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 25–80 years old without a known history of dementia, and its prevalence was comparable to the locus coeruleus (LC). By comparison, fewer cases were positive for other pathological proteins including α-synuclein, β-amyloid, and TDP-43. 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 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). Moreover, astrocytic density was elevated in the DRN and accompanied by an increase in IL-1α and Frk expression, which suggests increased inflammatory signaling. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen. 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.

脑干核中的蛋白质聚集被认为发生在阿尔茨海默病 （AD） 的早期阶段，但其在驱动前驱症状和疾病进展中的特定作用在很大程度上是未知的。中缝背核 （DRN） 包含大量 5-羟色胺（5-羟色胺;5-HT）神经元，这些神经元调节情绪、奖励相关行为和睡眠，这些神经元在 AD 中都会被破坏。我们在这里报告，tau 病理存在于 25-80 岁无已知痴呆病史的个体的 DRN 中，其患病率与蓝斑 （LC） 相当。相比之下，其他病理蛋白（包括 α-突触核蛋白、 β-淀粉样蛋白和 TDP-43）阳性的病例较少。为了评估早期 tau 病理学如何影响行为，我们在小鼠的 DRN 中过表达人类 P301L-tau，并观察到抑郁样行为和多动症，而空间记忆没有缺陷。Tau 病理学主要存在于相对于神经胶质细胞的神经元中，并与 DRN 中很大一部分表达 Tph2 的神经元共定位。P301L-tau^DRN 小鼠的 5-HT 神经元也高度兴奋，兴奋性突触后电流 （EPSC） 的振幅增加。此外，DRN 中的星形胶质细胞密度升高，并伴有 IL-1α 和 Frk 表达的增加，这表明炎症信号增加。此外，在丘脑、下丘脑、杏仁核和尾状壳核的轴突过程中检测到 tau 病理。这种 tau 病理学的很大一部分与血清素再摄取转运蛋白 （SERT） 共定位，表明 tau 可能以顺行方式扩散到 DRN 以外的区域。 总之，这些结果表明，tau 病理学在 50 岁以上的个体子集的 DRN 中积累，并可能导致行为失调、5-HT 神经元功能障碍和局部星形胶质细胞激活，这可能是 AD 的前驱指标。