The Locus Coeruleus in Aging and Alzheimer’s Disease: A Postmortem and Brain Imaging Review

Journal of Alzheimer s Disease, Journal Year: 2021, Volume and Issue: 83(1), P. 5 - 22

Published: July 3, 2021

The locus coeruleus (LC), a tiny nucleus in the brainstem and principal site of noradrenaline synthesis, has major role regulating autonomic function, arousal, attention, neuroinflammation. LC dysfunction been linked to range disorders; however particular interest is given it plays Alzheimer’s disease (AD). undergoes significant neuronal loss AD, thought occur early process. While also suggested aging, this relationship less clear as findings have contradictory. density be indicative cognitive reserve evidence for these claims will discussed. Recent imaging techniques allowing visualization vivo using neuromelanin-sensitive MRI are developing our understanding aging AD. Tau pathology within evident at an age most individuals; however, between tau accumulation why some individuals then develop AD not understood. Neuromelanin pigment accumulates cells with proposed toxic inflammatory when released into extracellular environment. This review explore current knowledge changes both from postmortem, imaging, experimental studies. We discuss reasons behind susceptibility loss, focus on neuromelanin neuroinflammation caused by LC-noradrenaline pathway.

Language: Английский

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Alzheimer’s disease: A clinical perspective and future nonhuman primate research opportunities

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(52), P. 26224 - 26229

Published: Dec. 23, 2019

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that the sixth leading cause of death and most common dementia worldwide. Over last few decades, significant advancements have been made in our understanding AD by investigating molecular mechanisms underlying amyloid-β tau pathology. Despite this progress, no disease-modifying treatments exist for AD, an issue will exacerbated rising costs prevalence disorder. Moreover, effective therapies to address devastating cognitive behavioral symptoms are also urgently needed. This perspective focuses on value nonhuman primate (NHP) models bridging molecular, circuit, levels analysis better understand complex genetic environmental/lifestyle factors contribute pathogenesis. These investigations could provide opportunity translating pathogenesis physiological related disorders into new diagnostic approaches prevent or restore brain function symptomatic individuals.

Language: Английский

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A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

Brain, Journal Year: 2021, Volume and Issue: 145(6), P. 1924 - 1938

Published: Dec. 14, 2021

Abstract The locus coeruleus is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration dementia. Locus dysfunction contributes to pathobiology experimental models, which can be rescued increasing norepinephrine transmission. To test augmentation as a potential disease-modifying therapy, we performed biomarker-driven phase II trial atomoxetine, clinically-approved transporter inhibitor, subjects mild cognitive impairment due disease. design was single-centre, 12-month double-blind crossover trial. Thirty-nine participants and biomarker evidence were randomized atomoxetine or placebo treatment. Assessments collected at baseline, 6- (crossover) 12-months (completer). Target engagement assessed CSF plasma measures metabolites. Prespecified primary outcomes levels IL1α TECK. Secondary/exploratory included clinical measures, analyses amyloid-β42, Tau, pTau181, mass spectrometry proteomics immune-based targeted inflammation-related cytokines, well brain imaging MRI fluorodeoxyglucose-PET. Baseline demographic similar across arms. Dropout rates 5.1% for 2.7% placebo, no significant differences adverse events. Atomoxetine robustly increased levels. IL-1α TECK not measurable most samples. There treatment effects on cognition outcomes, expected given short duration. associated reduction pTau181 compared but change amyloid-β42. also significantly altered abundances protein panels linked pathophysiologies, including synaptic, metabolism glial immunity, CDCP1, CD244, TWEAK osteoprotegerin proteins. Treatment brain-derived neurotrophic factor reduced triglycerides plasma. Resting state functional showed inter-network connectivity between insula hippocampus. Fluorodeoxyglucose-PET atomoxetine-associated uptake hippocampus, parahippocampal gyrus, middle temporal pole, inferior gyrus fusiform carry-over 6 months after In summary, safe, tolerated achieved target prodromal pTau, normalized synaptic function, activity key lobe circuits. Further study warranted repurposing drug slow progression.

Language: Английский

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Associations among locus coeruleus catecholamines, tau pathology, and memory in aging

Neuropsychopharmacology, Journal Year: 2022, Volume and Issue: 47(5), P. 1106 - 1113

Published: Jan. 15, 2022

Language: Английский

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Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(5), P. 2182 - 2196

Published: Jan. 15, 2023

Abstract The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau‐associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction cortical lesions. Accumulating evidence supports role behavioral neuropsychiatric manifestations featured AD. Experimental studies even suggest that AD‐associated drives brain neuroinflammatory status contributes to progression, including exacerbation Given important pathophysiologic etiologic roles involve AD stages, there is an urgent need expand our understanding mechanisms underlying vulnerability more precisely detail clinical progression changes Here, Professional Interest Area International Society Advance Research Treatment highlights knowledge gaps about within provides recommendations priorities specific research, biomarker development, modeling, intervention. Highlights Neuromodulatory degenerate pathological stages. pathophysiology exacerbated by degeneration. symptoms dementia. Biomarkers integrity would be value‐creating dementia care. present strategic prospects disease‐modifying therapies.

Language: Английский

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Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition

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

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Impact of high-fat diet on cognitive behavior and central and systemic inflammation with aging and sex differences in mice

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 118, P. 334 - 354

Published: Feb. 24, 2024

Language: Английский

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Chronic Sleep Disruption Advances the Temporal Progression of Tauopathy in P301S Mutant Mice

Journal of Neuroscience, Journal Year: 2018, Volume and Issue: 38(48), P. 10255 - 10270

Published: Oct. 15, 2018

Brainstem locus ceruleus neurons (LCn) are among the first across lifespan to evidence tau pathology, and LCn implicated in propagation throughout cortices. Yet, events influencing poorly understood. Activated persistently wakefulness, experience significant metabolic stress response chronic short sleep (CSS). Here we explored whether CSS influences biochemical, neuroanatomical, and/or behavioral progression of tauopathy male female P301S mice. early adult life advanced temporal neurobehavioral impairments resulted a lasting increase soluble oligomers. Intriguingly, an AT8 MC1 pathology LC. Over time including tangles, was evident forebrain tau-vulnerable regions. Sustained microglial astrocytic activation observed as well. Remarkably, loss two regions examined: basolateral amygdala A second, distinct form disruption, fragmentation sleep, during also increased deposition imparted impairment. Collectively, findings demonstrate that disruption has important effects on mice, hastening neurodegeneration, neuroinflammation, impairments. SIGNIFICANCE STATEMENT Chronic (CSS) is pervasive modern society. Here, found behavioral, neuroanatomic aspects mouse model mutation. Specifically, hastened onset motor impairment greater both basolateral/lateral amygdala. Importantly, despite protracted recovery opportunity after CSS, mice evidenced sustained pathogenic oligomers, limbic system nuclei. These unveil habits determinant tauopathy.

Language: Английский

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Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease

Neurobiology of Disease, Journal Year: 2020, Volume and Issue: 146, P. 105089 - 105089

Published: Sept. 22, 2020

Adrenergic systems regulate both cognitive function and immune function. The primary source of adrenergic signaling in the brain is norepinephrine (NE) neurons locus coeruleus (LC), which are vulnerable to age-related degeneration one earliest sites pathology neurodegenerative disorders such as Alzheimer's Disease (AD). Loss tone may potentiate neuroinflammation aging conditions. Importantly, beta-blockers (beta-adrenergic antagonists) a common treatment for hypertension, co-morbid with aging, further exacerbate associated loss central nervous system (CNS). present studies were designed examine proinflammatory consequences beta-blocker administration an acute lipopolysaccharide (LPS) model well chronic effects on behavior amyloid-beta protein precursor (APP) mouse AD. We provide evidence robust potentiation peripheral inflammation 4 different LPS. However, did not CNS this model. Notably, same model, genetic knockdown either beta1- or beta2-adrenergic receptors microglia inflammation. Furthermore, APP amyloid pathology, beta-blocker, metoprolol, also induced markers phagocytosis impaired wild-type mice. Given induction vivo, we examined synaptosomes vitro culture showed that enhanced whereas beta-adrenergic agonists inhibited synaptosomes. In conclusion, potentiated peripherally systemic centrally amyloidosis neuroinflammation. Additionally, learning memory modulated synaptic implications degeneration. These findings warrant consideration administration, restricted periphery patients disorders.

Language: Английский

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Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

Journal of Neuroscience Research, Journal Year: 2020, Volume and Issue: 98(12), P. 2406 - 2434

Published: Sept. 1, 2020

Abstract Locus coeruleus (LC) is the main noradrenergic (NA) nucleus of central nervous system. LC degenerates early during Alzheimer's disease (AD) and NA loss might concur to AD pathogenesis. Aside from neurons, terminals provide dense innervation brain intraparenchymal arterioles/capillaries, modulates astrocyte functions. The term neurovascular unit (NVU) defines strict anatomical/functional interaction occurring between glial cells, vessels. NVU plays a fundamental role in coupling energy demand activated regions with regional cerebral blood flow, it includes blood–brain barrier (BBB), an active neuroinflammation, participates also glymphatic alteration involved pathophysiology through several mechanisms, mainly related relative oligoemia impairment structural functional BBB integrity, which contributes intracerebral accumulation insoluble amyloid. We review existing data on morphological features LC‐NA NVU, as well its contribution proper functioning. After introducing experimental linking AD, have repeatedly shown key neuroinflammation increased amyloid plaque formation, we discuss potential mechanisms by modulation contribute Surprisingly, thus far not so many studies tested directly these models has been lesioned experimentally. Clarifying pathogenesis may disclose therapeutic targets for AD.

Language: Английский

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