Consequences of Hyperphosphorylated Tau in the Locus Coeruleus on Behavior and Cognition in a Rat Model of Alzheimer’s Disease

Michael A. Kelberman; Claire R. Anderson; Eli Chlan; Jacki M. Rorabaugh; Katharine E. McCann; David Weinshenker

doi:10.3233/jad-215546

journal article Apr 05, 2022

Consequences of Hyperphosphorylated Tau in the Locus Coeruleus on Behavior and Cognition in a Rat Model of Alzheimer’s Disease

Michael A. Kelberman Claire R. Anderson Eli Chlan Jacki M. Rorabaugh Katharine E. McCann David Weinshenker

Journal of Alzheimer’s Disease Vol. 86 No. 3 pp. 1037-1059 · SAGE Publications

View at Publisher Save 10.3233/jad-215546

Abstract

Background: The locus coeruleus (LC) is one of the earliest brain regions to accumulate hyperphosphorylated tau, but a lack of animal models that recapitulate this pathology has hampered our understanding of its contributions to Alzheimer’s disease (AD) pathophysiology. Objective: We previously reported that TgF344-AD rats, which overexpress mutant human amyloid precursor protein and presenilin-1, accumulate early endogenous hyperphosphorylated tau in the LC. Here, we used TgF344-AD rats and a wild-type (WT) human tau virus to interrogate the effects of endogenous hyperphosphorylated rat tau and human tau in the LC on AD-related neuropathology and behavior. Methods: Two-month-old TgF344-AD and WT rats received bilateral LC infusions of full-length WT human tau or mCherry control virus driven by the noradrenergic-specific PRSx8 promoter. Rats were subsequently assessed at 6 and 12 months for arousal (sleep latency), anxiety-like behavior (open field, elevated plus maze, novelty-suppressed feeding), passive coping (forced swim task), and learning and memory (Morris water maze and fear conditioning). Hippocampal microglia, astrocyte, and AD pathology were evaluated using immunohistochemistry. Results: In general, the effects of age were more pronounced than genotype or treatment; older rats displayed greater hippocampal pathology, took longer to fall asleep, had reduced locomotor activity, floated more, and had impaired cognition compared to younger animals. TgF344-AD rats showed increased anxiety-like behavior and impaired learning and memory. The tau virus had negligible influence on most measures. Conclusion: Effects of hyperphosphorylated tau on AD-like neuropathology and behavioral symptoms were subtle. Further investigation of different forms of tau is warranted.

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Metrics

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Citations

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References

Details

Published: Apr 05, 2022
Vol/Issue: 86(3)
Pages: 1037-1059

Authors

M

Michael A. Kelberman

Department of Human Genetics, Emory University, Atlanta, GA, USA; Neuroscience Program, Laney Graduate School, Emory University, Atlanta, GA, USA

C

Claire R. Anderson

Department of Human Genetics, Emory University, Atlanta, GA, USA

E

Eli Chlan

Neuroscience Program, Laney Graduate School, Emory University, Atlanta, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA

J

Jacki M. Rorabaugh

Department of Human Genetics, Emory University, Atlanta, GA, USA

K

Katharine E. McCann

Department of Human Genetics, Emory University, Atlanta, GA, USA

D

David Weinshenker

Department of Human Genetics, Emory University, Atlanta, GA, USA

Cite This Article

Michael A. Kelberman, Claire R. Anderson, Eli Chlan, et al. (2022). Consequences of Hyperphosphorylated Tau in the Locus Coeruleus on Behavior and Cognition in a Rat Model of Alzheimer’s Disease. Journal of Alzheimer’s Disease, 86(3), 1037-1059. https://doi.org/10.3233/jad-215546

Consequences of Hyperphosphorylated Tau in the Locus Coeruleus on Behavior and Cognition in a Rat Model of Alzheimer’s Disease

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