Transneuronal degeneration in the spread of Alzheimer's disease pathology: immunohistochemical evidence for the transmission of tau hyperphosphorylation.

Neurofibrillary tangles and dystrophic neurites appear to develop in a highly characteristic spatial and temporal sequence in AD. In order to examine the nature of the cellular progression we have studied the trisynaptic entorhinal, dentate gyrus, CA3/4 circuit, using an antibody to hyperphosphorylated tau which is a biochemical marker for tangle formation. In early AD cases, we found numerous ATB-stained boutons in the outer molecular layer of the dentate gyrus, the termination field of neurons from the entorhinal cortex. These AT8-stained boutons co-labeled with synaptophysin, indicating that they represent synaptic boutons in an early state of degeneration. Since the labeled boutons were apposed to or clustered around dendrites or soma that lacked or had less intense staining for AT8 or PHF-1, it appeared that presynaptic events preceded postsynaptic neurofibrillary tangle formation. Furthermore, as a function of disease progression, the pattern of degeneration moved through the circuit. In this progression tau, which is normally localized to axons, becomes redistributed into dendrites and hyperphosphorylated. These observations support the hypothesis that the presynaptic terminal changes may promote the formation of initial neurofibrillary pathology in the postsynaptic neurons via anterograde transneuronal mechanisms and that this initiates a breakdown of routing and sorting mechanisms for the cytoskeletal protein tau.