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

Fluorescent Sensing Platforms for Detecting and Imaging the Biomarkers of Alzheimer’s Disease DOI Creative Commons
Xingyun Liu, Yibiao Liu, Qiong Liu

et al.

Biosensors, Journal Year: 2023, Volume and Issue: 13(5), P. 515 - 515

Published: April 30, 2023

Alzheimer’s disease (AD) is an irreversible neurodegenerative with clinical symptoms of memory loss and cognitive impairment. Currently, no effective drug or therapeutic method available for curing this disease. The major strategy used to identify block AD at its initial stage. Thus, early diagnosis very important intervention the assessment efficacy. gold standards include measurement biomarkers in cerebrospinal fluid positron emission tomography imaging brain amyloid-β (Aβ) deposits. However, these methods are difficult apply general screening a large aging population because their high cost, radioactivity inaccessibility. Comparatively, blood sample detection less invasive more accessible AD. Hence, variety assays based on fluorescence analysis, surface-enhanced Raman scattering, electrochemistry, etc., were developed blood. These play significant roles recognizing asymptomatic predicting course In setting, combination biomarker may enhance accuracy diagnosis. Fluorescence-sensing techniques can be not only detect levels but also image real time due low toxicity, sensitivity good biocompatibility. review, we summarize newly fluorescent sensing platforms application detecting AD, such as Aβ tau last five years, discuss prospects applications.

Language: Английский

Citations

5
Sparse Asymmetry in Locus Coeruleus Pathology in Alzheimer’s Disease DOI Creative Commons
Elise Beckers, Joost M. Riphagen, Maxime Van Egroo

et al.

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 99(1), P. 105 - 111

Published: April 12, 2024

Tau accumulation in and neurodegeneration of locus coeruleus (LC) neurons is observed Alzheimer's disease (AD). We investigated whether tangle neuronal density the rostral caudal LC characterized by an asymmetric pattern 77 autopsy cases Rush Memory Aging Project. found left-right equivalence for across individuals with without AD pathology. However, density, particularly caudal-rostral axis LC, among Asymmetry may signal advanced progression should be considered neuroimaging studies neurodegeneration.

Language: Английский

Citations

1
Lower in vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer’s pathology: a cohort study DOI Creative Commons
Nina Engels, Elouise A. Koops, Stephanie Hsieh

et al.

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: June 17, 2024

Abstract Background Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition accompanied by reduced density of LC projections and reduction norepinephrine’s neuroprotective effects, potentially compromising neuronal integrity LC’s cortical targets. Previous studies suggest lower magnetic resonance imaging (MRI)-derived may signal tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven underlying AD pathology remains unknown. To end, we examined potential effect modifications beta-amyloid on association between vivo integrity, as quantified MRI intensity, neurodegeneration, indexed thickness. Methods A total 165 individuals (74.24 ± 9.72 years, ~ 60% female, 10% impaired) underwent whole-brain dedicated 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors ( n = 2000) assessed associations bilateral thickness i) intensity and, ii) interacted FTP or PiB (i.e., EC FTP, IT neocortical PiB) entire sample low subsample. Results Across sample, found direct effect, where was associated mediolateral temporal Evaluation revealed related thickness, particularly elevated (EC, IT) (neocortical) PiB. The latter result present starting from subthreshold values. In individuals, context FTP. Conclusions Our findings LC-related neurodegeneration patterns correspond representing Braak stages reflect combination projection loss emergence pathology. provides novel understanding downstream consequences AD-related pathology, rather than being exclusively aging.

Language: Английский

Citations

1
Elevated locus coeruleus metabolism provides resilience against cognitive decline in preclinical Alzheimer's disease DOI Creative Commons
Elouise A. Koops, Joyita Dutta, Bernard Hanseeuw

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 26, 2024

Alterations in locus coeruleus' (LC) metabolic turnover are associated with Alzheimer's disease (AD)-pathology and cognitive impairment. However, the evolution of these changes across stages their functional relevance remains unknown.

Language: Английский

Citations

1
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

Citations

7