Impact of early locus coeruleus lesions in the TgF344 Alzheimer’s disease rat model
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
INTRODUCTION
In murine models of Alzheimer’s 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.
METHODS
TgF344-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.
RESULTS
DSP-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.
DISCUSSION
Combined 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-Context
Systemic review: The authors reviewed existing literature using traditional sources, including PubMed. Previous studies investigated the impact of locus coeruleus (LC) lesions on Alzheimer’s 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.
Interpretation: 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.
Future 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.
Highlights
-
Locus coeruleus damage causes apathy-like behavior and changes in arousal
-
TgF344-AD genotype induces social recognition deficits and anxiety-like behavior
-
Locus coeruleus damage and TgF344-AD genotype rarely interact to worsen deficits
-
Interactions that exacerbate Alzheimer’s disease neuropathology were also scarce
