Transgenic Mice Expressing Human α-Synuclein in Noradrenergic Neurons Develop Locus Ceruleus Pathology and Nonmotor Features of Parkinson's Disease DOI Open Access

Laura M. Butkovich,

Madelyn C. Houser,

Termpanit Chalermpalanupap

et al.

Journal of Neuroscience, Journal Year: 2020, Volume and Issue: 40(39), P. 7559 - 7576

Published: Aug. 31, 2020

Degeneration of locus Coeruleus (LC) neurons and dysregulation noradrenergic signaling are ubiquitous features Parkinson9s disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms modulate immune cells, while NE neurotransmission may exacerbate progression, particularly nonmotor symptoms, contribute to chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing have previously been developed, transgene expression usually driven pan-neuronal promoters thus has not selectively targeted neurons. Here we report a novel mouse expressing human wild-type under control noradrenergic-specific dopamine β-hydroxylase promoter (DBH-hSNCA). These developed oligomeric conformation-specific in neurons, alterations hippocampal microglial abundance, upregulated GFAP expression, degeneration fibers, decreased striatal DA metabolism, age-dependent behaviors reminiscent symptoms that were rescued adrenergic receptor antagonists. provide insights into pathology central dysfunction early pathophysiology. SIGNIFICANCE STATEMENT ɑ-Synuclein loss two most neuropathologic Dysregulated PD, including sleep disturbances, emotional changes such as anxiety depression, cognitive decline. Importantly, inflammation in, progression of, PD. We generated investigate increased function transmission behaviors. cytotoxic effects asyn, astrogliosis, fiber degeneration, disruptions without inclusions.

Language: Английский

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases DOI Creative Commons
Matthew J. Betts, Evgeniya Kirilina, Maria Concepción García Otaduy

et al.

Brain, Journal Year: 2019, Volume and Issue: 142(9), P. 2558 - 2571

Published: June 11, 2019

Abstract Pathological alterations to the locus coeruleus, major source of noradrenaline in brain, are histologically evident early stages neurodegenerative diseases. Novel MRI approaches now provide an opportunity quantify structural features coeruleus vivo during disease progression. In combination with neuropathological biomarkers, imaging could help understand contribution neurodegeneration clinical and pathological manifestations Alzheimer’s disease, atypical dementias Parkinson’s disease. Moreover, as functional sensitivity noradrenergic system is likely change progression, measures integrity new pathophysiological insights into cognitive behavioural symptoms. Locus also holds promise stratify patients trials according dysfunction. this article, we present a consensus on how non-invasive assessment can be used for research We outline next steps vivo, post-mortem studies that lay groundwork evaluate potential biomarker

Language: Английский

Citations

301
Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease DOI Creative Commons
David Weinshenker

Trends in Neurosciences, Journal Year: 2018, Volume and Issue: 41(4), P. 211 - 223

Published: Feb. 20, 2018

Language: Английский

Citations

266
Rostral locus coeruleus integrity is associated with better memory performance in older adults DOI
Martin J. Dahl, Mara Mather,

Sandra Düzel

et al.

Nature Human Behaviour, Journal Year: 2019, Volume and Issue: 3(11), P. 1203 - 1214

Published: Sept. 9, 2019

Language: Английский

Citations

193
Neuronal regulation of immunity: why, how and where? DOI
Maya Schiller, Tamar L. Ben-Shaanan, Asya Rolls

et al.

Nature reviews. Immunology, Journal Year: 2020, Volume and Issue: 21(1), P. 20 - 36

Published: Aug. 18, 2020

Language: Английский

Citations

176
In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline DOI
Heidi I.L. Jacobs, J. Alex Becker, Kenneth K. Kwong

et al.

Science Translational Medicine, Journal Year: 2021, Volume and Issue: 13(612)

Published: Sept. 22, 2021

In vivo and autopsy evidence supports locus coeruleus MRI measures as proxy of initial TAU deposition amyloid-related memory decline.

Language: Английский

Citations

172
The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer’s disease DOI Creative Commons
Billie J. Matchett, Lea T. Grinberg, Panos Theofilas

et al.

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(5), P. 631 - 650

Published: Jan. 11, 2021

Abstract Alzheimer’s disease (AD) is neuropathologically characterized by the intracellular accumulation of hyperphosphorylated tau and extracellular deposition amyloid-β plaques, which affect certain brain regions in a progressive manner. The locus coeruleus (LC), small nucleus pons brainstem, widely recognized as one earliest sites neurofibrillary tangle formation AD. Patients with AD exhibit significant neuronal loss LC, resulting marked reduction its size function. vastly innervates several brain, primary source neurotransmitter norepinephrine (NE) central nervous system. Considering that NE major modulator behavior, contributing to neuroprotection suppression neuroinflammation, degeneration LC ultimate dysregulation LC–NE system has detrimental effects brain. In this review, we detail neuroanatomy function essential role neuroprotection, how dysregulated We discuss AD-related neuropathologic changes mechanisms neurons are selectively vulnerable insult. Further, elucidate neurotoxic de-innervation both locally at projection sites, augments pathology, progression severity. summarize preservation could be used treatment other neurodegenerative diseases affected degeneration.

Language: Английский

Citations

117
Probing locus coeruleus functional network in healthy aging and its association with Alzheimer’s disease biomarkers using pupillometry DOI Creative Commons
Junjie Wu, A. Toporek, Qixiang Lin

et al.

Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)

Published: Feb. 27, 2025

Abstract Background Alzheimer’s disease (AD) is the leading cause of dementia, and early detection disease-associated changes allows interventions. The locus coeruleus (LC) has been reported to be first brain region develop tau pathology in AD. However, functional network LC both healthy aging AD largely unknown due technical difficulties associated with small size LC. In this study, we used measurement spontaneous pupil constriction/dilation as a surrogate for activity study during aging. Methods Thirty-seven younger thirty-nine older adults were included from Emory Healthy Brain Study underwent resting-state MRI while simultaneously tracking diameter. measurements diameter dynamics reference signals connectivity analysis. identified networks was then compared between participants. Correlations regions neuropsychological assessments cerebrospinal fluid (CSF) biomarkers also evaluated. Results A 20 clusters identified, including well functionally connected found positively correlate salience negatively central executive network. Functional decreased within memory, executive, visuospatial functioning. CSF total closely correlated Conclusions Pupil provide valuable insights into LC-related processes. While they are not solely influenced by activity, constrictor/dilatory shows promise non-invasive approach probe warrants further studies evaluate its value an biomarker

Language: Английский

Citations

2
Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus DOI Open Access
Seong Su Kang, Xia Liu, Eun Hee Ahn

et al.

Journal of Clinical Investigation, Journal Year: 2019, Volume and Issue: 130(1), P. 422 - 437

Published: Dec. 2, 2019

Aberrant Tau inclusions in the locus coeruleus (LC) are earliest detectable Alzheimer's disease-like (AD-like) neuropathology human brain. However, why LC neurons selectively vulnerable to developing early pathology and degenerating later disease whether might seed stereotypical spread of rest brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively noradrenergic by monoamine oxidase A metabolism norepinephrine, activated asparagine endopeptidase cleaved at residue N368 into aggregation- propagation-prone forms, thus leading degeneration pathology. Activation endopeptidase-cleaved aggregation vitro intact cells was triggered resulting neurotoxicity propagation forebrain. Thus, our findings reveal norepinephrine cleavage represent specific molecular mechanism underlying selective vulnerability AD.

Language: Английский

Citations

91
Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer's disease DOI Creative Commons
Martin J. Dahl, Mara Mather, Markus Werkle‐Bergner

et al.

Neurobiology of Aging, Journal Year: 2021, Volume and Issue: 112, P. 39 - 54

Published: Dec. 8, 2021

Abnormally phosphorylated tau, an indicator of Alzheimer's disease, accumulates in the first decades life locus coeruleus (LC), brain's main noradrenaline supply. However, technical challenges in-vivo assessments have impeded research into role LC disease. We studied participants with or known to be at-risk for mutations genes causing autosomal-dominant disease (ADAD) early onset, providing a unique window pathogenesis largely disentangled from age-related factors. Using high-resolution MRI and tau PET, we found lower rostral integrity symptomatic participants. was associated individual differences burden memory decline. Post-mortem analyses separate set carriers same mutation confirmed substantial neuronal loss LC. Our findings link degeneration Alzheimer's, highlight noradrenergic system this neurodegenerative

Language: Английский

Citations

91
Alzheimer’s disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms DOI
Heidi I.L. Jacobs, Joost M. Riphagen, Inez H.G.B. Ramakers

et al.

Molecular Psychiatry, Journal Year: 2019, Volume and Issue: 26(3), P. 897 - 906

Published: May 28, 2019

Language: Английский

Citations

90