Rat transgenic models with a phenotype of intracellular Aβ accumulation in hippocampus and cortex

Article type: Research Article

Authors: Echeverria, Valentina^a | Ducatenzeiler, Adriana^a | Alhonen, Leena^b | Janne, Juhani^b | Grant, Susan M.^a | Wandosell, Francisco^c | Muro, Andres^d | Baralle, Francisco^d | Li, Hongshan^e | Duff, Karen^f | Szyf, Moshe^a | Cuello, A. Claudio^{a; g; h; *}

Affiliations: [a] Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada | [b] A .I. Virtanen Institute, University of Kuopio, Finland | [c] Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Spain | [d] International Center for Genetic Engineering and Biotechnology, Trieste, Italy | [e] Ciphergen, Canada | [f] Nathan Kline Institute, Orangeburg, New York, USA | [g] Department of Anatomy and Cell Biology, McGill University, Montreal, Canada | [h] Department of Neurology and Neurosurgery, McGill University, Montreal, Canada

Correspondence: [*] Corresponding author: A. Claudio Cuello, Dept of Pharmacology & Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, QC, Canada, H3G 1Y6. Tel.: +1 514 398 3618; Fax: +1 514 398 8317; E-mail: [email protected].

Abstract: In this communication we report the characterization of several transgenic rat lines expressing human AβPP carrying the Swedish and Indiana mutations (coded UKUR28), the human presenilin 1 transgene with the 'Finn' mutation (coded UKUR19) and double transgenic rats expressing both transgenes (coded UKUR25). In these Tg rats, the AβPP and PS1 transgene expression was largely restricted to the hippocampus and neocortex. The PS1 transgenic rats did not produce visible changes in Aβ immunoreactivity. The AβPP transgenic rats (both the single Tg UKUR28, and double Tg UKUR25) generated a phenotype of intra-neuronalβ accumulation without plaque formation and with no increased immunoreactivity for AβPP amino and carboxyl-terminal epitopes. This phenotype was apparent as early as 6 months of age in the transgenic rat lines carrying the human AβPP transgene. No senile plaques of aggregated Aβ were observed in any of the transgenic lines generated, up to 24 months of age. The hAβPP single homozygous Tg line (UKUR28) showed an increase in ERK2, without changes in glycogen synthase kinase 3 (GSK3) activity. A preliminary protein analysis of the hippocampus of the double transgenic rat (UKUR25) by mass spectrometry showed differences in the protein profile between this transgenic line and controls.

Keywords: Amyloid-β, transgenic rat, ERK/MAPK, tau phosphorylation

DOI: 10.3233/JAD-2004-6301

Journal: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 209-219, 2004