Sortilin C-terminal fragment deposition depicts tangle-related nonamyloid neuritic plaque growth in Alzheimer’s disease

Sortilin C-terminal fragments (sorfra) can co-deposit in β-amyloid (Aβ) plaques in human brain. However, sorfra plaques develop in the cerebrum with a spatiotemporal trajectory as of tauopathy. Here we examined sorfra pathogenesis relative to neuritic plaque evolution in the human brains with amyloid and tau pathologies converged in the neocortex and hippocampus. Sorfra plaques occurred in correlation with pTau/tangle, but not Aβ, pathologies across cerebral regions, neighboring cortical/hippocampal areas, and along the sulcal valley to gyral hilltop transition. Sorfra plaques and neuritic plaques were matchable in location, shape and size between consecutive sections, and were colocalized in double-labeling preparations. Microscopical study and tissue clearance three-dimensional imaging revealed sorfra/Aβ colocalized as well as independent plaques. Among the former, sorfra labeling correlated negatively to Aβ/amyloid labeling and β-secretase-1 labeling in dystrophic neurites. Sorfra plaques were depleted of microtubule-associated protein 2 (MAP2) labeled neuronal somata and dendrites, whereas normal looking MAP2/sortilin co-labeled profiles occurred nearby. Sorfra deposits were seen in astrocytes but not microglia around the plaques. Taken together, sorfra plaques are anatomically matchable to silver stained neuritic plaques. They develop with tangle-related somatodendritic degeneration, presenting as nonamyloid growth of the Aβ plaques and formation of Aβ-independent neuritic plaques during Alzheimer’s disease pathogenesis.