Involvement of WAVE accumulation in Abeta/APP pathology-dependent tangle modification in Alzheimer's disease.

Synaptic deficits are closely correlated with cognitive dysfunction in Alzheimer's disease (AD), and synaptic integrity is regulated by the actin cytoskeleton. We demonstrated here that the Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE), a key molecule for actin assembly, co-aggregated with both hyperphosphorylated tau and phosphorylated collapsin response mediator protein 2 (CRMP2) in neurofibrillary tangles and abnormal neurites of the AD brain. Although phosphorylated CRMP2 accumulation was induced in the brains of JNPL3 mice, WAVE accumulation was not detected in the brains of either JNPL3 or Tg2576 mice that developed neurofibrillary tangles and amyloid-beta (Abeta) plaques, respectively. Interestingly, both phosphorylated CRMP2 accumulation and WAVE accumulation were recapitulated in the brains of 3xTg-AD mice that developed neurofibrillary tangles and Abeta plaques. In addition, we found an interaction between WAVE, CRMP2, and hyperphosphorylated tau in the cytosolic fraction of the AD brain. Taken together, WAVE accumulation may require both Abeta/amyloid precursor protein and tau pathologies, and an interaction between WAVE, CRMP2, and hyperphosphorylated tau may be involved in this process. Thus, WAVE accumulation may be involved in Abeta/amyloid precursor protein mediated-tangle modification, suggesting a possible correlation between WAVE accumulation and synaptic deficits induced by disturbances in actin assembly in AD brains.