Association of Conformationally Altered Tau with α-1-antichymotrypsin in the Nuclei of Neurons in the Alzheimer's Disease Brain

Abstract

Conformational changes of Tau have been described to occur during its fibrillary and non-fibrillary aggregation inside neurons affected in the brain of Alzheimer’s disease (AD) patients. Two consecutive conformations have been described during the progression of the disease: an early conformation detected with the Alz-50 antibody, recognizing Tau molecules folding its amino terminus over its third repeated domain, and a later conformation involving the bending of the proline-rich region over the third repeated domain. α-1-antichymotrypsin (ACT) is an acute phase serum glycoprotein that is overexpressed in the brain of AD cases and associated with extracellular amyloid-ß aggregates. We have recently reported that in a large population of neurons affected in AD brains, Tau protein undergoing the conformational change detected by Tau-66 antibody accumulates as non-fibrillary aggregates and colocalizes with extensive accumulations of granular diffuse intracellular deposits of ACT. In this report, we further analyzed Tau-ACT interactions in the neurons from the hippocampus of AD brains. By using superresolution confocal microscopy and quantitative colocalization analysis, we corroborated the mutual association and mislocalization of conformationally altered Tau protein and ACT to the nuclear compartment. These results suggest that ACT can play an abnormal pathological role in AD by contributing to the abnormal transport of truncated and conformationally altered Tau protein to the nucleus.