Pathogenic tau modifications occur in axons before the somatodendritic compartment in mossy fiber and Schaffer collateral pathways.

The deposition of tau pathology in Alzheimer's disease (AD) may occur first in axons of neurons and then progress back into the cell bodies to form neurofibrillary tangles, however, studies have not directly analyzed this relationship in relatively discrete circuits within the human hippocampus. In the early phases of tau deposition, both AT8 phosphorylation and exposure of the amino terminus of tau occurs in tauopathies, and these modifications are linked to mechanisms of synaptic and axonal dysfunction. Here, we examined the localization of these tau pathologies in well-characterized post-mortem human tissue samples from the hippocampus of 44 cases ranging between non-demented and mild cognitively impaired to capture a time at which intrahippocampal pathways show a range in the extent of tau deposition. The tissue sections were analyzed for AT8 (AT8 antibody), amino terminus exposure (TNT2 antibody), and amyloid-β (MOAB2 antibody) pathology in hippocampal strata containing the axons and neuronal cell bodies of the CA3-Schaffer collateral and dentate granule-mossy fiber pathways. We show that tau pathology first appears in the axonal compartment of affected neurons in the absence of observable tau pathology in the corresponding cell bodies in several cases. Additionally, deposition of tau in these intrahippocampal pathways was independent of the presence of Aβ plaques. We confirmed that the majority of tau pathology positive neuropil threads were axonal in origin and not dendritic using an axonal marker (i.e. SMI312 antibody) and somatodendritic marker (i.e. MAP2 antibody). Taken together, these results support the hypothesis that AT8 phosphorylation and amino terminus exposure are early pathological events and that the deposition of tau pathology, at least in the studied pathways, occurs first in the axonal compartment prior to observable pathology in the somata. These findings highlight the importance on targeting tau deposition, ideally in the initial phases of its deposition in axons.