Ultrastructural differences in pretangles between Alzheimer disease and corticobasal degeneration revealed by comparative light and electron microscopy.

Pretangles are defined under the light microscope as diffuse and granular tau immunoreactivity in neurons in tissue from patients with Alzheimer disease (AD) or corticobasal degeneration (CBD) and are considered to be a premature stage before neurofibrillary tangle formation. However, the ultrastructure of pretangles remains to be described. To clarify the similarities and differences between pretangles from patients with AD and CBD (AD-pretangles and CBD-pretangles, respectively), we examined cortical pretangles in tissue from patients with each of diseases. For direct light and electron microscopic (LM/EM) correlation of the pretangles, we used quantum dot nanocrystals (QDs) with dual fluorescent and electron-dense properties. We first identified tau-labeled pretangles on fluorescence LM and subsequently examined the same neurons on EM. Energy dispersive X-ray spectrometry (EDX) color mapping identified selenium (Se) and cadmium (Cd) as elementary components of QDs and highlighted each QD particle clearly against gray-scale EM images. With these methods, we were successful for the first time in demonstrating accurately that LM-defined pretangles are tau-positive straight filaments sparsely distributed throughout neuronal cytoplasm and neurites in both AD and CBD at the EM level. Notably, AD-pretangles showed a strong tendency to form fibrillary tangles even at an early stage, whereas pretangles or Pick-like inclusions in tissue from patients with CBD did not even at an advanced stage. In conclusion, AD-pretangles and CBD-pretangles showed essential differences at the EM level.