The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease.

Autor:	Iannitelli AF; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322., Kelberman MA; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322., Lustberg DJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322., Korukonda A; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322., McCann KE; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322., Mulvey B; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110., Segal A; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322., Liles LC; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322., Sloan SA; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322., Dougherty JD; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110., Weinshenker D; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322 dweinsh@emory.edu.
Jazyk:	angličtina
Zdroj:	ENeuro [eNeuro] 2023 Jan 06; Vol. 10 (1). Date of Electronic Publication: 2023 Jan 06 (Print Publication: 2023).
DOI:	10.1523/ENEURO.0483-22.2022
Abstrakt:	The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg, one week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms. Competing Interests: The authors declare no competing financial interests. (Copyright © 2023 Iannitelli et al.)
Databáze:	MEDLINE
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