Adolescent social isolation facilitates tau spread in raphe nuclei, linking depression and hyperalgesia in Alzheimer's disease.

Tau pathology in brainstem serotonergic circuits drives early neuropsychiatric dysfunction in Alzheimer's disease (AD), yet mechanisms linking social stress exposures to depression and altered pain perception remain unclear. Here, we show that adolescent social isolation, a critical psychosocial exposome factor, facilitates tau propagation in the dorsal raphe nucleus (DRN) and downstream raphe nuclei, producing both neuropsychiatric and pain-related sequelae. Tau[P301L] was transduced into the DRN of 30-day-old socially isolated or group-housed C57BL/6J mice using AAV, with controls receiving AAV-GFP. Four weeks post-transduction, anxiety, social behavior, and pain sensitivity were assessed. Behavior data revealed that adolescent isolation alone increased anxiety-like behavior, while social deficits were observed only in tau[P301L] mice and were further exacerbated by isolation. Moreover, hyperalgesia was observed only in isolated tau[P301L] mice. Histological analysis at 8 weeks revealed focal phosphorylated tau (p-tau) in the DRN and trans-synaptic spread to median raphe (MRN) and raphe magnus (RMg) serotonergic neurons, accompanied by reduced TPH2 and increased p-tau in downstream nuclei. Fluorescence in situ hybridization confirmed altered expression of Slc6a4 and Tgm2, a stress-responsive gene implicated in AD. These results indicate that DRN p-tau under adolescent isolation stress drives neuropsychiatric phenotypes, while p-tau spread to MRN and RMg disrupts serotonergic modulation of pain. This study provides the first evidence that adolescent stress promotes p-tau propagation within the raphe nuclei, linking early neuropsychiatric and pain-processing deficits to prodromal Alzheimer's disease and identifying a critical pathway through which psychosocial exposome risk converges with p-tau pathology to enable early intervention.