Early and Selective Localization of Tau Filaments to Glutamatergic Subcellular Domains Within the Human Anterodorsal Thalamus

Sárkány, Barbara and Dávid, Csaba and Hortobágyi, Tibor and Gombás, Péter and Somogyi, Péter and Acsády, László and Viney, Tim J. (2024) Early and Selective Localization of Tau Filaments to Glutamatergic Subcellular Domains Within the Human Anterodorsal Thalamus. ACTA NEUROPATHOLOGICA : PATHOLOGY AND MECHANISMS OF NEUROLOGICAL DISEASE, 147. No.-98. ISSN 0001-6322 (print); 1432-0533 (online)

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Abstract

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.

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