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

Molecular Psychiatry volume 30, pages 532–546 (2025)Cite this article

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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 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-tauDRN 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.

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Fig. 1: Neurodegenerative markers in the DRN and LC of cognitively normal individuals and those with Alzheimer’s Disease.
Fig. 2: DRN tau pathology promotes depressive-like behaviors in male mice.
Fig. 3: Tau pathology colocalizes with serotonergic DRN neurons and results in astrocytic activation and neuroinflammation in the DRN of P301L-tauDRN mice.
Fig. 4: Tau pathology preferentially colocalizes with neurons instead of glia in the DRN.
Fig. 5: Neuronal excitability and glutamatergic transmission is elevated in P301L-tauDRN mice.
Fig. 6: Tau pathology propagates from the DRN to other brain regions.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We thank the Iowa Neurobank Core for providing human post-mortem tissues for this study, Mariah Leidinger of the Comparative Pathology Core at The University of Iowa for providing histology services for human and mouse tissues, and the personnel of the Department of Pathology’s Immunohistochemistry Lab at The University of Iowa for performing TDP-43 staining. We additionally thank Ramasamy Thangavel for performing the α-syn-AT8-TH triple stain in human LC tissue.

Funding

This work was supported by the National Institute on Alcohol Abuse and Alcoholism (R01 AA028931), the National Institute on Aging (R01 AG070841), and the Williams-Cannon Fellowship to CAM. SRP was supported by the National Institute of General Medical Sciences (T32 GM067795), KMK was supported by the National Institute of Diabetes and Digestive and Kidney Disease (T32 DK112751), and TDJ was supported by the National Heart, Lung, and Blood Institute (T32 HL007638). CAM, GA, and MMH also received generous support from the Roy J. and Lucille A Carver Trust for the “SMASH Dementia” Research Program of Excellence award which partially funded this project.

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Authors and Affiliations

  1. Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, 52242, USA

    Samantha R. Pierson, Ruixiang Wang, Nagalakshmi Balasubramanian, Jessica Reinhardt, Thomas D. James & Catherine A. Marcinkiewcz

  2. Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA

    Kimberly L. Fiock, Mikayla L. Hunter, Benjamin J. Cooper, Hannah R. Williamsen, Ryan Betters & Marco M. Hefti

  3. Psychological Sciences Department, Daemen University, Amherst, NY, 14226, USA

    Kanza M. Khan

  4. Department of Neurology, University of Iowa, Iowa City, IA, 52242, USA

    Kaancan Deniz & Georgina Aldridge

  5. Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Gloria Lee

  6. Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, 52242, USA

    Gloria Lee, Georgina Aldridge, Marco M. Hefti & Catherine A. Marcinkiewcz

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Contributions

CAM, GL, GA, and MMH conceived of the project and designed experiments. SRP, KLF, RW, NB, JR, KMK, TDJ, MLH, BJC, HRW, RB, MMH, and CAM performed experiments and contributed to data acquisition. CAM, SRP, KLF, RW, NB, JR, KMK, KD, GA, and MMH analyzed and interpreted the data. CAM and SRP wrote the original manuscript, and CAM, SRP, RW, NB, GA, and MMH edited the manuscript. CAM, GA, and MMH provided resources, and CAM was responsible for overall supervision. All authors approved the final version of the article.

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Correspondence to Catherine A. Marcinkiewcz.

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All procedures on mice in this study were approved by the Institutional Care and Use Committee at the University of Iowa.

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Pierson, S.R., Fiock, K.L., Wang, R. et al. Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease. Mol Psychiatry 30, 532–546 (2025). https://doi.org/10.1038/s41380-024-02664-9

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