TY - JOUR
T1 - The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease
AU - Iannitelli, Alexa F.
AU - Kelberman, Michael A.
AU - Lustberg, Daniel J.
AU - Korukonda, Anu
AU - McCann, Katharine E.
AU - Mulvey, Bernard
AU - Segal, Arielle
AU - Liles, L. Cameron
AU - Sloan, Steven A.
AU - Dougherty, Joseph D.
AU - Weinshenker, David
N1 - Publisher Copyright:
© 2022 Iannitelli et al.
PY - 2023/1
Y1 - 2023/1
N2 - The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and alpha- 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 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 (2 doses of 50 mg/kg, 1 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.
AB - The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and alpha- 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 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 (2 doses of 50 mg/kg, 1 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.
KW - Alzheimer’s disease
KW - DSP-4
KW - Parkinson’s disease
KW - locus coeruleus
KW - mice
KW - norepinephrine
UR - http://www.scopus.com/inward/record.url?scp=85146364118&partnerID=8YFLogxK
U2 - 10.1523/ENEURO.0483-22.2022
DO - 10.1523/ENEURO.0483-22.2022
M3 - Article
C2 - 36635251
AN - SCOPUS:85146364118
SN - 2373-2822
VL - 10
JO - eNeuro
JF - eNeuro
IS - 1
M1 - ENEURO.0483-22.2022
ER -