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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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Open field test.Counts for Ambulatory (A), Vertical (B) and Stereotypic (C) activities of mice over a period of 25 minutes in the open field. Symbol representations are - KOTg (open grey square; n = 7), KO (closed grey square; n = 15), WTTg (open black circle; n = 7) and WT (closed black circle; n = 9). Mean values ± SEM are plotted. Data were analyzed by two-way repeated measure ANOVA, which indicated that KOTg group showed significantly less (p = 0.004) than other groups. Differences were not statistically significant between other groups. (D) Total distance (in cm) traveled by the mice over a period of 30 minutes. Mean values ± SEM are plotted. Data were compared by t-tests. KOTg was significantly different from KO (p = 0.007) and WT (p = 0.017). (E) Zone time in center (black bars) and periphery (grey bars) for the mice during the 30 minutes. Data were compared by t-tests. Center zonetimes of both KO and KOTg were significantly different from WT (p = 0.023 for KO and p = 0.0006 for KOTg). Peripheral zonetimes were similar for all groups. (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).
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pone-0016550-g003: Open field test.Counts for Ambulatory (A), Vertical (B) and Stereotypic (C) activities of mice over a period of 25 minutes in the open field. Symbol representations are - KOTg (open grey square; n = 7), KO (closed grey square; n = 15), WTTg (open black circle; n = 7) and WT (closed black circle; n = 9). Mean values ± SEM are plotted. Data were analyzed by two-way repeated measure ANOVA, which indicated that KOTg group showed significantly less (p = 0.004) than other groups. Differences were not statistically significant between other groups. (D) Total distance (in cm) traveled by the mice over a period of 30 minutes. Mean values ± SEM are plotted. Data were compared by t-tests. KOTg was significantly different from KO (p = 0.007) and WT (p = 0.017). (E) Zone time in center (black bars) and periphery (grey bars) for the mice during the 30 minutes. Data were compared by t-tests. Center zonetimes of both KO and KOTg were significantly different from WT (p = 0.023 for KO and p = 0.0006 for KOTg). Peripheral zonetimes were similar for all groups. (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).

Mentions: First of all, WT and KO groups behaved similarly in terms of vertical counts, stereotypic counts and ambulatory counts indicating that loss of αB-crystallin/HspB2 alone had negligible effect on locomotion at this age group (Figure 3A, B & C). Age associated muscle degeneration reported with the knockout mice was not manifested in terms of locomotion defects at this age group as all 3 parameters counts of KO group of animals was comparable to WT. Similarly, the WTTg group was comparable to WT suggesting that the expression of mutant APP in mice did not significantly affect locomotion by itself. Interestingly, when the transgene expression was combined with αB-crystallin/HspB2 deficiency in the KOTg group, the effect was synergistically enhanced compared to KO group (P<0.004, 2-way repeated measure ANOVA) in ambulatory activity and vertical activity. Differences were not statistically significant in stereotypic activity.


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

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

Open field test.Counts for Ambulatory (A), Vertical (B) and Stereotypic (C) activities of mice over a period of 25 minutes in the open field. Symbol representations are - KOTg (open grey square; n = 7), KO (closed grey square; n = 15), WTTg (open black circle; n = 7) and WT (closed black circle; n = 9). Mean values ± SEM are plotted. Data were analyzed by two-way repeated measure ANOVA, which indicated that KOTg group showed significantly less (p = 0.004) than other groups. Differences were not statistically significant between other groups. (D) Total distance (in cm) traveled by the mice over a period of 30 minutes. Mean values ± SEM are plotted. Data were compared by t-tests. KOTg was significantly different from KO (p = 0.007) and WT (p = 0.017). (E) Zone time in center (black bars) and periphery (grey bars) for the mice during the 30 minutes. Data were compared by t-tests. Center zonetimes of both KO and KOTg were significantly different from WT (p = 0.023 for KO and p = 0.0006 for KOTg). Peripheral zonetimes were similar for all groups. (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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pone-0016550-g003: Open field test.Counts for Ambulatory (A), Vertical (B) and Stereotypic (C) activities of mice over a period of 25 minutes in the open field. Symbol representations are - KOTg (open grey square; n = 7), KO (closed grey square; n = 15), WTTg (open black circle; n = 7) and WT (closed black circle; n = 9). Mean values ± SEM are plotted. Data were analyzed by two-way repeated measure ANOVA, which indicated that KOTg group showed significantly less (p = 0.004) than other groups. Differences were not statistically significant between other groups. (D) Total distance (in cm) traveled by the mice over a period of 30 minutes. Mean values ± SEM are plotted. Data were compared by t-tests. KOTg was significantly different from KO (p = 0.007) and WT (p = 0.017). (E) Zone time in center (black bars) and periphery (grey bars) for the mice during the 30 minutes. Data were compared by t-tests. Center zonetimes of both KO and KOTg were significantly different from WT (p = 0.023 for KO and p = 0.0006 for KOTg). Peripheral zonetimes were similar for all groups. (n = 7 for KOTg; n = 15 for KO; n = 7 for WTTg and n = 9 for WT).
Mentions: First of all, WT and KO groups behaved similarly in terms of vertical counts, stereotypic counts and ambulatory counts indicating that loss of αB-crystallin/HspB2 alone had negligible effect on locomotion at this age group (Figure 3A, B & C). Age associated muscle degeneration reported with the knockout mice was not manifested in terms of locomotion defects at this age group as all 3 parameters counts of KO group of animals was comparable to WT. Similarly, the WTTg group was comparable to WT suggesting that the expression of mutant APP in mice did not significantly affect locomotion by itself. Interestingly, when the transgene expression was combined with αB-crystallin/HspB2 deficiency in the KOTg group, the effect was synergistically enhanced compared to KO group (P<0.004, 2-way repeated measure ANOVA) in ambulatory activity and vertical activity. Differences were not statistically significant in stereotypic activity.

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