Abstract
ABSTRACTProtein 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, all of which are disrupted in AD. We report here that tau pathology is present in the DRN of cognitively intact individuals 54-80 years of age, whereas synuclein and TDP-43 are relatively absent. Almost all AD cases had tau pathology in the DRN, whereas only a subset contained TDP-43 or synuclein, but not both. Mice overexpressing human P301L-tau in the DRN also exhibited depressive-like behaviors and hyperactivity without any deficits in spatial memory. There was a negative correlation between the density of Tph2-expressing neurons and phospho-tau (ptau) optical density in P301L-tauDRNmice, although mean Tph2 expression did not differ significantly from the controls. 5-HT neurons were hyperexcitable in P301L-tauDRNmice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs) which is suggestive of increased glutamatergic transmission. Astrocytic density was also elevated in the DRN and accompanied by an increase in GFAP expression, as well as changes inHtr2a, Htr2candHtr3agene expression. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen, suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together, these results suggest that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to prodromal AD symptoms, 5-HT neuronal dysfunction, and activation of local astrocytes. The presence of tau pathology in the DRN combined with psychiatric assessments for depression may be a useful screening tool for individuals at risk for AD.
Publisher
Cold Spring Harbor Laboratory