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Behavioral defects in chaperone-deficient Alzheimer's disease model mice.

Ojha J, Karmegam RV, Masilamoni JG, Terry AV, Cashikar AG - PLoS ONE (2011)

Bottom Line: Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation.We observed that the overall content of αB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner.Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Chaperones and Radiobiology, Medical College of Georgia, Augusta, Georgia, United States of America.

ABSTRACT
Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation. Neurotoxicity of amyloid-beta (Aβ) aggregates and their deposition in senile plaques are hallmarks of Alzheimer's disease (AD). We observed that the overall content of αB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner. We hypothesized that αB-crystallin protects cells against Aβ toxicity. To test this, we crossed αB-crystallin/HspB2 deficient (CRYAB⁻/⁻HSPB2⁻/⁻) mice with AD model transgenic mice expressing mutant human amyloid precursor protein. Transgenic and non-transgenic mice in chaperone-sufficient or deficient backgrounds were examined for representative behavioral paradigms for locomotion and memory network functions: (i) spatial orientation and locomotion was monitored by open field test; (ii) sequential organization and associative learning was monitored by fear conditioning; and (iii) evoked behavioral response was tested by hot plate method. Interestingly, αB-crystallin/HspB2 deficient transgenic mice were severely impaired in locomotion compared to each genetic model separately. Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases.

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Fear conditioning test.Percent freezing of mice over time during Training (Top), Cued test (middle) and Contextual test (bottom). Mean values ± SEM are plotted. Data were analyzed by two-way repeated measure ANOVA. Differences between groups were not significant for training and cued tests. In contextual tests, WT performed significantly better than WTTg (p = 0.003); difference between WTTg and KOTg was significant (p = 0.014); other groups were not significantly different. Blue hatched boxes represent two separate auditory signals (80dB) of 30 seconds each during training and a single auditory signal for 2 minutes during cued test followed by 2 sec foot shock. Symbol representations are - KOTg (red circle), KO (orange circle), WTTg (yellow triangle) and WT (green triangle). (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).
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pone-0016550-g005: Fear conditioning test.Percent freezing of mice over time during Training (Top), Cued test (middle) and Contextual test (bottom). Mean values ± SEM are plotted. Data were analyzed by two-way repeated measure ANOVA. Differences between groups were not significant for training and cued tests. In contextual tests, WT performed significantly better than WTTg (p = 0.003); difference between WTTg and KOTg was significant (p = 0.014); other groups were not significantly different. Blue hatched boxes represent two separate auditory signals (80dB) of 30 seconds each during training and a single auditory signal for 2 minutes during cued test followed by 2 sec foot shock. Symbol representations are - KOTg (red circle), KO (orange circle), WTTg (yellow triangle) and WT (green triangle). (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).

Mentions: In order to examine whether learning behavior was impaired in transgenic mice lacking αB-crystallin/HspB2, we performed fear-conditioning test. In this test paradigm the associative learning of a neutral cue (eg, sound tone) or a neutral context (eg, environment) with a brief aversive stimulus (eg, mild electric shock) is measured by monitoring the freezing behavior in mice (Figure 5). Fear conditioning test was performed by placing a mouse in a box equipped with a mechanism for monitoring the freezing behavior of the animal by recording photobeam breaks. The mice were first trained to associate the surroundings or a sound pulse (cue) with the mild aversive stimulus. Cue-dependent freezing was tested in a novel environment (i.e., one with different lighting, and olfactory and visual cues) and the freezing behavior associated with the tone was measured. Context-dependent freezing was monitored to evaluate the learned aversion of an animal for the environment associated with the mild aversive stimulus.


Behavioral defects in chaperone-deficient Alzheimer's disease model mice.

Ojha J, Karmegam RV, Masilamoni JG, Terry AV, Cashikar AG - PLoS ONE (2011)

Fear conditioning test.Percent freezing of mice over time during Training (Top), Cued test (middle) and Contextual test (bottom). Mean values ± SEM are plotted. Data were analyzed by two-way repeated measure ANOVA. Differences between groups were not significant for training and cued tests. In contextual tests, WT performed significantly better than WTTg (p = 0.003); difference between WTTg and KOTg was significant (p = 0.014); other groups were not significantly different. Blue hatched boxes represent two separate auditory signals (80dB) of 30 seconds each during training and a single auditory signal for 2 minutes during cued test followed by 2 sec foot shock. Symbol representations are - KOTg (red circle), KO (orange circle), WTTg (yellow triangle) and WT (green triangle). (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3040748&req=5

pone-0016550-g005: Fear conditioning test.Percent freezing of mice over time during Training (Top), Cued test (middle) and Contextual test (bottom). Mean values ± SEM are plotted. Data were analyzed by two-way repeated measure ANOVA. Differences between groups were not significant for training and cued tests. In contextual tests, WT performed significantly better than WTTg (p = 0.003); difference between WTTg and KOTg was significant (p = 0.014); other groups were not significantly different. Blue hatched boxes represent two separate auditory signals (80dB) of 30 seconds each during training and a single auditory signal for 2 minutes during cued test followed by 2 sec foot shock. Symbol representations are - KOTg (red circle), KO (orange circle), WTTg (yellow triangle) and WT (green triangle). (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).
Mentions: In order to examine whether learning behavior was impaired in transgenic mice lacking αB-crystallin/HspB2, we performed fear-conditioning test. In this test paradigm the associative learning of a neutral cue (eg, sound tone) or a neutral context (eg, environment) with a brief aversive stimulus (eg, mild electric shock) is measured by monitoring the freezing behavior in mice (Figure 5). Fear conditioning test was performed by placing a mouse in a box equipped with a mechanism for monitoring the freezing behavior of the animal by recording photobeam breaks. The mice were first trained to associate the surroundings or a sound pulse (cue) with the mild aversive stimulus. Cue-dependent freezing was tested in a novel environment (i.e., one with different lighting, and olfactory and visual cues) and the freezing behavior associated with the tone was measured. Context-dependent freezing was monitored to evaluate the learned aversion of an animal for the environment associated with the mild aversive stimulus.

Bottom Line: Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation.We observed that the overall content of αB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner.Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Chaperones and Radiobiology, Medical College of Georgia, Augusta, Georgia, United States of America.

ABSTRACT
Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation. Neurotoxicity of amyloid-beta (Aβ) aggregates and their deposition in senile plaques are hallmarks of Alzheimer's disease (AD). We observed that the overall content of αB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner. We hypothesized that αB-crystallin protects cells against Aβ toxicity. To test this, we crossed αB-crystallin/HspB2 deficient (CRYAB⁻/⁻HSPB2⁻/⁻) mice with AD model transgenic mice expressing mutant human amyloid precursor protein. Transgenic and non-transgenic mice in chaperone-sufficient or deficient backgrounds were examined for representative behavioral paradigms for locomotion and memory network functions: (i) spatial orientation and locomotion was monitored by open field test; (ii) sequential organization and associative learning was monitored by fear conditioning; and (iii) evoked behavioral response was tested by hot plate method. Interestingly, αB-crystallin/HspB2 deficient transgenic mice were severely impaired in locomotion compared to each genetic model separately. Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases.

Show MeSH
Related in: MedlinePlus