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Thy1-hAPP(Lond/Swe+) mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function.

Faizi M, Bader PL, Saw N, Nguyen TV, Beraki S, Wyss-Coray T, Longo FM, Shamloo M - Brain Behav (2012)

Bottom Line: We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior.This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients.In conclusion, the Thy1-hAPP(Lond/Swe+) mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.

View Article: PubMed Central - PubMed

ABSTRACT
Alzheimer's disease (AD), the most common form of dementia, is an age-dependent progressive neurodegenerative disorder. β-amyloid, a metabolic product of the amyloid precursor protein (APP), plays an important role in the pathogenesis of AD. The Thy1-hAPP(Lond/Swe+) (line 41) transgenic mouse overexpresses human APP751 and contains the London (V717I) and Swedish (K670M/N671L) mutations. Here, we used a battery of behavioral tests to evaluate general activity, cognition, and social behavior in six-month-old male Thy1-hAPP(Lond/Swe+) mice. We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior. In fear conditioning (FC), Thy1-hAPP(Lond/Swe+) mice did not display deficits in acquisition or in memory retrieval in novel context of tone-cued FC, but they showed significant memory retrieval impairment during contextual testing in an identical environment. Surprisingly, in a standard hidden platform water maze, no significant deficit was detected in mutant mice. However, a delayed-matching-to-place paradigm revealed a significant deficit in Thy1-hAPP(Lond/Swe+) mice. Lastly, in the social novelty session of a three-chamber test, Thy1-hAPP(Lond/Swe+) mice exhibited a significantly decreased interest in a novel versus a familiar stranger compared to control mice. This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients. In conclusion, the Thy1-hAPP(Lond/Swe+) mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.

No MeSH data available.


Related in: MedlinePlus

Social behavior. (a) Three-chamber test. After a 10-min habituation to a three-chambered box, an empty cup and a cup containing stranger 1 were introduced in the side chambers for a 10-min sociability session. Thereafter, stranger 2 was added under the empty cup for a 10-min social novelty session. n(control) = 11, n(Thy1-hAPPLond/Swe+) = 9. (b) Sociability session. Left, Thy1-hAPPLond/Swe+ and control mice both sniffed significantly longer at the cage containing stranger 1 than at the empty cup (effect of object, P < 0.0001; genotype × object interaction, P = 0.58). Right, both genotypes showed the same preference (ratio time sniffing stranger 1 vs. empty cup) for the occupied versus the empty cup (P = 0.1, t-test). (c) Social novelty session. Left, control mice appeared to prefer stranger 2 whereas Thy1-hAPPLond/Swe+ mice did not seem to show this preference. However, both the object effect (P = 0.06) and object × genotype interaction (P = 0.055) failed to reach significance level. Right, the preference index (ratio time sniffing stranger 2 vs. stranger 1), however, revealed a significantly decreased preference of Thy1-hAPPLond/Swe+ mice for stranger 2 compared to control mice (P = 0.04, t-test). (d) Six-trial social memory test. Four repeated presentations of the SAME intruder showed a significant effect (effect of object, P = 0.0014) and this effect did not differ by genotype (genotype × object interaction, P = 0.77). Introduction of a NOVEL intruder in trial 5 followed by the SAME intruder in trial 6 revealed a significant object effect in both cases (effect of object P < 0.0001 in both cases). Both effects did not differ by genotype (genotype × object interaction, P = 0.77 and P = 0.28, respectively). n(control) = 14, n(Thy1-hAPPLond/Swe+) = 13.
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fig03: Social behavior. (a) Three-chamber test. After a 10-min habituation to a three-chambered box, an empty cup and a cup containing stranger 1 were introduced in the side chambers for a 10-min sociability session. Thereafter, stranger 2 was added under the empty cup for a 10-min social novelty session. n(control) = 11, n(Thy1-hAPPLond/Swe+) = 9. (b) Sociability session. Left, Thy1-hAPPLond/Swe+ and control mice both sniffed significantly longer at the cage containing stranger 1 than at the empty cup (effect of object, P < 0.0001; genotype × object interaction, P = 0.58). Right, both genotypes showed the same preference (ratio time sniffing stranger 1 vs. empty cup) for the occupied versus the empty cup (P = 0.1, t-test). (c) Social novelty session. Left, control mice appeared to prefer stranger 2 whereas Thy1-hAPPLond/Swe+ mice did not seem to show this preference. However, both the object effect (P = 0.06) and object × genotype interaction (P = 0.055) failed to reach significance level. Right, the preference index (ratio time sniffing stranger 2 vs. stranger 1), however, revealed a significantly decreased preference of Thy1-hAPPLond/Swe+ mice for stranger 2 compared to control mice (P = 0.04, t-test). (d) Six-trial social memory test. Four repeated presentations of the SAME intruder showed a significant effect (effect of object, P = 0.0014) and this effect did not differ by genotype (genotype × object interaction, P = 0.77). Introduction of a NOVEL intruder in trial 5 followed by the SAME intruder in trial 6 revealed a significant object effect in both cases (effect of object P < 0.0001 in both cases). Both effects did not differ by genotype (genotype × object interaction, P = 0.77 and P = 0.28, respectively). n(control) = 14, n(Thy1-hAPPLond/Swe+) = 13.

Mentions: Social behavior was assessed with the three-chamber and six-trial social memory tests (Fig. 3). In the three-chamber test, a subject mouse was first habituated to the test environment in a habituation session, then tested for sociability in a sociability session, and finally tested for preference for social novelty in a social novelty session (Fig. 3a). No side preference was detected during the habituation session (data not shown). During the sociability test (Fig. 3b), both Thy1-hAPPLond/Swe+ and control mice preferred to sniff at a cage containing a stranger mouse versus sniffing at an empty cage (Fig. 3b; effect of object, F1, 16 = 34.64, P < 0.0001), and this preference did not differ by genotype (genotype × object interaction, F1, 16 = 0.31, P = 0.58). Calculating a preference index (ratio of time sniffing stranger 1 vs. empty cage) showed no difference between genotypes (P = 0.1). During the subsequent social novelty test, control mice seemed to spend more time sniffing the novel stranger's cage than the now-familiar mouse's cage whereas Thy1-hAPPLond/Swe+ mice did not demonstrate such a preference (Fig. 3c). A two-way ANOVA showed a trend close to significance for the object effect (F1, 18 = 4.01, P = 0.06) and genotype × object interaction (F1, 18 = 4.20, P = 0.055). However, the preference index (ratio of time sniffing stranger 2 vs. stranger 1) revealed a significantly decreased preference of mutant mice for the novel stranger's cage (Fig. 3c; P = 0.031). Significance level was also reached when two outliers (33 for control mice and 3.5 for mutant mice) were excluded (P = 0.009). In the six-trial social memory test, we found a significant habituation to the SAME intruder (Fig. 3d; trial 1–4: effect of object, F3, 75 = 5.69, P = 0.0014) and this effect did not differ by genotype (genotype × object interaction, F3, 75 = 0.33, P = 0.81). Furthermore, we found a significant dishabituation with the presentation of a NOVEL intruder (trial 4–5: effect of object, F1, 25 = 49.73, P < 0.0001, genotype × object interaction, F1, 25 = 0.09, P = 0.77) and a significant effect of an additional presentation of the SAME intruder in trial 6 (trial 5–6: effect of object, F1, 25 = 71.75, P < 0.0001, genotype × object interaction, F1, 25 = 1.22, P = 0.28). No significant differences in genotype × object interactions were detected.


Thy1-hAPP(Lond/Swe+) mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function.

Faizi M, Bader PL, Saw N, Nguyen TV, Beraki S, Wyss-Coray T, Longo FM, Shamloo M - Brain Behav (2012)

Social behavior. (a) Three-chamber test. After a 10-min habituation to a three-chambered box, an empty cup and a cup containing stranger 1 were introduced in the side chambers for a 10-min sociability session. Thereafter, stranger 2 was added under the empty cup for a 10-min social novelty session. n(control) = 11, n(Thy1-hAPPLond/Swe+) = 9. (b) Sociability session. Left, Thy1-hAPPLond/Swe+ and control mice both sniffed significantly longer at the cage containing stranger 1 than at the empty cup (effect of object, P < 0.0001; genotype × object interaction, P = 0.58). Right, both genotypes showed the same preference (ratio time sniffing stranger 1 vs. empty cup) for the occupied versus the empty cup (P = 0.1, t-test). (c) Social novelty session. Left, control mice appeared to prefer stranger 2 whereas Thy1-hAPPLond/Swe+ mice did not seem to show this preference. However, both the object effect (P = 0.06) and object × genotype interaction (P = 0.055) failed to reach significance level. Right, the preference index (ratio time sniffing stranger 2 vs. stranger 1), however, revealed a significantly decreased preference of Thy1-hAPPLond/Swe+ mice for stranger 2 compared to control mice (P = 0.04, t-test). (d) Six-trial social memory test. Four repeated presentations of the SAME intruder showed a significant effect (effect of object, P = 0.0014) and this effect did not differ by genotype (genotype × object interaction, P = 0.77). Introduction of a NOVEL intruder in trial 5 followed by the SAME intruder in trial 6 revealed a significant object effect in both cases (effect of object P < 0.0001 in both cases). Both effects did not differ by genotype (genotype × object interaction, P = 0.77 and P = 0.28, respectively). n(control) = 14, n(Thy1-hAPPLond/Swe+) = 13.
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fig03: Social behavior. (a) Three-chamber test. After a 10-min habituation to a three-chambered box, an empty cup and a cup containing stranger 1 were introduced in the side chambers for a 10-min sociability session. Thereafter, stranger 2 was added under the empty cup for a 10-min social novelty session. n(control) = 11, n(Thy1-hAPPLond/Swe+) = 9. (b) Sociability session. Left, Thy1-hAPPLond/Swe+ and control mice both sniffed significantly longer at the cage containing stranger 1 than at the empty cup (effect of object, P < 0.0001; genotype × object interaction, P = 0.58). Right, both genotypes showed the same preference (ratio time sniffing stranger 1 vs. empty cup) for the occupied versus the empty cup (P = 0.1, t-test). (c) Social novelty session. Left, control mice appeared to prefer stranger 2 whereas Thy1-hAPPLond/Swe+ mice did not seem to show this preference. However, both the object effect (P = 0.06) and object × genotype interaction (P = 0.055) failed to reach significance level. Right, the preference index (ratio time sniffing stranger 2 vs. stranger 1), however, revealed a significantly decreased preference of Thy1-hAPPLond/Swe+ mice for stranger 2 compared to control mice (P = 0.04, t-test). (d) Six-trial social memory test. Four repeated presentations of the SAME intruder showed a significant effect (effect of object, P = 0.0014) and this effect did not differ by genotype (genotype × object interaction, P = 0.77). Introduction of a NOVEL intruder in trial 5 followed by the SAME intruder in trial 6 revealed a significant object effect in both cases (effect of object P < 0.0001 in both cases). Both effects did not differ by genotype (genotype × object interaction, P = 0.77 and P = 0.28, respectively). n(control) = 14, n(Thy1-hAPPLond/Swe+) = 13.
Mentions: Social behavior was assessed with the three-chamber and six-trial social memory tests (Fig. 3). In the three-chamber test, a subject mouse was first habituated to the test environment in a habituation session, then tested for sociability in a sociability session, and finally tested for preference for social novelty in a social novelty session (Fig. 3a). No side preference was detected during the habituation session (data not shown). During the sociability test (Fig. 3b), both Thy1-hAPPLond/Swe+ and control mice preferred to sniff at a cage containing a stranger mouse versus sniffing at an empty cage (Fig. 3b; effect of object, F1, 16 = 34.64, P < 0.0001), and this preference did not differ by genotype (genotype × object interaction, F1, 16 = 0.31, P = 0.58). Calculating a preference index (ratio of time sniffing stranger 1 vs. empty cage) showed no difference between genotypes (P = 0.1). During the subsequent social novelty test, control mice seemed to spend more time sniffing the novel stranger's cage than the now-familiar mouse's cage whereas Thy1-hAPPLond/Swe+ mice did not demonstrate such a preference (Fig. 3c). A two-way ANOVA showed a trend close to significance for the object effect (F1, 18 = 4.01, P = 0.06) and genotype × object interaction (F1, 18 = 4.20, P = 0.055). However, the preference index (ratio of time sniffing stranger 2 vs. stranger 1) revealed a significantly decreased preference of mutant mice for the novel stranger's cage (Fig. 3c; P = 0.031). Significance level was also reached when two outliers (33 for control mice and 3.5 for mutant mice) were excluded (P = 0.009). In the six-trial social memory test, we found a significant habituation to the SAME intruder (Fig. 3d; trial 1–4: effect of object, F3, 75 = 5.69, P = 0.0014) and this effect did not differ by genotype (genotype × object interaction, F3, 75 = 0.33, P = 0.81). Furthermore, we found a significant dishabituation with the presentation of a NOVEL intruder (trial 4–5: effect of object, F1, 25 = 49.73, P < 0.0001, genotype × object interaction, F1, 25 = 0.09, P = 0.77) and a significant effect of an additional presentation of the SAME intruder in trial 6 (trial 5–6: effect of object, F1, 25 = 71.75, P < 0.0001, genotype × object interaction, F1, 25 = 1.22, P = 0.28). No significant differences in genotype × object interactions were detected.

Bottom Line: We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior.This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients.In conclusion, the Thy1-hAPP(Lond/Swe+) mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.

View Article: PubMed Central - PubMed

ABSTRACT
Alzheimer's disease (AD), the most common form of dementia, is an age-dependent progressive neurodegenerative disorder. β-amyloid, a metabolic product of the amyloid precursor protein (APP), plays an important role in the pathogenesis of AD. The Thy1-hAPP(Lond/Swe+) (line 41) transgenic mouse overexpresses human APP751 and contains the London (V717I) and Swedish (K670M/N671L) mutations. Here, we used a battery of behavioral tests to evaluate general activity, cognition, and social behavior in six-month-old male Thy1-hAPP(Lond/Swe+) mice. We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior. In fear conditioning (FC), Thy1-hAPP(Lond/Swe+) mice did not display deficits in acquisition or in memory retrieval in novel context of tone-cued FC, but they showed significant memory retrieval impairment during contextual testing in an identical environment. Surprisingly, in a standard hidden platform water maze, no significant deficit was detected in mutant mice. However, a delayed-matching-to-place paradigm revealed a significant deficit in Thy1-hAPP(Lond/Swe+) mice. Lastly, in the social novelty session of a three-chamber test, Thy1-hAPP(Lond/Swe+) mice exhibited a significantly decreased interest in a novel versus a familiar stranger compared to control mice. This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients. In conclusion, the Thy1-hAPP(Lond/Swe+) mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.

No MeSH data available.


Related in: MedlinePlus