A Longitudinal Study of Behavioral Deficits in an AβPP Transgenic Mouse Model of Alzheimer's Disease

Article type: Research Article

Authors: Havas, Daniel^{a; *} | Hutter-Paier, Birgit^a | Ubhi, Kiren^b | Rockenstein, Edward^b | Crailsheim, Karl^d | Masliah, Eliezer^{b; c} | Windisch, Manfred^a

Affiliations: [a] JSW LIFESCIENCES, Grambach, Austria | [b] Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA | [c] Department of Pathology, University of California, San Diego, La Jolla, CA, USA | [d] Department of Zoology, Karl Franzens-University, Graz, Austria

Correspondence: [*] Correspondence to: Daniel Havas, JSW LIFESCIENCES Parkring 12, 8074 Graz, Austria. Tel.: +43 316 258 111 224; Fax: +43 316 258 111 300; E-mail: dhavas@jsw-lifesciences.com.

Abstract: Elucidating the age-dependent alterations in transgenic (Tg) mice overexpressing amyloid-β protein precursor (AβPP) is important for understanding the pathogenesis of Alzheimer's disease (AD) and designing experimental therapies. Cross-studies have previously characterized some time-dependent behavioral and pathological alterations in AβPP Tg mice, however, a more comprehensive longitudinal study is needed to fully examine the progressive nature of behavioral deficits in these mice. In order to better understand the age- and gender-dependent progression of behavioral alterations, we performed a longitudinal study wherein Tg mice overexpressing human AβPP751 with the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the neuron specific murine (m)Thy-1 promoter (mThy1-hAβPP751) were behaviorally analyzed at 3 months and then re-tested at 6 and 9 months of age. The results show that there was an age-associated impairment in learning in the water maze task and habituation in the hole-board task. Motor coordination of the mThy1-hAβPP751 Tg mice was well-preserved throughout the investigated life span however, gender-specific deficits were observed in spontaneous activity and thigmotaxis. Neuropathologically, mThy1-hAβPP751 Tg mice displayed a progressive increase in the number of Aβ plaques and mean plaque size in the cortex and hippocampus from 3 to 6 and from 6 to 9 months of age. Taken together, these results indicate that the mThy1-hAβPP751 Tg mice model AD from the early onset of the disease through to later stages, allowing them to be utilized at numerous points during the timeline for drug test designs.

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, hole board task, memory, motor coordination, rodent, transgenic, water maze

DOI: 10.3233/JAD-2011-101866

Journal: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 231-243, 2011