Original ArticlesSpatial learning in transgenic mice expressing human presenilin 1 (PS1) transgenes
Introduction
Dominant mutations in the amyloid-β precursor protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2) are implicated as major causes of familial Alzheimer’s Disease (FAD) [37]. Dementia is usually the earliest cognitive change seen in AD patients [1], and the damage to the hippocampal formation characterizes the early stages of the disease [19], [21]. Neuropathological hallmarks include deposition of the Alzheimer amyloid-β peptide (Aβ) in amyloid plaques, accumulation of intracellular neurofibrillary tangles, and neuronal loss. Although the crucial events in the pathobiology of AD remain to be established, because mutations in the aforementioned FAD genes all enhance the cleavage of the Alzheimer precursor protein to Aβ [37], this peptide is believed to play a key role in a pathogenic cascade that ultimately leads to dementia. In recent years several transgenic (Tg) mice expressing different forms of the human mutated genes have been created to study mechanisms of the disease in vivo and to model some of its neuropathological and cognitive hallmarks [6], [11], [18], [20], [32]. For example, it was reported that Tg mice expressing mutant human APP transgenes showed correlative spatial memory deficits [20] and impairments in spatial reference memory or spatial alternation [29], [32].
In the present paper, we investigated learning behavior of Tg mice expressing another AD gene, Presenilin 1. Mice expressing mutant human PS1 (lines Tg(M146L)1, Tg(M146L)76, Tg(L286V)198), or wild-type human PS1(line Tg(PS1wt)195) genes [6] were used in the experiment. First, in the series of behavioral tests we investigated mice sensorimotor abilities that, if changed, could confound the interpretation of the data obtained in the learning paradigms. Second, to evaluate cognitive abilities we investigated mice spatial learning and memory by using the place discrimination (PD) or hidden platform versions of the Morris water maze (WM) test [30]. To solve this test, a mouse has to find a position of a submerged under water escape platform using distal, extra-maze spatial cues available in the testing room. The successful solution of this task depends on fully functional hippocampal formation [15], [30], [31], [39], [40]. To establish whether the transgenes cause age-dependent impairment in Tg mice cognitive abilities we tested all groups longitudinally at 6 and 9 months of age.
Section snippets
Methods
Mutant-, and wild-type Tg mice, as well as their respective non-transgenic (non-Tg) littermates were the second back-cross of FVB/N and C57BL/6 mouse strains. These mice were constructed using PS1 cDNAs inserted into the hamster prion protein (PrP) expression vector cos.Tet [35] and have been described previously [6]. Mice were genotyped by hybridization using a transgene-specific probe positioned in the PrP gene 3′untranslated region [34]. They were housed in same-sex groups of two to four
Results
For these experiments we used previously described Tg lines [6] expressing FAD mutant PS1 (Tg(M146L)1, Tg(M146L)76, and Tg(L286V)198), wt human PS1 (Tg(PS1wt)195) transgenes, and non-Tg littermates, as indicated.
There was no significant difference in body weight between Tg and non-Tg mice within and between each transgenotype group. The average weight ( ± SEM) for all mutated Tg lines at 6 months was 30.4 ± 0.5 g and 29.4 ± 0.8 g, and at 9 months, 37.9 ± 1.2 g and 37.4 ± 2.6 g, for non-Tg and
Discussion
In a series of experiments we investigated the behavior of transgenic mice expressing mutated and wild type human Presenilin 1 gene. We report that at 6 months of age both the mutated and wild type Tg PS1 mice did not differ from their non-Tg littermates in the physical development assessed by body weight, sensorimotor abilities, responsiveness to novel stimulation, or exploration of new environment. Also, the locomotor activity of Tg(M146L)1 mice during the dry land exploration in the open
Acknowledgements
This work was supported by the Medical Research Council of Canada, the Alzheimer Society of Ontario, and the Scottish Rite Foundation. We thank Jacqueline Pearson and two anonymous referees for helpful comments on the manuscript.
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