The locus coeruleus (LC) is involved in the modulation of sleep and wakefulness. In humans, tau pathology develops in the LC decades before Alzheimer's disease (AD) cognitive symptoms manifest. Widespread LC degeneration is observed with disease progression; however, there is a paucity of research exploring the effect of tau pathology on the functional properties of LC neurons prior to cell death.
Objective
To investigate the intrinsic electrical properties of LC neurons in aged PS19 and rTg4510 tau transgenic murine models.
Methods
Whole cell recordings of LC neurons were performed in two murine models of tauopathy, the PS19 and rTg4510 strains, versus respective age-matched wildtype (WT) littermate controls.
Results
Basic LC neuronal properties were not significantly different from WT in either PS19 or rTg4510 mice at 9 months of age, which represents a stage where AD-like symptoms are evident, and tau pathology is present in the LC. However, the resting membrane potential of LC neurons was significantly depolarized in 9-month-old PS19 transgenic mice, compared to 5-month-old PS19 transgenic mice.
Conclusions
Tau pathology may act to accelerate aging, contributing to hyperactivity of the LC and consequent sleep disruption in patients with tauopathy.
LindvallOBjorklundA. Organization of ascending catecholamine neuron systems in rat-brain as revealed by glyoxylic-acid fluorescence method. Acta Physiol Scand1974; 412: 1–48.
2.
SalesACFristonKJJonesMW, et al.Locus coeruleus tracking of prediction errors optimises cognitive flexibility: an active inference model. PLoS Comput Biol2019; 15: e1006267.
3.
Aston-JonesGBloomFE. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle. J Neurosci1981; 1: 876–886.
4.
EschenkoOMagriCPanzeriS, et al.Noradrenergic neurons of the locus coeruleus are phase locked to cortical up-down states during sleep. Cereb Cortex2012; 22: 426–435.
5.
SaraSJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci2009; 10: 211–223.
6.
SaraSJBouretS. Orienting and reorienting: the locus coeruleus mediates cognition through arousal. Neuron2012; 76: 130–141.
7.
AkaikeT. Periodic bursting activities of locus coerulleus neurons in the rat. Brain Res1982; 239: 629–633.
8.
Aston-JonesGBloomFE. Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli. J Neurosci1981; 1: 887–900.
9.
CohenRMRezai-ZadehKWeitzTM, et al.A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci2013; 33: 6245–6256.
10.
RorabaughJMChalermpalanupapTBotz-ZappCA, et al.Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease. Brain2017; 140: 3023–3038.
11.
KelbermanMARorabaughJMAndersonCR, et al.Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimer's disease. Neurobiol Aging2023; 125: 98–108.
12.
WangZMGrinevichVMeekerWR, et al.Early signs of neuron autonomous and non-autonomous hyperexcitability in locus coeruleus noradrenergic neurons of a mouse model of tauopathy and Alzheimer's disease. Acta Physiol (Oxf)2025; 241: e70022.
13.
DownsAMKmiecGCataveroCM, et al.Loss of excitatory inputs and decreased tonic and evoked activity of locus coeruleus neurons in aged P301S mice. Neurobiol Dis2025; 208: 106883.
14.
KellySCCountsSEHeB, et al.Locus coeruleus cellular and molecular pathology during the progression of Alzheimer's disease. Acta Neuropathol Commun2017; 5: 8.
15.
VermeirenYJanssensJAertsT, et al.Brain serotonergic and noradrenergic deficiencies in behavioral variant frontotemporal dementia compared to early-onset Alzheimer's disease. J Alzheimers Dis2016; 53: 1079–1096.
16.
BenarrochEESchmeichelAMParisiJE. Depletion of mesopontine cholinergic and sparing of raphe neurons in multiple system atrophy. Neurology2002; 59: 944–946.
17.
HallidayGMHowePRCBlessingWW, et al.Neuropathology of immunohistochemically identified brainstem neurons in Parkinson's disease. Ann Neurol1990; 27: 373–385.
18.
ZweigRMRossCAHedreenJC, et al.Locus coeruleus involvement in Huntington's disease. Arch Neurol1992; 49: 152–156.
19.
GauthierSWebsterCServaesS, et al.World Alzheimer Report 2022: Life after diagnosis: Navigating treatment, care and support. London, England: Alzheimer's Disease International, 2022.
20.
BraakHAlafuzoffIArzbergerT, et al.Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol2006; 112: 389–404.
BraakHDel TrediciK. Spreading of tau pathology in sporadic Alzheimer's disease along cortico-cortical top-down connections. Cereb Cortex2018; 28: 3372–3384.
23.
BondareffWMountjoyCQRothM. Selective loss of neurones of origin of adrenergic projection to cerebral cortex (nucleus locus coeruleus) in senile dementia. Lancet1981; 317: 783–784.
24.
Chan-PalayV. Alterations in catecholamine neurons in the locus coeruleus in dementias of Alzheimer's and Parkinson's diseases. J Neural Transm Park Dis Dement Sect1989; 1: 19–20.
25.
HoogendijkWJGPoolCWVan ZwietenE, et al.Image analyser-assisted morphometry of the locus coeruleus in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Brain1995; 118: 131–143.
26.
TheofilasPEhrenbergAJDunlopS, et al.Locus coeruleus volume and cell population changes during Alzheimer's disease progression: a stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement2017; 13: 236–246.
27.
ZhuYFenikPZhanG, et al.Intermittent short sleep results in lasting sleep wake disturbances and degeneration of locus coeruleus and orexinergic neurons. Sleep2016; 39: 1601–1611.
28.
ZhuYZhanGFenikP, et al.Chronic sleep disruption advances the temporal progression of tauopathy in P301S mutant mice. J Neurosci2018; 38: 10255.
29.
MatthewsKLChenCPEsiriMM, et al.Noradrenergic changes, aggressive behavior, and cognition in patients with dementia. Biol Psychiatry2002; 51: 407–416.
30.
ParentJHCiampaCJHarrisonTM, et al.Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging. Neuroimage2022; 263: 119658.
31.
LiuLHWangWHLuoSP, et al.Degenerative alterations in noradrenergic neurons of the locus coeruleus in Alzheimer's disease. Neural Regen Res2013; 8: 2249–2255.
32.
GermanDCNelsonOLiangFEN, et al.The PDAPP mouse model of alzheimer's disease: locus coeruleus neuronal shrinkage. J Comp Neurol2005; 492: 469–476.
33.
KalininSPolakPELinSX, et al.The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease. Neurobiol Aging2012; 33: 1651–1663.
34.
HenekaMTDumitrescu-OzimekLKlockgetherT, et al.Noradrenergic depletion potentiates β-amyloid-induced cortical inflammation: implications for Alzheimer's disease. J Neurosci2002; 22: 2434–2442.
35.
HenekaMTNadrignyFRegenT, et al.Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A2010; 107: 6058–6063.
36.
KalininSGavrilyukVPolakPE, et al.Noradrenaline deficiency in brain increases β-amyloid plaque burden in an animal model of Alzheimer's disease. Neurobiol Aging2007; 28: 1206–1214.
37.
CaoSFisherDRodriguezG, et al.Comparisons of neuroinflammation, microglial activation, and degeneration of the locus coeruleus-norepinephrine system in APP/PS1 and aging mice. J Neuroinflammation2021; 18: 10.
38.
Jardanhazi-KurutzDKummerMPTerwelD, et al.Distinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in APP/PS1 transgenic mice. Neuroscience2011; 176: 396–407.
39.
RamsdenMKotilinekLPaulsonJ, et al.Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci2005; 25: 10637–10647.
40.
YoshiyamaYHiguchiMZhangB, et al.Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron2007; 53: 337–351.
41.
DongQPtáčekLJFuYH. Mutant β(1)-adrenergic receptor improves REM sleep and ameliorates tau accumulation in a mouse model of tauopathy. Proc Natl Acad Sci U S A2023; 120: e2221686120.
42.
KeenanRJOberrauchSChallisLM, et al.Decreased orexin receptor 1 mRNA expression in the locus coeruleus in both tau transgenic rTg4510 and tau knockout mice and accompanying ascending arousal system tau invasion in rTg4510. J Alzheimers Dis2021; 79: 693–708.
43.
DejanovicBHuntleyMADe MazièreA, et al.Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron2018; 100: 1322–1336.e1327.
44.
MartinSCJoyceKKLordJS, et al.Sleep disruption precedes forebrain synaptic tau burden and contributes to cognitive decline in a sex-dependent manner in the P301S tau transgenic mouse model. eNeuro2024; 11: ENEURO.0004–24.2024.
45.
SantaCruzKLewisJSpiresT, et al.Tau suppression in a neurodegenerative mouse model improves memory function. Science2005; 309: 476–481.
46.
GamacheJKemperLHlynialukC, et al.Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice. Nat Commun2019; 10: 2479.
47.
GuzmanSJSchlöglASchmidt-HieberC. Stimfit: quantifying electrophysiological data with Python. Front Neuroinform2014; 8: 16.
48.
McKinneyAHuMHoskinsA, et al.Cellular composition and circuit organization of the locus coeruleus of adult mice. Elife2023; 12: e80100.
49.
ChandlerDJGaoWJWaterhouseBD. Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices. Proc Natl Acad Sci U S A2014; 111: 6816–6821.
50.
ChalermpalanupapTSchroederJPRorabaughJM, et al.Locus coeruleus ablation exacerbates cognitive deficits, neuropathology, and lethality in P301S tau transgenic mice. J Neurosci2018; 38: 74–92.
51.
DownsAMCataveroCMKastenMR, et al.Tauopathy and alcohol consumption interact to alter locus coeruleus excitatory transmission and excitability in male and female mice. Alcohol2023; 107: 97–107.
52.
SaharaNYanaiR. Limitations of human tau-expressing mouse models and novel approaches of mouse modeling for tauopathy. Front Neurosci2023; 17: 1149761.
53.
BaileyRMHowardJKnightJ, et al.Effects of the C57BL/6 strain background on tauopathy progression in the rTg4510 mouse model. Mol Neurodegener2014; 9: 8.
54.
OhJEserRAEhrenbergAJ, et al.Profound degeneration of wake-promoting neurons in Alzheimer's disease. Alzheimers Dement2019; 15: 1253–1263.
55.
LiSBDamonteVMWangGX, et al.Hyperexcitable arousal circuits drive sleep instability during aging. Science2022; 375: eabh3021.
56.
BroekaartDWMSharmaARamakrishnanA, et al.Molecular signatures of regional vulnerability to tauopathy in excitatory cortical neurons. Acta Neuropathol2025; 149: 60.
57.
CriminsJLRocherABLuebkeJI. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol2012; 124: 777–795.
58.
AdolfssonRGottfriesCGRoosBE, et al.Changes in the brain catecholamines in patients with dementia of Alzheimer type. Br J Psychiatry1979; 135: 216–223.
59.
HoogendijkWJFeenstraMGBotterblomMH, et al.Increased activity of surviving locus ceruleus neurons in Alzheimer's disease. Ann Neurol1999; 45: 82–91.
60.
PalmerAMFrancisPTBowenDM, et al.Monoaminergic innervation of the frontal and temporal lobes in Alzheimer's disease. Brain Res1987; 401: 231–238.
61.
AtzoriMCuevas-OlguinREsquivel-RendonE, et al.Locus ceruleus norepinephrine release: a central regulator of CNS spatio-temporal activation?Front Synaptic Neurosci2016; 8: 25.
62.
McCall JordanGAl-HasaniRSiuda EdwardR, et al.CRH Engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron2015; 87: 605–620.
63.
GrantMMWeissJM. Effects of chronic antidepressant drug administration and electroconvulsive shock on locus coeruleus electrophysiologic activity. Biol Psychiatry2001; 49: 117–129.
64.
ZhuMYKlimekVDilleyGE, et al.Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry1999; 46: 1275–1286.
65.
ZubenkoGSMoossyJ. Major depression in primary dementia. Clinical and neuropathologic correlates. Arch Neurol1988; 45: 1182–1186.
66.
WeinshenkerD. Long road to ruin: noradrenergic dysfunction in neurodegenerative disease. Trends Neurosci2018; 41: 211–223.
67.
PalopJJChinJRobersonED, et al.Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron2007; 55: 697–711.
68.
Alcantara-GonzalezDKennedyMCriscuoloC, et al.Increased excitability of dentate gyrus mossy cells occurs early in life in the Tg2576 model of Alzheimer's disease. Alzheimers Res Ther2025; 17: 105.
69.
LisgarasCPScharfmanHE. Interictal spikes in Alzheimer's disease: preclinical evidence for dominance of the dentate gyrus and cholinergic control by the medial septum. Neurobiol Dis2023; 187: 106294.
70.
MusaeusCSFrederiksenKSAndersenBB, et al.Detection of subclinical epileptiform discharges in Alzheimer's disease using long-term outpatient EEG monitoring. Neurobiol Dis2023; 183: 106149.
71.
BakkerAKraussGLAlbertMS, et al.Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron2012; 74: 467–474.
72.
OrlandoIFShineJMRobbinsTW, et al.Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing. Neurosci Biobehav Rev2023; 149: 105167.
73.
WuJToporekALinQ, et al.Probing locus coeruleus functional network in healthy aging and its association with Alzheimer’s disease biomarkers using pupillometry. Alzheimers Res Ther2025; 17: 53.
74.
WienkeCGrueschowMHaghikiaA, et al.Phasic, event-related transcutaneous auricular vagus nerve stimulation modifies behavioral, pupillary, and low-frequency oscillatory power responses. J Neurosci2023; 43: 6306.
75.
KeenanRJDaykinHMethaJ, et al.Orexin 2 receptor antagonism sex-dependently improves sleep/wakefulness and cognitive performance in tau transgenic mice. Br J Pharmacol2024; 181: 87–106.
76.
HolthJKMahanTERobinsonGO, et al.Altered sleep and EEG power in the P301S tau transgenic mouse model. Ann Clin Transl Neurol2017; 4: 180–190.
77.
KronJOJKeenanRJHoyerD, et al.Orexin receptor antagonism: normalizing sleep architecture in old age and disease. Annu Rev Pharmacol Toxicol2024; 64: 359–386.
78.
HirokiTMichiyoIHaruhisaI, et al.P301s mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. PLoS One2011; 6: e21050.
79.
Targa Dias AnastacioHMatosinNOoiL. Neuronal hyperexcitability in Alzheimer's disease: what are the drivers behind this aberrant phenotype?Transl Psychiatry2022; 12: 257.
80.
IbaMGuoJLMcBrideJD, et al.Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci2013; 33: 1024–1037.
81.
Van Den PolANGhoshPKLiuRJ, et al.Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP-expressing locus coeruleus. Journal of Physiology2002; 541: 169–185.
82.
WilliamsJTNorthRAShefnerSA, et al.Membrane properties of rat locus coeruleus neurones. Neuroscience1984; 13: 137–156.
83.
ShimizuNOhnishiSSatohK, et al.Cellular organization of locus coeruleus in the rat as studied by Golgi method. Arch Histol Jpn1978; 41: 103–112.
84.
SwansonLW. The locus coeruleus: a cytoarchitectonic, Golgi and immunohistochemical study in the albino rat. Brain Res1976; 110: 39–56.
85.
OkatyBWSturrockNEscobedo LozoyaY, et al.A single-cell transcriptomic and anatomic atlas of mouse dorsal raphe Pet1 neurons. Elife2020; 9: e55523.
86.
EberwineJBartfaiT. Single cell transcriptomics of hypothalamic warm sensitive neurons that control core body temperature and fever response signaling asymmetry and an extension of chemical neuroanatomy. Pharmacol Ther2011; 129: 241–259.
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