Pretangles and neurofibrillary changes: Similarities and differences between AD and CBD based on molecular and morphological evolution

Pretangles are cytoplasmic tau immunoreactivity in neurons without apparent formation of fibrillary structures. In Alzheimer disease, such tau deposition is considered to represent a premature state prior to fibril formation (AD-pretangles), later to form neurofibrillary tangles and finally ghost tangles. This morphological evolution from pretangles to ghost tangles is in parallel with their profile shift from four repeat (4R) tau-positive pretangles to three repeat (3R) tau-positive ghost tangles with both positive neurofibrillary tangles in between. This complementary shift of tau profile from 4R to 3R suggests that these tau epitopes are represented interchangeably along tangle evolution. Similar tau immunoreactivity without fibril formation is also observed in corticobasal degeneration (CBD-pretangles). CBD-pretangles and AD-pretangles share: (i) selective 4R tau immunoreactivity without involvement of 3R tau; and (ii) argyrophilia with Gallyas silver impregnation. However, CBD-pretangles neither evolve into ghost tangles nor exhibit 3R tau immunoreactivity even at the advanced stage. Because electron microscopic studies on these pretangles are quite limited, it remains to be clarified whether such differences in later evolution are related to their primary ultrastructures, potentially distinct between AD and CBD. As double staining for 3R and 4R tau clarified complementary shift from 4R to 3R tau along evolution from pretangles to ghost tangles, double immunoelectron microscopy, if possible, may clarify similar profile shifts in relation to each tau fibril at the ultrastructural dimension. This will provide a unique viewpoint on how molecular (epitope) representations are related to pathogenesis of fibrillary components.