3(pE) immunoreactivity in all postmortem AD brain samples studied. We believe that our results are potentially important for evaluation of novel therapeutic molecules/strategies targeting Aβ peptides in a suitable non-transgenic animal model.

Keywords: Alzheimer's disease, amyloid-β, animal model, cholesterol-fed rabbit, pyroglutamate-modified amyloid

DOI: 10.3233/JAD-130590

Journal: Journal of Alzheimer's Disease, vol. 39, no. 2, pp. 441-455, 2014