Widespread cortical accumulation of misfolded pathological tau proteins (ptau) in
the form of paired helical filaments is a major hallmark of Alzheimer’s disease. Subcellular
localization of ptau at various stages of disease progression is likely to be informative
of the cellular mechanisms involving its spread. Here, we found that the density of
ptau within several distinct rostral thalamic nuclei in post-mortem human tissue (
n = 25 cases) increased with the disease stage, with the anterodorsal nucleus (ADn)
consistently being the most affected. In the ADn, ptau-positive elements were present
already in the pre-cortical (Braak 0) stage. Tau pathology preferentially affected
the calretinin-expressing subpopulation of glutamatergic neurons in the ADn. At the
subcellular level, we detected ptau immunoreactivity in ADn cell bodies, dendrites,
and in a specialized type of presynaptic terminal that expresses vesicular glutamate
transporter 2 (vGLUT2) and likely originates from the mammillary body. The ptau-containing
terminals displayed signs of degeneration, including endosomal/lysosomal organelles.
In contrast, corticothalamic axon terminals lacked ptau. The data demonstrate the
involvement of a specific cell population in ADn at the onset of the disease. The
presence of ptau in subcortical glutamatergic presynaptic terminals supports hypotheses
about the transsynaptic spread of tau selectively affecting specialized axonal pathways.
