Elsevier

Neurobiology of Aging

Volume 21, Issue 4, July–August 2000, Pages 541-549
Neurobiology of Aging

Original Articles
Spatial learning in transgenic mice expressing human presenilin 1 (PS1) transgenes

https://doi.org/10.1016/S0197-4580(00)00107-XGet rights and content

Abstract

Dominant mutations in the Presenilin 1 gene are linked to an aggressive, early-onset form of familial Alzheimer’s Disease (FAD). Spatial memory of transgenic (Tg) mice expressing either mutant (lines Tg(M146L)1, Tg(M146L)76, Tg(L286V)198) or wild type (line Tg(PS1wt)195) human PS1 transgenes was investigated in the Morris water maze (WM) test at 6 and 9 months of age. The results showed that the mutated Tg mice had increased swim speed when compared to non-Tg littermates or Tg PS1 wild type mice. The swim speed difference did not, however, significantly affect the spatial learning in the WM test and all groups showed comparable search paths during training and similar spatial bias during probe trials. When re-tested at 9 months, all mice showed significantly improved learning acquisition of spatial information. The lack of progressive spatial learning impairment in mice expressing the mutated human PS1 transgene in the WM does not preclude impairments in other cognitive tasks but suggests that full phenotypic expression of mutant PS1 alleles may require co-expression of human versions of other AD-associated genes.

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.

References (44)

  • M. Scott et al.

    Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques

    Cell

    (1989)
  • R.J. Sutherland et al.

    Spatial mappingdefinitive disruption by hippocampal or medial frontal cortical damage in the rat

    Neurosci Lett

    (1982)
  • J.M. Wehner et al.

    Hippocampal protein kinase C activity is reduced in poor spatial learners

    Brain Res

    (1990)
  • Albert MS. Cognitive and neurobiologic markers of early Alzheimer disease. Proc Natl Acad Sci USA...
  • Recommendations

    Neuron

    (1997)
  • D.K. Candland et al.

    Development of fear in the rat as measured by behavior in the open field

    J Comp Physiol Psychol

    (1962)
  • D.H. Chui et al.

    Transgenic mice with Alzheimer Presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation

    Nat Med

    (1999)
  • M. Citron et al.

    Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice

    Nat Med

    (1997)
  • J. Cohen

    Statistical Power Analysis for the Behavioral Sciences

    (1988)
  • J. Cohen

    Things I have learned (so far)

    Am Psychol

    (1990)
  • D.H. Dodd et al.

    Computational procedures for estimating magnitude of effect for some analysis of variance designs

    Psychol Bull

    (1973)
  • K. Duff et al.

    Increased amyloid-β42(43) in brains of mice expressing mutant Presenilin 1

    Nature

    (1996)
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