ABSTRACT Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer’s disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, which are all disrupted in AD. We report here that tau pathology is present in the DRN of individuals 54-80 years old without a known history of dementia and was found at higher frequency than α-synuclein and TDP-43. Most AD cases had tau pathology in the DRN (90%), whereas only a subset contained TDP-43 or α-synuclein, but not both (30%). To evaluate how early tau pathology impacts behavior, we overexpressed human P301L-tau in the DRN of mice and observed depressive-like behaviors and hyperactivity without any deficits in spatial memory. Tau pathology was predominantly found in neurons relative to glia and colocalized with a significant proportion of Tph2-expressing neurons in the DRN. 5-HT neurons were also hyperexcitable in P301L-tau DRN mice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs), suggestive of increased glutamatergic transmission. Moreover, astrocytic density was elevated in the DRN and accompanied by an increase in IL-1α and Frk expression, which is indicative of inflammation. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen and a significant proportion of this tau pathology colocalized with the serotonin reuptake transporter (SERT), suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together these results indicate that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to behavioral dysregulation, 5-HT neuronal dysfunction, and activation of local astrocytes which may be prodromal indicators of AD.

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease