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bioRxiv · 10.1101/2025.11.09.687363

Impact of early locus coeruleus lesions in the TgF344 Alzheimer's disease rat model

Marriott, A. E.·Schroeder, J. P.·Korukonda, A.·Pate, B. S.·McCann, K. E.·Weinshenker, D.·Kelberman, M. A.
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Abstract

INTRODUCTIONIn murine models of Alzheimers disease (AD), lesioning the locus coeruleus-norepinephrine (LC-NE) system with DSP-4 exacerbates AD-like neuropathology and cognitive impairment. However, the impact of LC lesions during prodromal stages is poorly characterized. METHODSTgF344-AD and wild-type rats received monthly injections of DSP-4 or saline from 1-5 months of age, a time point preceding forebrain plaque or tangle deposition in TgF344-AD rats, after which behavior and pathology were assessed. RESULTSDSP-4 compromised LC cell bodies, fibers, and NE content. LC lesion and the AD transgene each affected several affective behaviors and/or cognition individually, but few interactions were found and DSP-4 failed to exacerbate behavioral phenotypes or neuropathology in TgF344-AD rats. DISCUSSIONCombined with previous literature, our data suggest that LC lesions exacerbate pre-existing AD-like pathology and behavioral impairments, rather than accelerate their onset. Further characterization of LC lesions in TgF344-AD rats at different ages is warranted. Research-in-ContextO_LISystemic review: The authors reviewed existing literature using traditional sources, including PubMed. Previous studies investigated the impact of locus coeruleus (LC) lesions on Alzheimers disease (AD)-like neuropathology and behavior in murine models of AD. However, the impact of LC degeneration in an animal model that expresses both amyloid and endogenous tau pathology at a time point before the emergence of significant forebrain pathology is underexplored. C_LIO_LIInterpretation: We expanded the behavioral and molecular characterization of TgF344-AD rats in response to N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4)-induced LC lesions during the pre-pathology stages of disease. Unexpectedly, we found that TgF344-AD genotype and DSP-4 rarely interacted to exacerbate AD-related symptoms or pathology. C_LIO_LIFuture Directions: Our results indicate LC lesions do not accelerate onset of AD-like neuropathology or behavioral impairment in this model. Future studies in older TgF344-AD animals and using different DSP-4 treatment regimens would help clarify the relationship between LC integrity and AD progression. C_LI HighlightsO_LILocus coeruleus damage causes apathy-like behavior and changes in arousal C_LIO_LITgF344-AD genotype induces social recognition deficits and anxiety-like behavior C_LIO_LILocus coeruleus damage and TgF344-AD genotype rarely interact to worsen deficits C_LIO_LIInteractions that exacerbate Alzheimers disease neuropathology were also scarce C_LI

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Marriott, A. E., Schroeder, J. P., Korukonda, A., Pate, B. S., McCann, K. E., Weinshenker, D., Kelberman, M. A.. 2025-11-10. Impact of early locus coeruleus lesions in the TgF344 Alzheimer's disease rat model. https://doi.org/10.1101/2025.11.09.687363

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