Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer's disease

Abstract

Recently, interest in the rat as an animal model of Alzheimer's disease (AD) has been growing. We have previously described the Tg6590 transgenic rat line expressing the amyloid precursor protein containing the Swedish AD mutation (K670M/N671L) that shows early stages of Abeta deposition, predominantly in cerebrovascular blood vessels, after 15 months of age. Here we show that by the age of 9 months, that is long before the appearance of Abeta deposits, the Tg6590 rats exhibit deficits in the Morris water maze spatial navigation task and altered spontaneous behaviour in the open-field test. The levels of soluble Abeta were elevated both in the hippocampus and cortex of transgenic animals. Magnetic resonance imaging showed no major changes in the brains of transgenic animals, although they tended to have enlarged lateral ventricles when compared to control animals. The Tg6590 transgenic rat line should prove a suitable model of early AD for advanced studies including serial cerebrospinal fluid sampling, electrophysiology, neuroimaging or complex behavioural testing.

Fig 1

Spontaneous behaviour of Tg6590 transgenic and control animals during 60 min. of open-field test. (A) Rearing activity. The group means ± S.E. in 10-min. bins. Significant difference was found in rearing activity of transgenic and control rats during the first 40 min. of the test (P < 0.01). (B) Locomotor (distance traversed) activity.

Fig 2

Spatial learning in Tg6590 transgenic and control animals, assessed by Morris water maze. Blocks of four trials/day during 5 days of acquisition training shown as group means ± S.E. (A) Escape latency, P < 0.0005. (B) Speed of swimming, P < 0.05. (C) Swim path length, P < 0.005. (D) Thigmotaxis as percentage of total swim path spent in the periphery area, P < 0.005. Significant group differences by Tukey’s post hoc following ANOVA with repeated measures.

Fig 3

Preference for pool quadrant during probe trial in Morris water maze. Mean percentage of time ± S.E. spent in each quadrant by Tg6590 transgenic and control animals. **P < 0.0001 by Tukey’s pairwise multiple test comparing percentage search time in target quadrant versus opposite; target versus right; target versus left.

Fig 4

Aβ40 and Aβ42 levels in the hippocampus and cortex of 11-month-old transgenic Tg6590 and control animals (pmol/g brain tissue).