• Significance of Small Heat Shock Proteins HSPB1 and HSPB5 in Aggregation and Degradation of Amyloid Proteins

      Ojha, Juhi; Department of Biochemistry and Molecular Biology (2011-06-10)
      Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation. Neurotoxicity of amyloid-beta (Ap) aggregates and its deposition in senile plaques are hallmarks of Alzheimer's disease (AD). We observed that the overall content of aB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner. We hypothesized that aB-crystallin protects cells against Ap toxicity. To test this, we crossed aB-crystallin/HspB2 deficient (CRYAB'A HSPB2'A) 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, aB-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.