The interaction between drebrin and its binding partners seems to play important roles in higher brain functions, because drebrin is involved in the pathogenesis of some neurological diseases with cognitive defects.
Indeed, comp-B reduces not only α-synuclein but also insoluble Aβ42 levels, prevents the reductions in synaptophysin and drebrin, and rescues cognitive deficits in transgenic APdE9 mice model of AD.
Analysis of the brains of transgenic mice used as models of Alzheimer's disease (AD) reveals that the loss of drebrin from dendritic spines predates the emergence of synaptic dysfunction and cognitive impairment, suggesting that this form of homeostatic plasticity contributes toward cognition.
Dysfunction in PAK leads to cofilin activation, drebrin displacement from its actin-binding site, actin depolymerization/severing, and, ultimately, defects in spine dynamics and cognitive impairment in mice.
Associated with the cognitive deficit are increases in brain microvascular AGE and iNOS expression, and the loss of the synaptic spine protein drebrin.
We propose that an imbalanced regulation of the actin-regulatory machinery (loss of drebrin and increase of dephosphorylated cofilin) results in synaptic dysfunction, which underlies the cognitive impairment accompanying neurological disorders and normal aging.