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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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Hot plate test.The duration of time to elicit a thermo-sensitive reflex response in mice is shown on the left axis (black bars). The temperature at which the response was recorded is shown on the right axis (grey bars). Mean values ± SEM are plotted. Data for different groups were compared by t-tests. Both the time and temperature required elicit a response in KOTg were significantly higher than those for KO (p = 0.022 and 0.031, respectively), WT (p = 0.001 and 0.001, respectively) and WTTg (p = 0.05 and 0.05, respectively). All other groups were statistically similar. WT is CRYAB+/+, Tg0/0; WTTg is CRYAB+/+, Tg+/0; KO is CRYAB-/-, Tg0/0 and KOTg is CRYAB-/-, Tg+/0. (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).
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pone-0016550-g004: Hot plate test.The duration of time to elicit a thermo-sensitive reflex response in mice is shown on the left axis (black bars). The temperature at which the response was recorded is shown on the right axis (grey bars). Mean values ± SEM are plotted. Data for different groups were compared by t-tests. Both the time and temperature required elicit a response in KOTg were significantly higher than those for KO (p = 0.022 and 0.031, respectively), WT (p = 0.001 and 0.001, respectively) and WTTg (p = 0.05 and 0.05, respectively). All other groups were statistically similar. WT is CRYAB+/+, Tg0/0; WTTg is CRYAB+/+, Tg+/0; KO is CRYAB-/-, Tg0/0 and KOTg is CRYAB-/-, Tg+/0. (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).

Mentions: To understand whether the observed locomotion defects were coupled with sensory defects, we examined the mice for pain sensitivity to thermal stimulus (nociception). Each mouse was placed on a hot plate and the temperature of the heating surface was raised by 3°C per minute. The minimum time and temperature required to elicit response (paw licking or jumping) was noted (Figure 4). Somatosensation and its response as motor activity were scored to test for spinal cord related reflexes. The KO, WTTg and WT mice showed comparable responses and the differences were not significant. Maximum latency and higher temperatures were required for the KOTg group to elicit a response and were significantly greater than all other groups of mice with respect to both time and temperature. This result suggests that the combined effect of αB-crystallin/HspB2 loss and transgene expression caused a decreased sensory function not observed with each genotype individually, thus underscoring the synergism.


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

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

Hot plate test.The duration of time to elicit a thermo-sensitive reflex response in mice is shown on the left axis (black bars). The temperature at which the response was recorded is shown on the right axis (grey bars). Mean values ± SEM are plotted. Data for different groups were compared by t-tests. Both the time and temperature required elicit a response in KOTg were significantly higher than those for KO (p = 0.022 and 0.031, respectively), WT (p = 0.001 and 0.001, respectively) and WTTg (p = 0.05 and 0.05, respectively). All other groups were statistically similar. WT is CRYAB+/+, Tg0/0; WTTg is CRYAB+/+, Tg+/0; KO is CRYAB-/-, Tg0/0 and KOTg is CRYAB-/-, Tg+/0. (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

Show All Figures
getmorefigures.php?uid=PMC3040748&req=5

pone-0016550-g004: Hot plate test.The duration of time to elicit a thermo-sensitive reflex response in mice is shown on the left axis (black bars). The temperature at which the response was recorded is shown on the right axis (grey bars). Mean values ± SEM are plotted. Data for different groups were compared by t-tests. Both the time and temperature required elicit a response in KOTg were significantly higher than those for KO (p = 0.022 and 0.031, respectively), WT (p = 0.001 and 0.001, respectively) and WTTg (p = 0.05 and 0.05, respectively). All other groups were statistically similar. WT is CRYAB+/+, Tg0/0; WTTg is CRYAB+/+, Tg+/0; KO is CRYAB-/-, Tg0/0 and KOTg is CRYAB-/-, Tg+/0. (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).
Mentions: To understand whether the observed locomotion defects were coupled with sensory defects, we examined the mice for pain sensitivity to thermal stimulus (nociception). Each mouse was placed on a hot plate and the temperature of the heating surface was raised by 3°C per minute. The minimum time and temperature required to elicit response (paw licking or jumping) was noted (Figure 4). Somatosensation and its response as motor activity were scored to test for spinal cord related reflexes. The KO, WTTg and WT mice showed comparable responses and the differences were not significant. Maximum latency and higher temperatures were required for the KOTg group to elicit a response and were significantly greater than all other groups of mice with respect to both time and temperature. This result suggests that the combined effect of αB-crystallin/HspB2 loss and transgene expression caused a decreased sensory function not observed with each genotype individually, thus underscoring the synergism.

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