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

Alexa F. Iannitelli,

Michael A. Kelberman, Daniel J. Lustberg

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Sept. 28, 2022

Abstract The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and alpha-synuclein pathology in Alzheimer’s disease (AD) Parkinson’s (PD), respectively. onset these pathologies coincides with loss fibers LC target regions emergence prodromal symptoms including sleep disturbances anxiety. Paradoxically, are indicative a hyperactivity phenotype, rather than predicted norepinephrine (NE) transmission following damage, suggesting engagement complex compensatory mechanisms. Because current therapeutic efforts targeting early disease, interest has grown, it critical to identify links between dysfunction. We employed LC-specific neurotoxin DSP-4, which preferentially damages axons, model changes LC-NE system pertinent AD PD male female mice. DSP-4 (2 doses 50 mg/kg, 1 week apart) induced axon degeneration, triggered neuroinflammation oxidative stress, reduced tissue NE levels. There was no cell death or firing, but transcriptomics revealed expression genes that define identity other relevant neurodegenerative disease. Despite dramatic fibers, turnover signaling were elevated terminal associated anxiogenic phenotypes multiple behavioral tests. These results represent comprehensive analysis how responds axon/terminal damage reminiscent at molecular, cellular, systems, levels, provides potential mechanisms underlying neuropsychiatric symptoms.

Language: Английский

Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing DOI Creative Commons
Isabella F. Orlando, James M. Shine, Trevor W. Robbins

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 149, P. 105167 - 105167

Published: April 11, 2023

Noradrenergic and cholinergic systems are among the most vulnerable brain in neuropsychiatric diseases of ageing, including Alzheimer's disease, Parkinson's Lewy body dementia, progressive supranuclear palsy. As these fail, they contribute directly to many characteristic cognitive psychiatric symptoms. However, their contribution symptoms is not sufficiently understood, pharmacological interventions targeting noradrenergic have met with mixed success. Part challenge complex neurobiology systems, operating across multiple timescales, non-linear changes adult lifespan disease course. We address challenges a detailed review outlining roles cognition behaviour, how influence disease. By bridging levels analysis, we highlight opportunities for improving drug therapies pursuing personalised medicine strategies.

Language: Английский

Citations

33
Proteostasis failure exacerbates neuronal circuit dysfunction and sleep impairments in Alzheimer’s disease DOI Creative Commons
Christopher D. Morrone, Radha Raghuraman, S. Abid Hussaini

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: April 21, 2023

Abstract Failed proteostasis is a well-documented feature of Alzheimer’s disease, particularly, reduced protein degradation and clearance. However, the contribution failed to neuronal circuit dysfunction an emerging concept in neurodegenerative research will prove critical understanding cognitive decline. Our objective convey disease progression with growing evidence for bidirectional relationship sleep disruption failure. Proteostasis tauopathy disrupts neurons that regulate sleep–wake cycle, which presents behavior as impaired slow wave rapid eye movement patterns. Subsequent loss further impairs Sleep defined seen early many disorders contributes memory impairments disease. Canonical pathological hallmarks, β-amyloid, tau, directly disrupt sleep, neurodegeneration locus coeruleus, hippocampal hypothalamic from tau proteinopathy causes circuitry sleep. Acting positive-feedback-loop, circadian rhythm then increase spread β-amyloid through proteasome, autophagy, unfolded response glymphatic This phenomenon extends beyond interactions impairment homeostasis TDP-43, α-synuclein, FUS, huntingtin proteins, implicating important consideration array diseases cases mixed neuropathology. Critically, dynamics this interaction environment are not fully elucidated deserving discussion research. Finally, we propose sleep-enhancing therapeutics potential interventions promoting healthy proteostasis, including clearance, mechanistically linking these processes. With clinical preclinical research, dynamic diagnostic therapeutic framework, informing precise single- combinatorial-treatments other brain disorders. Graphical

Language: Английский

Citations

28
Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition DOI Creative Commons
Elisenda Bueichekú, Ibai Díez, Chan Mi Kim

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: 4(5), P. 625 - 637

Published: April 25, 2024

Abstract Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer’s disease. By combining vivo longitudinal magnetic resonance imaging measures of LC integrity, positron emission tomography and cognition with autopsy data transcriptomic information, we examined whether changes precede deposition specific genetic features underlie LC’s selective vulnerability to tau. We found integrity preceded medial temporal lobe accumulation, together these processes were associated lower cognitive performance. Common gene expression profiles between LC–medial lobe–limbic map biological functions protein transport regulation. These findings advance our understanding spatiotemporal patterns initial spreading from disease pathology. can be a promising indicator for identifying time window when individuals are at risk progression underscore importance interventions mitigating spread.

Language: Английский

Citations

16
Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer’s disease and Parkinson’s disease DOI Creative Commons
Chen‐Pei Lin, Irene Frigerio,

John G. J. M. Bol

et al.

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Feb. 9, 2024

Abstract Background Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer’s disease (AD) and Parkinson’s (PD). Diffusion magnetic resonance imaging (MRI) has potential evaluate integrity LC system. The aim current study was determine whether diffusion MRI-measured its tracts are sensitive degeneration AD PD. Methods Post-mortem situ T1-weighted multi-shell MRI performed for 9 AD, 14 PD, 8 control brain donors. Fractional anisotropy (FA) mean diffusivity were derived from LC, between anterior cingulate cortex, dorsolateral prefrontal cortex (DLPFC), primary motor (M1) or hippocampus. Brain tissue sections cortical regions obtained immunostained dopamine-beta hydroxylase (DBH) quantify cell density fiber load. Group comparisons correlations outcome measures using linear regression partial correlations. Results PD cases showed loss cells fibers. In increased DBH + immunoreactivity DLPFC compared controls, while reduced M1 controls. Higher FA within found which correlated with fibers LC. Increased LC-DLPFC tract combined group, whereas LC-M1 neuronal group. alterations not immunoreactivity. Conclusions MRI-detected associated local rather than changes cortex.

Language: Английский

Citations

10
Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau DOI Creative Commons
Maxime Van Egroo, Joost M. Riphagen, Nicholas J. Ashton

et al.

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(6), P. 2412 - 2422

Published: April 5, 2023

Abstract Autopsy data indicate that the locus coeruleus (LC) is one of first sites in brain to accumulate hyperphosphorylated tau pathology, with rostral part possibly being more vulnerable earlier stages disease. Taking advantage recent developments ultra-high field (7 T) imaging, we investigated whether imaging measures LC also reveal a specific anatomic correlation using novel plasma biomarkers different species tau, how early adulthood these associations can be detected and if are associated worse cognitive performance. To validate correlations, tested rostro-caudal gradient pathology at autopsy from Rush Memory Aging Project (MAP). We found higher phosphorylated particular ptau 231 , correlated negatively dorso-rostral integrity, whereas correlations for neurodegenerative markers (neurofilament light, total tau) were scattered throughout including middle caudal sections. In contrast, Aβ 42/40 ratio, amyloidosis, did not correlate integrity. These findings observed when entire or hippocampus. Furthermore, MAP data, than tangle density LC, independent disease stage. The vivo LC-phosphorylated became significant midlife, earliest effect starting about age 55. Finally, interactions between lower integrity concentrations predicted Together, demonstrate vulnerability dedicated magnetic resonance measures, highlighting promise as an marker AD-related processes.

Language: Английский

Citations

22
Neuronal diversity of neuropeptide signaling, including galanin, in the mouse locus coeruleus DOI Creative Commons

Martino Caramia,

Roman A. Romanov, Spyridon Sideromenos

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(31)

Published: July 24, 2023

The locus coeruleus (LC) is a small nucleus in the pons from which ascending and descending projections innervate major parts of central nervous system. Its transmitter norepinephrine (NE). This system evolutionarily conserved, including humans, its functions are associated with wakefulness related to disorders, such as depression. Here, we performed single-cell ribonucleic acid-sequencing (RNA-seq) subdivide neurons LC (24 clusters total) into 3 NE, 17 glutamate, 5 γ-aminobutyric acid (GABA) subtypes, chart their neuropeptide, cotransmitter, receptor profiles. We found that NE expressed at least 19 neuropeptide transcripts, notably galanin (

Language: Английский

Citations

18
The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease DOI Creative Commons

Alexa F. Iannitelli,

Michael A. Kelberman, Daniel J. Lustberg

et al.

eNeuro, Journal Year: 2022, Volume and Issue: 10(1), P. ENEURO.0483 - 22.2022

Published: Dec. 9, 2022

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer's disease (AD) Parkinson's (PD), respectively. onset these pathologies coincides with loss fibers LC target regions emergence prodromal symptoms including sleep disturbances anxiety. Paradoxically, are indicative a hyperactivity phenotype, rather than predicted norepinephrine (NE) transmission following damage, suggesting engagement complex compensatory mechanisms. Because current therapeutic efforts targeting early disease, interest has grown, it critical to identify links between dysfunction. We employed LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages axons, model changes LC-NE system pertinent AD PD male female mice. DSP-4 (two doses 50 mg/kg, one week apart) induced axon degeneration, triggered neuroinflammation oxidative stress, reduced tissue NE levels. There was no cell death or firing, but transcriptomics revealed expression genes that define identity other relevant neurodegenerative disease. Despite dramatic fibers, turnover signaling were elevated terminal associated anxiogenic phenotypes multiple behavioral tests. These results represent comprehensive analysis how responds axon/terminal damage reminiscent at molecular, cellular, systems, levels, provides potential mechanisms underlying neuropsychiatric symptoms.

Language: Английский

Citations

23
Riddles in the dark: Decoding the relationship between neuromelanin and neurodegeneration in locus coeruleus neurons DOI Creative Commons

Alexa F. Iannitelli,

David Weinshenker

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 152, P. 105287 - 105287

Published: June 15, 2023

Language: Английский

Citations

15
Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions DOI Creative Commons
Dániel Veréb, Mite Mijalkov, Anna Canal‐Garcia

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: May 9, 2023

The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown the LC heterogeneous connections cellular features, no yet assessed functional topography vivo, how this heterogeneity changes over aging, whether it associated with cognition mood. Here, we employ gradient-based approach to characterize organization aging using 3T resting-state fMRI population-based cohort aged from 18 88 years age (Cambridge Centre for Ageing Neuroscience cohort, n=618). We show exhibits rostro-caudal gradient along longitudinal axis, which was replicated independent dataset (Human Connectome Project [HCP] 7T dataset, n=184). main direction consistent across groups, spatial features varied increasing age, emotional memory, emotion regulation. More specifically, loss rostral-like connectivity, more clustered topography, greater asymmetry between right left gradients higher worse behavioral performance. Furthermore, participants higher-than-normal Hospital Anxiety Depression Scale (HADS) ratings exhibited alterations as well, manifested asymmetry. These results provide vivo account imply are relevant markers LC-related measures psychopathology.

Language: Английский

Citations

13
Microstructural alterations in the locus coeruleus‐entorhinal cortex pathway in Alzheimer's disease and frontotemporal dementia DOI Creative Commons
Giulia Quattrini, Lorenzo Pini, Ilaria Boscolo Galazzo

et al.

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring, Journal Year: 2024, Volume and Issue: 16(1)

Published: Jan. 1, 2024

We investigated in vivo the microstructural integrity of pathway connecting locus coeruleus to transentorhinal cortex (LC-TEC) patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD).

Language: Английский

Citations

4