Early and selective subcortical Tau pathology within the human Papez circuit

The Papez circuit comprises several interconnected brain areas important for spatial navigation and orientation. An early symptom of dementia is disorientation, suggesting that brain regions responsible for providing a sense of direction are adversely affected. We examined post-mortem human tissue from cases with no cognitive impairment, mild cognitive impairment, and Alzheimers disease. A key part of the Papez circuit, the anterodorsal thalamic nucleus (ADn), contained a high density of misfolded pathological Tau (pTau) at all disease stages, including in control cases. Moreover, pTau preferentially accumulated in calretinin-expressing neurons. At the subcellular level, we detected pTau filaments in ADn cell bodies, dendrites, and in specialized presynaptic terminals. Large vesicular-glutamate-transporter-2-containing terminals from the lateral mammillary nucleus, rather than corticothalamic terminals, preferentially contained pTau, suggesting that Tau crosses specific synapses within the Papez circuit. As the ADn contains a high density of head direction cells, pTau may degrade the processing of orientation signals, explaining why people become disorientated years-to-decades before memory deficits emerge.