The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer’s disease

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

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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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ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer’s disease

Neuron, Journal Year: 2025, Volume and Issue: 113(5), P. 719 - 736.e5

Published: Jan. 14, 2025

Language: Английский

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Inflaming the Brain with Iron

Antioxidants, Journal Year: 2021, Volume and Issue: 10(1), P. 61 - 61

Published: Jan. 6, 2021

Iron accumulation and neuroinflammation are pathological conditions found in several neurodegenerative diseases, including Alzheimer’s disease (AD) Parkinson’s (PD). inflammation intertwined a bidirectional relationship, where iron modifies the inflammatory phenotype of microglia infiltrating macrophages, turn, these cells secrete diffusible mediators that reshape neuronal homeostasis regulate entry into brain. Secreted include cytokines reactive oxygen/nitrogen species (ROS/RNS), notably hepcidin nitric oxide (·NO). Hepcidin is small cationic peptide with central role regulating systemic homeostasis. Also present cerebrospinal fluid (CSF), can reduce export from neurons decreases through blood–brain barrier (BBB) by binding to exporter ferroportin 1 (Fpn1). Likewise, ·NO selectively converts cytosolic aconitase (c-aconitase) regulatory protein (IRP1), which regulates cellular its response elements (IRE) located mRNAs iron-related proteins. Nitric oxide-activated IRP1 impair during neuroinflammation, triggering accumulation, especially mitochondria, leading death. In this review, we will summarize findings connect support their causal association processes observed AD PD.

Language: Английский

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Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer’s Disease Patients

Frontiers in Systems Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: Sept. 24, 2021

Pathological proteins contributing to Alzheimer’s disease (AD) are known disrupt normal neuronal functions in the brain, leading unbalanced excitatory-inhibitory tone, distorted synchrony, and network oscillations. However, it has been proposed that abnormalities activity directly contribute pathogenesis of disease, fact demonstrated induction synchronized 40 Hz gamma oscillation networks by sensory stimulation reverses AD-related pathological markers transgenic mice carrying human genes. Based on these findings, current study evaluated whether non-invasive inducing cortical is clinically beneficial for AD patients. Patients with mild moderate ( n = 22) were randomized active treatment group 14; therapy) or sham 8). Participants received precisely timed, visual auditory stimulations during eye-closed condition induce steady-state oscillations 1-h daily sessions over a 6-month period. exposed similar designed not evoke observed During trial, nighttime activities patients monitored continuous actigraphy recordings, their functional abilities measured Disease Cooperative Study – Activities Daily Living (ADCS-ADL) scale. Results this therapy was well tolerated throughout period all subjects. receiving showed significantly reduced periods, contrast, deterioration sleep quality also expected, significant decline ADCS-ADL scores, whereas fully maintained These findings confirm safe application demonstrate high adherence treatment. Furthermore, first time clinical effects reported, justifying expanded longer trials explore additional benefits disease-modifying properties therapy. Clinical Trial Registration: clinicaltrials.gov , identifier: NCT03556280.

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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Neural consequences of chronic sleep disruption

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 45(9), P. 678 - 691

Published: June 9, 2022

Recent evidence in humans reveals that chronic sleep disruption can lead to protracted recovery of neurobehavioral performance, particularly sustained vigilance and episodic memory.Studies animal models demonstrate even incomplete recovery, including neuron loss brain areas critical for memory, specifically, the locus coeruleus hippocampus.The severity neural injury incurred by varies with duration type disruption, age at which exposure occurs, neuronal populations being assessed, genetic predisposition neurodegenerative processes.Early oxidative stress inflammation contribute a metabolic resetting, behavioral impairment, pathologic findings associated disruption. studies both call into question completeness after Studies have identified cognitive domains vulnerable delayed or memory. These findings, turn, provide focus model critically test lasting impact on brain. Here, we summarize human response then discuss recent examining responses circuits pertinent We propose pathways common various forms consider implications this aging disorders. Chronic humans: evolving thoughts recoveryChronic curtailment is modern society related part increased work demands, lifestyle choices, development use medications substances suppress disrupt sleep, addition artificial light-emitting devices delay sleep. A generally held presumption has been while results impairments, performance deficits are reversed limited-period (e.g., over weekend). collection loss, however, challenges belief suggests impairments persist, additionally, individuals may be poor judges their time. From 1 2 weeks restriction <7 h sleep/night adults shown repeatedly result cumulative increases propensity, along decrements mood [1.Dinges D.F. et al.Cumulative sleepiness, disturbance, psychomotor during week restricted 4-5 hours per night.Sleep. 1997; 20: 267-277PubMed Google Scholar, 2.Van Dongen H.P. al.The cost additional wakefulness: dose-response effects functions physiology from total deprivation.Sleep. 2003; 26: 117-126Crossref PubMed Scopus (2126) 3.Belenky G. al.Patterns degradation restoration subsequent recovery: study.J. Sleep Res. 12: 1-12Crossref (979) Scholar]. Objective subjective discrepancies, were evident, as study participants unaware progressive deterioration across Scholar,2.Van While (sleepiness mood) typically normalized 1–2 nights objective measures showed persistent deficits, relative baseline 2–3 [3.Belenky 4.Banks S. al.Neurobehavioral dynamics following restriction: one night recovery.Sleep. 2010; 33: 1013-1026Crossref 5.Pejovic al.Effects mild interleukin-6 cortisol secretion daytime sleepiness performance.Am. J. Physiol. Endocrinol. Metab. 2013; 305: E890-E896Crossref (105) similarly was evident adolescents [6.Lo J.C. successive cycles without naps adolescents.Sleep. 2017; 40zsw042Crossref (51) In young adults, impaired 5 days 4 h/night restriction, frequency lapses not despite 3 [7.Axelsson al.Sleepiness repeated semi-laboratory conditions.Chronobiol. Int. 2008; 25: 297-308Crossref (93) More recently, field conducted time reduced third 10 consecutive [8.Ochab J.K. al.Observing changes functioning induced deficiency periods.PLoS One. 2021; 16e0255771Crossref (0) Neither accuracy interference assay (Stroop) nor eyes-open alpha power spectra had 7-day period When deprived all 40 hours, resolved tasks requiring higher function reading comprehension, serial addition, go-no-go tasks) did normalize [9.Ikegami K. al.Recovery fatigue deprivation.J. Occup. Health. 2009; 51: 412-422Crossref (28) As deprivation overestimate own [10.Boardman J.M. ability self-monitor 60 sleep.J. 2018; 27e12633Crossref (12) vigilance, impairs memory hippocampal connectivity prefrontal cortex default mode network [11.Chai Y. al.Two restores but deprivation.Sci. Rep. 2020; 10: 8774Crossref (14) connectivity, persists. Collectively, these lines strongly support notion manifest imperceptions impairments. The latter finding contributed false sense security upon weekend sleep.Neurobehavioral largely attributed homeostatic wake-induced extracellular adenosine; levels readily reverse short-term [12.Porkka-Heiskanen T. al.Adenosine: mediator sleep-inducing prolonged wakefulness.Science. 276: 1265-1268Crossref (895) 13.Kalinchuk A.V. course adenosine, nitric oxide (NO) inducible NO synthase role non-rapid eye movement cascade.J. 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Neurosci. 2014; 34: 1879-1891Crossref By contrast, Thus, caused acute loss. However, presence recoveries partial absence elevations raises possibility sleep-loss-induced injury.Neural difficult assess predefined indices indicative glial modification, and/or dysfunction. This challenge illustrated series experiments performed three decades ago, aimed potential cell damage using methodologies available Adult extreme form weeks. resulted profound systemic (severe weight malnutrition, bacterial sepsis, hormonal dysregulation, ultimately death), yet examination brains immediately general histology, apoptosis, necrosis, yielded no significant abnormalities [19.Cirelli C. al.No degeneration long-term rats.Brain 1999; 840: 184-193Crossref Does mean does injure brain? would argue when defined impairment circuit dysfunction, analyses needed exclude injury.With improved definitions, assays strategies paradigm shift emerging, transition considering reversible response, greater appreciation Review, begin highlighting models, emphasizing more how reversibility influenced, only chronicity also exposure, interval used assessment, subtypes regions, propensity protein aggregation. review what learned regarding mechanisms suggest future directions identify therapies lessen commonly encountered scenarios disruption.Neural modelsConsideration paradigmsVarious modalities developed rapid (REM) fragmentation. There some inherent overlap modes For example, definition, includes REM methods impart non-REM (NREM) [20.Arthaud al.Paradoxical mice small-platforms-over-water method: polysomnographic melanin-concentrating hormone hypocretin/orexin activation before, 2015; 24: 309-319Crossref Scholar,21.Silva R.H. mice.Neuropharmacology. 2004; 46: 895-903Crossref (250) simple technique platform-over-water prevent depending size platforms animals studied. platform should adjusted so initiate disrupted, state-dependent reductions postural muscle tone falling water abruptly waking up. Larger control environment; show [22.Machado R.B. modified multiple technique: quantification recovery.Brain 1004: 45-51Crossref (285) Platform approaches elevated plasma corticosterone Scholar,23.Tobler I. effect rat.Neurosci. Lett. 1983; 35: 297-300Crossref Scholar,24.Suchecki D. al.Increased ACTH different paradoxical 1998; 7: 276-281Crossref Additionally, each continuum NREM patterns 24-h cycle.Most date, those discussed here, implemented physical means although it now possible elicit chemogenetic wake [25.Holth sleep-wake cycle regulates interstitial fluid tau CSF humans.Science. 2019; 363: 880-884Crossref (252) Scholar] or, potentially, inactivation circuits. Commonly paradigms types targeted Figure 1, advantages, disadvantages, confounding factors. there differences level arousal amount learning experienced where exploratory wakefulness induce robust immediate early gene wake-activated neurons, gentle handling same [26.Deurveilher al.Social environmental contexts modulate deprivation-induced c-Fos rats.Behav. Brain 256: 238-249Crossref (8) Exploratory locomotor activity, providing continuously enriched changing environment, involve other constant (or expected) environments. Techniques require continuous experimenter like handling, allow breakthrough automated systems rotating platform) intervene soon electroencephalographic detected computer algorithm [27.Leenaars C.H. al.A new method rat minimal activity.J. Methods. 196: 107-117Crossref Scholar,28.Deboer al.Long term mammalian circadian pacemaker.Sleep. 30: 257-262Crossref elicited either bar sweeping floor cage set intervals way rotor table briskly moves cages fraction every minute two. Methods fragment shorten amounts [29.Sinton al.Validation novel interrupt mouse.J. 184: 71-78Crossref approach effective long periods (weeks) seems influence body [30.Li wake-active neurons hypercapnic response.Sleep. 37: 51-64Crossref Scholar,31.Wallace E. al.Differential spatial synaptic plasticity pubertal mice.Brain 1615: 116-128Crossref (15) allows group housing, ad libitum eating drinking, access undisturbed nests. sweeper nests cannot maintained, group-housed. its strengths limitations, techniques provided similar results.Locus coeruleus: hitDelayed supports concept could affect within circuit, anterior cingulate cortical [32.Gompf H.S. al.Locus ceruleus sustain environment.J. 14543-14551Crossref (109) Locus (LCn) noradrenergic pontine firing rates highest unexpected uncertainties Scholar,33.Bliss-Moreau al.Anterior ablation affective vigor vigilance.J. 41: 8075-8087Crossref (4) change wakefulness, influences LCn. Upon brief (3 h) LCn adult upregulate mitochondrial deacetylase sirtuin (SirT3), initiates antioxidant maintain redox [34.Zhang al.Extended compromised metabolics neurons.J. 4418-4431Crossref (Figure 2) . 8 wakefulness/day environment paradigm, SirT3 activating enzymes upregulated develop stress, acetylation, acetylation electron transport chain proteins, counts Whether observed represent adaptation dysfunction injury, requires point further termination outlined above adaptive temporarily downregulate activity tyrosine hydroxylase; marker forementioned study. Of note, noradrenaline metabolites, 3,4-dihydroxyphenylglycoaldehyde, modifies tau, increasing aggregate propagate [35.Kang S.S. al.Norepinephrine metabolite DOPEGAL activates AEP pathological Tau aggregation coeruleus.J. Clin. Invest. 130: 422-437Crossref (26) hydroxylase faced restriction. According scenario, once reinstated, resume. continued 12 weeks, year counts, [36.Owen J.E. al.Late-in-life neurodegeneration mice.Sleep. 44zsab057Crossref (7) Scholar], indicating irreversible Similarly, whole-cell patch clamp recordings step currents after-hyperpolarization amplitudes supporting functional [37.Li hypercapneic remaining LCn, [38.Zhu al.Degeneration modeling apnea.Front. Neurol. 6: 109Crossref Not studies, One rats, instance, drum alternated enforced ambulation rest, days/week nonrotating drums [39.Deurveilher orexin/hypocretin, restriction.Eur. 54: 6027-6043Crossref count variability high controls, conceivable brevity prevented engaged protective wakefulness. output Rats task, [40.Lu H.J. Lv β-Adrenergic receptor dentate gyrus participates sleep-deprived rats.Exp. Neurobiol. 144-154Crossref Because unclear whether reduction represents dysfunction.Figure 2Duration-dependent (LCn).Show full captionShort-term [awake habitual (lights-on) period] upregulates (SirT3) nuclear translocation FoxO3a transcriptional antioxidants PGC-1α enhance biogenesis. extended (for day lights-on days) reduces NAD+-synthesizing enzymes, thereby (and inactivating) FoxO3a. Mechanisms switch maladaptive known.View Large Image ViewerDownload Hi-res image Download (PPT)Why disruption? status dictate vulnerability Mice deficient lower baseline, decline suggesting susceptible waking. second because exposures [41.Vankov A. al.Response novelty habituation exploring rat.Eur. 1995; 1180-1187Crossref (201) most active autoreceptor lowest, [42.Aston-Jones Bloom F.E. Activity norepinephrine-containing behaving anticipates fluctuations sleep-waking cycle.J. 1981; 1: 876-886Crossref Opening l-type calcium channels arousal, mitochondria activate calcium-dependent synthesis, impairing superoxide production [43.Sanchez-Padilla al.Mitochondrial oxidant regulated synthase.Nat. 17: 832-840Crossref (92) identification underlying (see Outstanding questions), determined implemented, resolve perturbance.Hippocampal disruptionIn humans, hippocampal-dependent persist Th

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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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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