Consequences of locus coeruleus degeneration in a rat model of Alzheimer’s disease Restricted; Files Only
Marriott, Alexia (Spring 2025)
Abstract
Background
The locus coeruleus (LC), the main source of the neurotransmitter norepinephrine (NE) in the central nervous system, is exceptionally susceptible to insult in Alzheimer’s disease (AD), beginning with the early accumulation of hyperphosphorylated tau and culminating in frank neuronal loss. Inducing LC damage with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) exacerbates AD-like neuropathology and cognitive impairment in amyloid- and tau-based murine models of AD, indicating a causal relationship between LC degeneration and disease progression. TgF344-AD rats uniquely display amyloid and tau pathology, and develop endogenous hyperphosphorylated tau in the LC prior to other brain regions as observed in human AD. By inducing LC-specific damage in TgF344-AD rats, this study explored the impact of LC degeneration on AD- and noradrenergic-relevant behaviors.
Methods
At ~1 month of age, male and female TgF344-AD rats and wild-type littermates received 2 injections of DSP-4 (50 mg/kg, i.p.) or saline spaced 1 week apart, followed by single monthly injections until ~5 months of age. Behavioral testing began ~1 week following the final injection. At ~6 months of age, animals were sacrificed and the effects of DSP-4 on AD-like pathology and noradrenergic integrity were assessed using immunohistochemistry and high-performance liquid chromatography.
Results
DSP-4 administration resulted in a similarly profound loss of NE, LC fibers/terminals, and LC cell bodies, regardless of genotype. While main effects of DSP-4 (e.g. blunted stress-induced repetitive behaviors and arousal) and genotype (e.g. AD-like neuropathology, locomotor hyperactivity, impaired social discrimination) were observed, DSP-4 failed to exacerbate any measure of behavior or neuropathology in TgF344-AD rats.
Conclusions
DSP-4-induced damage of the LC-NE system unexpectedly did not exacerbate/uncover behavioral deficits or AD-like neuropathology in TgF344-AD rats. Unlike most studies utilizing DSP-4 that examined timepoints reflecting late disease, we examined TgF344-AD rats at a timepoint when little to no AD-like forebrain pathology is present. Thus, we propose that LC lesions exacerbate pre-existing AD-like pathology and cognitive deficits, rather than accelerate their onset. Further characterization at later timepoints is needed to better understand the relationship between DSP-4-induced LC lesioning and the development of AD-like pathology and behavioral symptoms in TgF344-AD animals and other rodent models of AD.
Table of Contents
Introduction……………………………………………………………………………………...…1
Materials and Methods…………………………………………...………………………………11
Results…………………………………………………………………….....………………………18
Discussion………………………………………………………………………………………......25
Figures and Table…………………………...…………………………………………………..…35
Figure 1. DSP-4 administration reduced hippocampal NE levels……………...…..35
Figure 2. Assessment of NE innervation……………………………………………......36
Figure 3. Assessment of locus coeruleus volume……………………………………...37
Figure 4. Assessment of social discrimination………………………………………...38
Figure 5. Assessment of general activity………………………………………………..39
Figure 6. Assessment of repetitive behavior……………………………………………40
Figure 7. Assessment of general arousal…………………………………………………41
Figure 8. Assessment of sleep latency…………………………………………………...42
Figure 9. Assessment of anxiety-like behavior………………………………………...43
Figure 10. Assessment of anxiety-like behavior……………………………………….44
Figure 11. Assessment of learning and memory……………………………………….45
Figure 12. Assessment of amyloid pathology…………………………………………..46
Figure 13. Assessment of p-tau pathology………………………………………………47
Figure 14. Assessment of microglial pathology………………………………………..48
Figure 15. Assessment of astrocyte pathology………………………………………...49
Table 1. Antibody information…………………………………………………………....50
References………………………………………………………………………………………......51
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