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

PLoS One. 2011 Feb 17;6(2):e16550. doi: 10.1371/journal.pone.0016550.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / physiopathology
  • Animals
  • Avoidance Learning / physiology
  • Behavior, Animal / physiology
  • Disease Models, Animal*
  • HSP27 Heat-Shock Proteins / deficiency
  • HSP27 Heat-Shock Proteins / genetics*
  • Humans
  • Locomotion / genetics
  • Locomotion / physiology
  • Male
  • Mental Disorders / diagnosis
  • Mental Disorders / etiology*
  • Mental Disorders / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic*
  • Molecular Chaperones / genetics
  • Pain Measurement
  • Physical Conditioning, Animal
  • alpha-Crystallin B Chain / genetics

Substances

  • Cryab protein, mouse
  • HSP27 Heat-Shock Proteins
  • Hspb2 protein, mouse
  • Molecular Chaperones
  • alpha-Crystallin B Chain