Behavioral Defects in Chaperone-Deficient Alzheimers Disease Model MiceReport as inadecuate

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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.

Author: Juhi Ojha, Rajalakshmi V. Karmegam, J. Gunasingh Masilamoni, Alvin V. Terry Jr., Anil G. Cashikar



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