The Contribution of the Locus Coeruleus-Noradrenaline System Degeneration during the Progression of Alzheimer's Disease.

Mercan, Dilek; Heneka, Michael

doi:10.3390/biology11121822

Article (Scientific journals)

The Contribution of the Locus Coeruleus-Noradrenaline System Degeneration during the Progression of Alzheimer's Disease.

Mercan, Dilek; Heneka, Michael

2022 • In Biology, 11 (12)

Peer Reviewed verified by ORBi

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https://hdl.handle.net/10993/54166

DOI
10.3390/biology11121822

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36552331

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Keywords :

Alzheimer’s disease; cognition; locus coeruleus; neurodegeneration; neuroinflammation; noradrenaline; norepinephrine

Abstract :

[en] Alzheimer's disease (AD), which is characterized by extracellular accumulation of amyloid-beta peptide and intracellular aggregation of hyperphosphorylated tau, is the most common form of dementia. Memory loss, cognitive decline and disorientation are the ultimate consequences of neuronal death, synapse loss and neuroinflammation in AD. In general, there are many brain regions affected but neuronal loss in the locus coeruleus (LC) is one of the earliest indicators of neurodegeneration in AD. Since the LC is the main source of noradrenaline (NA) in the brain, degeneration of the LC in AD leads to decreased NA levels, causing increased neuroinflammation, enhanced amyloid and tau burden, decreased phagocytosis and impairment in cognition and long-term synaptic plasticity. In this review, we summarized current findings on the locus coeruleus-noradrenaline system and consequences of its dysfunction which is now recognized as an important contributor to AD progression.

Disciplines :

Neurology

Author, co-author :

Mercan, Dilek

Heneka, Michael ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) ; University of Massachusetts Medical School > Division of Infectious Diseases and Immunology

External co-authors :

yes

Language :

English

Title :

The Contribution of the Locus Coeruleus-Noradrenaline System Degeneration during the Progression of Alzheimer's Disease.

Publication date :

2022

Journal title :

Biology

ISSN :

2079-7737

Publisher :

Multidisciplinary Digital Publishing Institute (MDPI), Switzerland

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

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since 26 January 2023

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Bibliography

World Alzheimer Reports Available online: https://www.alz.co.uk/research/world-report (accessed on 20 December 2019)
Kawas C. Gray S. Brookmeyer R. Fozard J. Zonderman A. Age-specific incidence rates of Alzheimer’s disease Neurology 2000 54 2072 2077 10.1212/WNL.54.11.2072 10851365
Huang H.-C. Jiang Z.-F. Accumulated Amyloid-β Peptide and Hyperphosphorylated Tau Protein: Relationship and Links in Alzheimer’s Disease J. Alzheimer’s Dis. 2009 16 15 27 10.3233/JAD-2009-0960 19158417
Yankner B.A. Mesulam M.-M. β-Amyloid and the Pathogenesis of Alzheimer’s Disease N. Engl. J. Med. 1991 325 1849 1857
Roher A.E. Esh C.L. Kokjohn T.A. Castaño E.M. Van Vickle G.D. Kalback W.M. Patton R.L. Luehrs D.C. Daugs I.D. Kuo Y. et al. Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer’s disease Alzheimer’s Dement. 2009 5 18 29 10.1016/j.jalz.2008.10.004
Ludewig S. Korte M. Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity Front. Mol. Neurosci. 2017 9 161 10.3389/fnmol.2016.00161 28163673
Kögel D. Deller T. Behl C. Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging Exp. Brain Res. 2011 217 471 479 10.1007/s00221-011-2932-4 22086493
Mockett B.G. Richter M. Abraham W.C. Müller U.C. Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα Front. Mol. Neurosci. 2017 10 30 10.3389/fnmol.2017.00030
Sasmita A.O. Current viral-mediated gene transfer research for treatment of Alzheimer’s disease Biotechnol. Genet. Eng. Rev. 2018 35 26 45 10.1080/02648725.2018.1523521
Polanco J.C. Li C. Bodea L.-G. Martinez-Marmol R. Meunier F.A. Gotz J. Amyloid-β and tau complexity—Towards improved biomarkers and targeted therapies Nat. Rev. Neurol. 2017 14 22 39 10.1038/nrneurol.2017.162
Olsson F. Schmidt S. Althoff V. Munter L. Jin S. Rosqvist S. Lendahl U. Multhaup G. Lundkvist J. Characterization of Intermediate Steps in Amyloid Beta (Aβ) Production under Near-native Conditions J. Biol. Chem. 2014 289 1540 1550 10.1074/jbc.M113.498246
Hefter D. Kaiser M. Weyer S.W. Papageorgiou I.E. Both M. Kann O. Muller U.C. Draguhn A. Amyloid Precursor Protein Protects Neuronal Network Function after Hypoxia via Control of Volt-age-Gated Calcium Channels J. Neurosci. 2016 36 8356 8371 10.1523/JNEUROSCI.4130-15.2016 27511009
Grimm M.O.W. Grosgen S. Rothhaar T.L. Burg V.K. Hundsdorfer B. Haupenthal V.J. Friess P. Muller U. Fassbender K. Riemenschneider M. et al. Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer’s Disease Int. J. Alzheimer’s Dis. 2011 2011 1 8 10.4061/2011/695413 21660213
Tarasoff-Conway J.M. Carare R.O. Osorio R.S. Glodzik L. Butler T. Fieremans E. Axel L. Rusinek H. Nicholson C. Zlokovic B.V. et al. Clearance systems in the brain-implications for Alzheimer disease Nat. Rev. Neurol. 2015 11 457 470 10.1038/nrneurol.2015.119 26195256
Li Q.-X. Fuller S.J. Beyreuther K. Masters C.L. The amyloid precursor protein of Alzheimer disease in human brain and blood J. Leukoc. Biol. 1999 66 567 574 10.1002/jlb.66.4.567
Bali J. Gheinani A.H. Zurbriggen S. Rajendran L. Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides Proc. Natl. Acad. Sci. USA 2012 109 15307 15311 10.1073/pnas.1201632109
Bird T.D. Genetic aspects of Alzheimer disease Anesthesia Analg. 2008 10 231 239 10.1097/GIM.0b013e31816b64dc
Tanzi R.E. The genetics of Alzheimer disease Cold Spring Harb. Perspect. Med. 2012 2 a006296 10.1101/cshperspect.a006296
Mandelkow E.-M. Mandelkow E. Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration Cold Spring Harb. Perspect. Med. 2012 2 a006247 10.1101/cshperspect.a006247
Iqbal K. Liu F. Gong C.-X. Grundke-Iqbal I. Tau in Alzheimer Disease and Related Tauopathies Curr. Alzheimer Res. 2010 7 656 664 10.2174/156720510793611592
Barron M. Gartlon J. Dawson L.A. Atkinson P.J. Pardon M.-C. A state of delirium: Deciphering the effect of in-flammation on tau pathology in Alzheimer’s disease Exp. Gerontol. 2017 94 103 107 10.1016/j.exger.2016.12.006
Niewiadomska G. Niewiadomski W. Steczkowska M. Gasiorowska A. Tau Oligomers Neurotoxicity Life 2021 11 28 10.3390/life11010028 33418848
Yamada K. Cirrito J.R. Stewart F.R. Jiang H. Finn M.B. Holmes B. Binder L.I. Mandelkow E.-M. Diamond M.I. Lee V.M.-Y. et al. In Vivo Microdialysis Reveals Age-Dependent Decrease of Brain Interstitial Fluid Tau Levels in P301S Human Tau Transgenic Mice J. Neurosci. 2011 31 13110 13117 10.1523/JNEUROSCI.2569-11.2011 21917794
Yamada K. Holth J.K. Liao F. Stewart F.R. Mahan T. Jiang H. Cirrito J.R. Patel T.K. Hochgräfe K. Mandelkow E.-M. et al. Neuronal activity regulates extracellular tau in vivo J. Exp. Med. 2014 211 387 393 10.1084/jem.20131685 24534188
Evans L.D. Wassmer T. Fraser G. Smith J. Perkinton M. Billinton A. Livesey F.J. Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways Cell Rep. 2018 22 3612 3624 10.1016/j.celrep.2018.03.021
Ittner L.M. Fath T. Ke Y.D. Bi M. van Eersel J. Li K.M. Gunning P. Götz J. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia Proc. Natl. Acad. Sci. USA 2008 105 15997 16002 10.1073/pnas.0808084105
Li B. Chohan M.O. Grundke-Iqbal I. Iqbal K. Disruption of microtubule network by Alzheimer abnormally hyper-phosphorylated tau Acta Neuropathol. 2007 113 501 511 10.1007/s00401-007-0207-8
Hoover B.R. Reed M.N. Su J. Penrod R.D. Kotilinek L.A. Grant M.K. Pitstick R. Carlson G.A. Lanier L.M. Yuan L.-L. et al. Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegen-eration Neuron 2010 68 1067 1081 10.1016/j.neuron.2010.11.030
Walters A. Phillips E. Zheng R. Biju M. Kuruvilla T. Evidence for neuroinflammation in Alzheimer’s disease: Neu-roinflammation in Alzheimer’s Prog. Neurol. Psychiatry 2016 20 25 31 10.1002/pnp.444
Tuppo E.E. Arias H.R. The role of inflammation in Alzheimer’s disease Int. J. Biochem. Cell Biol. 2005 37 289 305 10.1016/j.biocel.2004.07.009
McGeer P.L. McGeer E.G. The inflammatory response system of brain: Implications for therapy of Alzheimer and other neurodegenerative diseases Brain Res. Rev. 1995 21 195 218 10.1016/0165-0173(95)00011-9
Akiyama H. Barger S. Barnum S. Bradt B. Bauer J. Cole G.M. Cooper N.R. Eikelenboom P. Emmerling M. Fiebich B.L. et al. Inflammation and Alzheimer’s disease Neurobiol. Aging 2000 39 383 421 10.1016/S0197-4580(00)00124-X 10858586
Dansokho C. Heneka M.T. Neuroinflammatory responses in Alzheimer’s disease J. Neural. Transm. 2017 125 771 779 10.1007/s00702-017-1831-7 29273951
Kinney J.W. Bemiller S.M. Murtishaw A.S. Leisgang A.M. Salazar A.M. Lamb B.T. Inflammation as a central mechanism in Alzheimer’s disease Alzheimer’s Dement. Transl. Res. Clin. Interv. 2018 4 575 590 10.1016/j.trci.2018.06.014 30406177
Sarlus H. Heneka M.T. Microglia in Alzheimer’s disease J. Clin. Investig. 2017 127 3240 3249 10.1172/JCI90606
Ginhoux F. Greter M. Leboeuf M. Nandi S. See P. Gokhan S. Mehler M.F. Conway S.J. Ng L.G. Stanley E.R. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages Science 2010 330 841 845 10.1126/science.1194637
Hoeffel G. Ginhoux F. Ontogeny of Tissue-Resident Macrophages Front. Immunol. 2015 6 486 10.3389/fimmu.2015.00486
Ginhoux F. Guilliams M. Tissue-Resident Macrophage Ontogeny and Homeostasis Immunity 2016 44 439 449 10.1016/j.immuni.2016.02.024
Aguzzi A. Barres B.A. Bennett M.L. Microglia: Scapegoat, Saboteur, or Something Else? Science 2013 339 156 161 10.1126/science.1227901
Ransohoff R.M. A polarizing question: Do M1 and M2 microglia exist? Nat. Neurosci. 2016 19 987 991 10.1038/nn.4338
Lenz K.M. McCarthy M.M. A Starring Role for Microglia in Brain Sex Differences Neuroscientist 2015 21 306 321 10.1177/1073858414536468
Sierra A. Encinas J.M. Deudero J.J.P. Chancey J. Enikolopov G. Wadiche L. Tsirka S.E. Maletic-Savatic M. Microglia Shape Adult Hippocampal Neurogenesis through Apoptosis-Coupled Phagocytosis Cell. Stem. Cell. 2010 7 483 495 10.1016/j.stem.2010.08.014 20887954
Wake H. Moorhouse A.J. Jinno S. Kohsaka S. Nabekura J. Resting Microglia Directly Monitor the Functional State of Synapses In Vivo and Determine the Fate of Ischemic Terminals J. Neurosci. 2009 29 3974 3980 10.1523/JNEUROSCI.4363-08.2009 19339593
Paolicelli R.C. Bolasco G. Pagani F. Maggi L. Scianni M. Panzanelli P. Giustetto M. Ferreira T.A. Guiducci E. Dumas L. et al. Synaptic Pruning by Microglia Is Necessary for Normal Brain Development Science 2011 333 1456 1458 10.1126/science.1202529 21778362
Hristovska I. Pascual O. Deciphering Resting Microglial Morphology and Process Motility from a Synaptic Prospect Front. Integr. Neurosci. 2016 9 73 10.3389/fnint.2015.00073
Davalos D. Grutzendler J. Yang G. Kim J.V. Zuo Y. Jung S. Littman D.R. Dustin M.L. Gan W.-B. ATP mediates rapid microglial response to local brain injury in vivo Nat. Neurosci. 2005 8 752 758 10.1038/nn1472
Tremblay M.-È. Stevens B. Sierra A. Wake H. Bessis A. Nimmerjahn A. The Role of Microglia in the Healthy Brain J. Neurosci. 2011 31 16064 16069 10.1523/JNEUROSCI.4158-11.2011
Nimmerjahn A. Kirchhoff F. Helmchen F. Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Paren-chyma in Vivo Science 2005 308 1314 1318 10.1126/science.1110647
Bolmont T. Haiss F. Eicke D. Radde R. Mathis C.A. Klunk W. Kohsaka S. Jucker M. Calhoun M.E. Dynamics of the Microglial/Amyloid Interaction Indicate a Role in Plaque Maintenance J. Neurosci. 2008 28 4283 4292 10.1523/JNEUROSCI.4814-07.2008
Graeber M.B. Tetzlaff W. Streit W.J. Kreutzberg G.W. Microglial cells but not astrocytes undergo mitosis following rat facial nerve axotomy Neurosci. Lett. 1988 85 317 321 10.1016/0304-3940(88)90585-X
Mrak R.E. Microglia in Alzheimer Brain: A Neuropathological Perspective Int. J. Alzheimer’s Dis. 2012 2012 1 6 10.1155/2012/165021
Colonna M. Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration Annu. Rev. Immunol. 2017 35 441 468 10.1146/annurev-immunol-051116-052358 28226226
Czeh M. Gressens P. Kaindl A.M. The Yin and Yang of Microglia Dev. Neurosci. 2011 33 199 209 10.1159/000328989 21757877
Serpente M. Bonsi R. Scarpini E. Galimberti D. Innate Immune System and Inflammation in Alzheimer’s Disease: From Pathogenesis to Treatment Neuroimmunomodulation 2014 21 79 87 10.1159/000356529 24557039
Monje M.L. Toda H. Palmer T.D. Inflammatory Blockade Restores Adult Hippocampal Neurogenesis Science 2003 302 1760 1765 10.1126/science.1088417 14615545
Waisman A. Liblau R.S. Becher B. Innate and adaptive immune responses in the CNS Lancet Neurol. 2015 14 945 955 10.1016/S1474-4422(15)00141-6 26293566
Heneka M.T. Kummer M. Latz E. Innate immune activation in neurodegenerative disease Nat. Rev. Immunol. 2014 14 463 477 10.1038/nri3705
Sochocka M. Diniz B.S. Leszek J. Inflammatory Response in the CNS: Friend or Foe? Mol. Neurobiol. 2017 54 8071 8089 10.1007/s12035-016-0297-1
Baik S.H. Kang S. Son S.M. Mook-Jung I. Microglia contributes to plaque growth by cell death due to uptake of am-yloid β in the brain of Alzheimer’s disease mouse model: Aβ Plaque Formation and Microglial Activation Glia 2016 64 2274 2290 10.1002/glia.23074
Stalder M. Phinney A. Probst A. Sommer B. Staufenbiel M. Jucker M. Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice Am. J. Pathol. 1999 154 1673 1684 10.1016/S0002-9440(10)65423-5
Bard F. Cannon C. Barbour R. Burke R.-L. Games D. Grajeda H. Guido T. Hu K. Huang J. Johnson-Wood K. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease Nat. Med. 2000 6 916 919 10.1038/78682
Hickman S.E. Allison E.K. El Khoury J. Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer’s Disease Mice J. Neurosci. 2008 28 8354 8360 10.1523/JNEUROSCI.0616-08.2008 18701698
Kummer M.P. Vogl T. Axt D. Griep A. Vieira-Saecker A. Jessen F. Gelpi E. Roth J. Heneka M.T. Mrp14 Deficiency Ameliorates Amyloid Burden by Increasing Microglial Phagocytosis and Modula-tion of Amyloid Precursor Protein Processing J. Neurosci. 2012 32 17824 17829 10.1523/JNEUROSCI.1504-12.2012 23223301
Bisht K. Sharma K.P. Lecours C. Gabriela Sanchez M. El Hajj H. Milior G. Olmos-Alonso A. Gomez-Nicola D. Luheshi G. Vallieres L. et al. Dark microglia: A new phenotype predominantly associated with pathological states: A New Microglial Phenotype Glia 2016 64 826 839 10.1002/glia.22966 26847266
Martini A.C. Helman A.M. Mccarty K.L. Lott I.T. Doran E. Schmitt F.A. Head E. Distribution of microglial phenotypes as a function of age and Alzheimer’s disease neuropathology in the brains of people with Down syndrome Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2020 12 e12113 10.1002/dad2.12113
Keren-Shaul H. Spinrad A. Weiner A. Matcovitch-Natan O. Dvir-Szternfeld R. Ulland T.K. David E. Baruch K. Lara-Astaiso D. Toth B. et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease Cell 2017 169 1276 1290 10.1016/j.cell.2017.05.018
Chen Y. Colonna M. Microglia in Alzheimer’s disease at single-cell level. Are there common patterns in humans and mice? J. Exp. Med. 2021 218 e20202717 10.1084/jem.20202717
Paolicelli R.C. Sierra A. Stevens B. Tremblay M.-E. Aguzzi A. Ajami B. Amit I. Audinat E. Bechmann I. Bennett M. et al. Microglia states and nomenclature: A field at its crossroads Neuron 2022 110 3458 3483 10.1016/j.neuron.2022.10.020
Heneka M.T. Carson M.J. El Khoury J. Landreth G.E. Brosseron F. Feinstein D.L. Jacobs A.H. Wyss-Coray T. Vitorica J. Ransohoff R.M. et al. Neuroinflammation in Alzheimer’s disease Lancet Neurol. 2015 14 388 405 10.1016/S1474-4422(15)70016-5
Patel N.S. Paris D. Mathura V. Quadros A.N. Crawford F.C. Mullan M.J. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease J. Neuroinflammation 2005 2 9 10 10.1186/1742-2094-2-9
Lue L.-F. Rydel R. Brigham E.F. Yang L.-B. Hampel H. Murphy G.M. Brachova L. Yan S.-D. Walker D.G. Shen Y. et al. Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro Glia 2001 35 72 79 10.1002/glia.1072
Prieto G.A. Tong L. Smith E.D. Cotman C.W. TNFα and IL-1β but not IL-18 Suppresses Hippocampal Long-Term Potentiation Directly at the Synapse Neurochem. Res. 2018 44 49 60 10.1007/s11064-018-2517-8 29619614
Liu X. Quan N. Microglia and CNS Interleukin-1: Beyond Immunological Concepts Front. Neurol. 2018 9 8 10.3389/fneur.2018.00008 29410649
Hewett S.J. Csernansky C.A. Choi D.W. Selective potentiation of NMDA-induced neuronal injury following induc-tion of astrocytic iNOS Neuron 1994 13 487 494 10.1016/0896-6273(94)90362-X 7520256
Amaral D.G. Sinnamon H.M. The locus coeruleus: Neurobiology of a central noradrenergic nucleus Prog. Neurobiol. 1977 9 147 196 10.1016/0301-0082(77)90016-8
Berridge C.W. Waterhouse B.D. The locus coeruleus–noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes Brain Res. Rev. 2003 42 33 84 10.1016/S0165-0173(03)00143-7 12668290
Ishikawa M. Tanaka C. Morphological organization of catecholamine terminals in the diencephalon of the rhesus monkey Brain Res. 1977 119 43 55 10.1016/0006-8993(77)90090-7
Jones B.E. Yang T.-Z. The efferent projections from the reticular formation and the locus coeruleus studied by antero-grade and retrograde axonal transport in the rat J. Comp. Neurol. 1985 242 56 92 10.1002/cne.902420105
Osaka T. Matsumura H. Noradrenergic inputs to sleep-related neurons in the preoptic area from the locus coeruleus and the ventrolateral medulla in the rat Neurosci. Res. 1994 19 39 50 10.1016/0168-0102(94)90006-X
Modirrousta M. Mainville L. Jones B.E. Gabaergic neurons with α2-adrenergic receptors in basal forebrain and preop-tic area express c-Fos during sleep Neuroscience 2004 129 803 810 10.1016/j.neuroscience.2004.07.028
Swanson L.W. E Sawchenko P. Hypothalamic Integration: Organization of the Paraventricular and Supraoptic Nuclei Annu. Rev. Neurosci. 1983 6 269 324 10.1146/annurev.ne.06.030183.001413
Proudfit H. Clark F. The projections of locus coeruleus neurons to the spinal cord Prog. Brain Res. 1991 88 123 141 10.1016/s0079-6123(08)63803-0 1813919
Olson L. Fuxe K. On the projections from the locus coeruleus noradrealine neurons: The cerebellar innervation Brain Res. 1971 28 165 171 10.1016/0006-8993(71)90533-6 4104275
Chandler D.J. Waterhouse B.D.P.D. Evidence for Broad Versus Segregated Projections from Cholinergic and Noradrenergic Nuclei to Functionally and Anatomically Discrete Subregions of Prefrontal Cortex Front. Behav. Neurosci. 2012 6 20 10.3389/fnbeh.2012.00020 22661934
Chandler D.J. Lamperski C.S. Waterhouse B.D. Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex Brain Res. 2013 1522 38 58 10.1016/j.brainres.2013.04.057
Chandler D.J. Gao W.-J. Waterhouse B.D. Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices Proc. Natl. Acad. Sci. USA 2014 111 6816 6821 10.1073/pnas.1320827111
Breton-Provencher V. Drummond G.T. Sur M. Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets Front. Neural Circuits 2021 15 46 10.3389/fncir.2021.638007
Hammerschmidt T. Kummer M.P. Terwel D. Martinez A. Gorji A. Pape H.-C. Rommelfanger K.S. Schroeder J.P. Stoll M. Schultze J. et al. Selective Loss of Noradrenaline Exacerbates Early Cognitive Dysfunction and Synaptic Deficits in APP/PS1 Mice Biol. Psychiatry 2013 73 454 463 10.1016/j.biopsych.2012.06.013
Sara S.J. The locus coeruleus and noradrenergic modulation of cognition Nat. Rev. Neurosci. 2009 10 211 223 10.1038/nrn2573
Sara S.J. Bouret S. Orienting and Reorienting: The Locus Coeruleus Mediates Cognition through Arousal Neuron 2012 76 130 141 10.1016/j.neuron.2012.09.011
Mason S.T. Fibiger H.C. Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase J. Comp. Neurol. 1979 187 703 724 10.1002/cne.901870405
Waterhouse B.D. Lin C.S. Burne R.A. Woodward D.J. The distribution of neocortical projection neurons in the locus coeruleus J. Comp. Neurol. 1983 217 418 431 10.1002/cne.902170406 6886061
Schwarz L.A. Luo L. Organization of the Locus Coeruleus-Norepinephrine System Curr. Biol. 2015 25 R1051 R1056 10.1016/j.cub.2015.09.039 26528750
Atzori M. Cuevas-Olguin R. Esquivel-Rendon E. Garcia-Oscos F. Salgado-Delgado R.C. Saderi N. Miranda-Morales M. Trevino M. Pineda J.C. Salgado H. Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation? Front. Synaptic Neurosci. 2016 8 25 10.3389/fnsyn.2016.00025 27616990
Aston-Jones G. Bloom F. Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle J. Neurosci. 1981 1 876 886 10.1523/JNEUROSCI.01-08-00876.1981 7346592
Aston-Jones G. Bloom F.E. Norepinephrine-containing locus coeruleus neurons in behaving rats exhibit pronounced responses to non-noxious environmental stimuli J. Neurosci. 1981 1 887 900 10.1523/JNEUROSCI.01-08-00887.1981
Hobson J.A. McCarley R.W. Wyzinski P.W. Sleep Cycle Oscillation: Reciprocal Discharge by Two Brainstem Neuronal Groups Science 1975 189 55 58 10.1126/science.1094539
Foote S.L. Aston-Jones G. Bloom F.E. Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal Proc. Natl. Acad. Sci. USA 1980 77 3033 3037 10.1073/pnas.77.5.3033
Iijima K. An immunocytochemical study on the GABA-ergic and serotonin-ergic neurons in rat locus ceruleus with special reference to possible existence of the masked indoleamine cells Acta Histochem. 1989 87 43 57 10.1016/S0065-1281(89)80029-7
McLean J.H. Shipley M.T. Nickell W.T. Aston-Jones G. Reyher C.K.H. Chemoanatomical organization of the nor-adrenergic input from locus coeruleus to the olfactory bulb of the adult rat J. Comp. Neurol. 1989 285 339 349 10.1002/cne.902850305
Olpe H.-R. Steinmann M. Responses of locus coeruleus neurons to neuropeptides Prog. Brain Res. 1991 88 241 248 10.1016/s0079-6123(08)63813-3
Simpson K. Waterhouse B. Lin R. Origin, distribution, and morphology of galaninergic fibers in the rodent trigeminal system J. Comp. Neurol. 1999 411 524 534 10.1002/(SICI)1096-9861(19990830)411:3<524::AID-CNE13>3.0.CO;2-X
Bylund D. Bylund K. Norepinephrine Encyclopedia of the Neurological Sciences Elsevier Amsterdam, The Netherlands 2014 614 616 10.1016/B978-0-12-385157-4.00047-6
Wassall R. Teramoto N. Cunnane T. Noradrenaline Encyclopedia of Neuroscience Squire L.R. Academic Press Cambridge, MA, USA 2009 1221 1230 10.1016/B978-008045046-9.00681-1
Benarroch E.E. The locus ceruleus norepinephrine system: Functional organization and potential clinical significance Neurology 2009 73 1699 1704 10.1212/WNL.0b013e3181c2937c 19917994
Lewis D.A. The Catecholaminergic Innervation of Primate Prefrontal Cortex Advances in Neuroscience and Schizophrenia Tuma A.H. Springer Berlin/Heidelberg, Germany 1992
Foote S.L. Morrison J.H. Extrathalamic modulation of cortical function Annu. Rev. Neurosci. 1987 10 67 95 10.1146/annurev.ne.10.030187.000435 3551766
Ramos B.P. Arnsten A.F. Adrenergic pharmacology and cognition: Focus on the prefrontal cortex Pharmacol. Ther. 2007 113 523 536 10.1016/j.pharmthera.2006.11.006 17303246
Waterhouse B.D. Devilbiss D. Fleischer D. Sessler F.M. Simpson K.L. New Perspectives on the Functional Organi-zation and Postsynaptic Influences of the Locus Ceruleus Efferent Projection System Advances in Pharmacology Elsevier Amsterdam, The Netherlands 1997 Volume 42 749 754
Sirviö J. MacDonald E. Central α1-adrenoceptors: Their role in the modulation of attention and memory formation Pharmacol. Ther. 1999 83 49 65 10.1016/S0163-7258(99)00017-0 10501595
Goldman-Rakic P. Lidow M. Gallager D. Overlap of dopaminergic, adrenergic, and serotoninergic receptors and com-plementarity of their subtypes in primate prefrontal cortex J. Neurosci. 1990 10 2125 2138 10.1523/JNEUROSCI.10-07-02125.1990
Minneman K.P. Pittman R.N. Molinoff P.B. Beta-Adrenergic Receptor Subtypes: Properties, Distribution, and Regulation Annu. Rev. Neurosci. 1981 4 419 461 10.1146/annurev.ne.04.030181.002223
Tully K. Bolshakov V.Y. Emotional enhancement of memory: How norepinephrine enables synaptic plasticity Mol. Brain 2010 3 15 10.1186/1756-6606-3-15
Murugaiah K. O’Donnell J. Beta adrenergic receptors facilitate norepinephrine release from rat hypothalamic and hip-pocampal slices Res. Commun. Mol. Pathol. Pharmacol. 1995 90 179 190
Samuels E.R. Szabadi E.R.S.A.E. Functional Neuroanatomy of the Noradrenergic Locus Coeruleus: Its Roles in the Regulation of Arousal and Autonomic Function Part I: Principles of Functional Organisation Curr. Neuropharmacol. 2008 6 235 253 10.2174/157015908785777229
Sara S.J. Locus Coeruleus in time with the making of memories Curr. Opin. Neurobiol. 2015 35 87 94 10.1016/j.conb.2015.07.004 26241632
Harley C.W. Norepinephrine and dopamine as learning signals Neural Plast. 2004 11 191 204 10.1155/NP.2004.191 15656268
Roozendaal B. Mcgaugh J. Memory Modulation Behav. Neurosci. 2011 125 797 824 10.1037/a0026187 22122145
Ferry B. Parrot S. Marien M. Lazarus C. Cassel J.-C. McGaugh J.L. Noradrenergic influences in the basolateral amygdala on inhibitory avoidance memory are mediated by an action on α2-adrenoceptors Psychoneuroendocrinology 2014 51 68 79 10.1016/j.psyneuen.2014.09.010
Tanaka T. Yokoo H. Mizoguchi K. Yoshida M. Tsuda A. Tanaka M. Noradrenaline release in the rat amygdala is increased by stress: Studies with intracerebral microdialysis Brain Res. 1991 544 174 176 10.1016/0006-8993(91)90902-8 1855137
Galvez R. Mesches M.H. Mcgaugh J.L. Norepinephrine Release in the Amygdala in Response to Footshock Stimula-tion Neurobiol. Learn. Mem. 1996 66 253 257 10.1006/nlme.1996.0067
McIntyre C.K. Hatfield T. McGaugh J.L. Amygdala norepinephrine levels after training predict inhibitory avoidance retention performance in rats: Amygdala norepinephrine predicts long-term memory Eur. J. Neurosci. 2002 16 1223 1226 10.1046/j.1460-9568.2002.02188.x
McGaugh J.L. Introini-Collison I.B. Cahill L.F. Castellano C. Dalmaz C. Parent M.B. Williams C.L. Neuromodulatory systems and memory storage: Role of the amygdala Behav. Brain Res. 1993 58 81 90 10.1016/0166-4328(93)90092-5
Van Stegeren A.H. The role of the noradrenergic system in emotional memory Acta Psychologica 2008 127 532 541 10.1016/j.actpsy.2007.10.004
McGaugh J.L. The Amygdala Modulates the Consolidation of Memories of Emotionally Arousing Experiences Annu. Rev. Neurosci. 2004 27 1 28 10.1146/annurev.neuro.27.070203.144157
Stanton P. Sarvey J. Depletion of norepinephrine, but not serotonin, reduces long-term potentiation in the dentate gy-rus of rat hippocampal slices J. Neurosci. 1985 5 2169 2176 10.1523/JNEUROSCI.05-08-02169.1985 4040556
Hopkins W. Johnston D. Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocam-pus Science 1984 226 350 352 10.1126/science.6091272 6091272
Hopkins W.F. Johnston D. Noradrenergic enhancement of long-term potentiation at mossy fiber synapses in the hip-pocampus J. Neurophysiol. 1988 59 667 687 10.1152/jn.1988.59.2.667 2832552
O’Dell T.J. Connor S.A. Gelinas J.N. Nguyen P.V. Viagra for your synapses: Enhancement of hippocampal long-term potentiation by activation of beta-adrenergic receptors Cell. Signal. 2010 22 728 736 10.1016/j.cellsig.2009.12.004 20043991
Salgado H. Treviño M. Atzori M. Layer- and area-specific actions of norepinephrine on cortical synaptic transmission Brain Res. 2016 1641 163 176 10.1016/j.brainres.2016.01.033 26820639
Ito M. Long-Term Depression: Cerebellum Encyclopedia of Neuroscience Squire L.R. Academic Press Cambridge, MA, USA 2009 533 539 10.1016/B978-008045046-9.00807-X
Trevino M. Frey S. Kohr G. Alpha-1 Adrenergic Receptors Gate Rapid Orientation-Specific Reduction in Visual Dis-crimination Cerebral Cortex 2012 22 2529 2541 10.1093/cercor/bhr333
Scheiderer C.L. Dobrunz L.E. McMahon L.L. Novel Form of Long-Term Synaptic Depression in Rat Hippocampus Induced by Activation of α1 Adrenergic Receptors J. Neurophysiol. 2004 91 1071 1077 10.1152/jn.00420.2003
Marien M.R. Colpaert F.C. Rosenquist A.C. Noradrenergic mechanisms in neurodegenerative diseases: A theory Brain Res. Rev. 2004 45 38 78 10.1016/j.brainresrev.2004.02.002
Braak H. Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty Acta Neuropathol. 2010 121 171 181 10.1007/s00401-010-0789-4
Braak H. Del Tredici K. Alzheimer’s pathogenesis: Is there neuron-to-neuron propagation? Acta Neuropathol. 2011 121 589 595 10.1007/s00401-011-0825-z
Grudzien A. Shaw P. Weintraub S. Bigio E. Mash D.C. Mesulam M.M. Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alz-heimer’s disease Neurobiol. Aging 2007 28 327 335 10.1016/j.neurobiolaging.2006.02.007 16574280
Bondareff W. Mountjoy C.Q. Roth M. Rossor M.N. Iversen L.L. Reynolds G.P. Hauser D.L. Neuronal Degeneration in Locus Ceruleus and Cortical Correlates of Alzheimer Disease Alzheimer Dis. Assoc. Disord. 1987 1 256 262 10.1097/00002093-198701040-00005 3453748
Matthews K.L. Chen C.P.-H. Esiri M.M. Keene J. Minger S.L. Francis P.T. Noradrenergic changes, aggressive behavior, and cognition in patients with dementia Biol. Psychiatry 2002 51 407 416 10.1016/S0006-3223(01)01235-5 11904135
Palmer A.M. Wilcock G.K. Esiri M.M. Francis P.T. Bowen D.M. Monoaminergic innervation of the frontal and temporal lobes in Alzheimer’s disease Brain Res. 1987 401 231 238 10.1016/0006-8993(87)91408-9 2434191
Mann D.M.A. Lincoln J. Yates P.O. Stamp J.E. Toper S. Changes in the Monoamine Containing Neurones of the Human Cns in Senile Dementia Br. J. Psychiatry 1980 136 533 541 10.1192/bjp.136.6.533
Adolfsson R. Gottfries C.G. Roos B.E. Winblad B. Gartner J. Langford A. O’Brien A. Hosang G.M. Fisher H.L. Hodgson K. et al. Changes in the Brain Catecholamines in Patients with Dementia of Alzheimer Type Br. J. Psychiatry 1979 135 216 223 10.1192/bjp.135.3.216
Šimic G. Leko M.B. Wray S. Harrington C.R. Delalle I. Jovanov-Milosevic N. Bavzadona D. Buee L. De Silva R. Di Giovanni G. et al. Monoaminergic neuropathology in Alzheimer’s disease Prog. Neurobiol. 2017 151 101 138 10.1016/j.pneurobio.2016.04.001
Manaye K.F. McIntire D.D. Mann D.M.A. German D.C. Locus coeruleus cell loss in the aging human brain: A non-random process J. Comp. Neurol. 1995 358 79 87 10.1002/cne.903580105
Gulyás B. Brockschnieder D. Nag S. Pavlova E. Kasa P. Beliczai Z. Legradi A. Gulya K. Thiele A. Dyrks T. et al. The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer’s disease: A post-mortem autoradiographic study Neurochem. Int. 2010 56 789 798 10.1016/j.neuint.2010.03.001
Gannon M. Wang Q. Complex noradrenergic dysfunction in Alzheimer’s disease: Low norepinephrine input is not always to blame Brain Res. 2019 1702 12 16 10.1016/j.brainres.2018.01.001
Vincent S. Norepinephrine Transporter Encyclopedia of Endocrine Diseases Martini L. Elsevier Amsterdam, The Netherlands 2004 382 386 10.1016/B0-12-475570-4/00928-8
Zhou J. Norepinephrine transporter inhibitors and their therapeutic potential Drugs Future 2004 29 1235 1244 10.1358/dof.2004.029.12.855246 16871320
Jardanhazi-Kurutz D. Kummer M. Terwel D. Vogel K. Dyrks T. Thiele A. Heneka M.T. Induced LC degeneration in APP/PS1 transgenic mice accelerates early cerebral amyloidosis and cognitive deficits Neurochem. Int. 2010 57 375 382 10.1016/j.neuint.2010.02.001 20144675
Ross S.B. Stenfors C. DSP4, a Selective Neurotoxin for the Locus Coeruleus Noradrenergic System. A Review of Its Mode of Action Neurotox. Res. 2014 27 15 30 10.1007/s12640-014-9482-z 24964753
Heneka M.T. Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Trans-genic Mice J. Neurosci. 2006 26 1343 1354 10.1523/JNEUROSCI.4236-05.2006
Kummer M.P. Hermes M. Delekarte A. Hammerschmidt T. Kumar S. Terwel D. Walter J. Pape H.-C. König S. Roeber S. et al. Nitration of Tyrosine 10 Critically Enhances Amyloid β Aggregation and Plaque Formation Neuron 2011 71 833 844 10.1016/j.neuron.2011.07.001
Heneka M.T. Nadrigny F. Regen T. Martinez-Hernandez A. Dumitrescu-Ozimek L. Terwel D. Jardanhazi-Kurutz D. Walter J. Kirchhoff F. Hanisch U.-K. et al. Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine Proc. Natl. Acad. Sci. USA 2010 107 6058 6063 10.1073/pnas.0909586107
Kummer M.P. Hammerschmidt T. Martinez A. Terwel D. Eichele G. Witten A. Figura S. Stoll M. Schwartz S. Pape H.-C. et al. Ear2 Deletion Causes Early Memory and Learning Deficits in APP/PS1 Mice J. Neurosci. 2014 34 8845 8854 10.1523/JNEUROSCI.4027-13.2014
Chalermpalanupap T. Schroeder J.P. Rorabaugh J.M. Liles L.C. Lah J.J. Levey A.I. Weinshenker D. Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice J. Neurosci. 2017 38 74 92 10.1523/JNEUROSCI.1483-17.2017
Szot P. Miguelez C. White S. Franklin A. Sikkema C. Wilkinson C. Ugedo L. Raskind M. A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat Neuroscience 2010 166 279 291 10.1016/j.neuroscience.2009.12.027
Weinshenker D. Miller N.S. Blizinsky K. Laughlin M.L. Palmiter R.D. Mice with chronic norepinephrine deficiency resemble amphetamine-sensitized animals Proc. Natl. Acad. Sci. USA 2002 99 13873 13877 10.1073/pnas.212519999
Warnecke M. Oster H. Revelli J.-P. Alvarez-Bolado G. Eichele G. Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception Genes Dev. 2005 19 614 625 10.1101/gad.317905 15741322
Heneka M.T. Dumitrescu-Ozimek L. Klockgether T. Feinstein D.L. Galea E. Gavrilyak V. Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: Implications for Alzheimer’s disease J. Neurosci. 2002 22 2434 2442 10.1523/JNEUROSCI.22-07-02434.2002 11923407
Heneka M.T. Gavrilyuk V. Landreth G.E. O’Banion M.K. Weinberg G. Feinstein D.L. Noradrenergic depletion increases inflammatory responses in brain: Effects on IκB and HSP70 expres-sion: PPARγ agonist reduce brain inflammatory responses J. Neurochem. 2003 85 387 398 10.1046/j.1471-4159.2003.01694.x 12675915
Pugh P.L. Vidgeon-Hart M.P. Ashmeade T. Culbert A.A. Seymour Z. Perren M.J. Joyce F. Bate S.T. Babin A. Virley D.J. et al. Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and prese-nilin-1 mutant transgenes J. Neuroinflammation 2007 4 8 10.1186/1742-2094-4-8
Kalinin S. Gavrilyuk V. Polak P.E. Vasser R. Zhao J. Heneka M.T. Feinstein D.L. Noradrenaline deficiency in brain increases β-amyloid plaque burden in an animal model of Alzheimer’s disease Neurobiol. Aging 2007 28 1206 1214 10.1016/j.neurobiolaging.2006.06.003
Jardanhazi-Kurutz D. Kummer M.P. Terwel D. Vogel K. Thiele A. Heneka M.T. Distinct adrenergic system changes and neuroinflammation in response to induced locus ce-ruleus degeneration in APP/PS1 transgenic mice Neuroscience 2011 176 396 407 10.1016/j.neuroscience.2010.11.052
Rey N.L. Jardanhazi-Kurutz D. Terwel D. Kummer M.P. Jourdan F. Didier A. Heneka M.T. Locus coeruleus degeneration exacerbates olfactory deficits in APP/PS1 transgenic mice Neurobiol. Aging 2012 33 426.e1 426.e11 10.1016/j.neurobiolaging.2010.10.009
Kang S.S. Liu X. Ahn E.H. Xiang J. Manfredsson F.P. Yang X. Luo H.R. Liles L.C. Weinshenker D. Ye K. Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus J. Clin. Investig. 2019 130 422 437 10.1172/JCI130513
Liu L. Luo S. Zeng L. Wang W. Yuan L. Jian X. Degenerative alterations in noradrenergic neurons of the locus coeruleus in Alzheimer’s disease Neural Regen. Res. 2013 8 2249 2255 10.3969/j.issn.1673-5374.2013.24.004
Braun D.J. Kalinin S. Feinstein D.L. Conditional Depletion of Hippocampal Brain-Derived Neurotrophic Factor Exac-erbates Neuropathology in a Mouse Model of Alzheimer’s Disease ASN Neuro 2017 9 1 14 10.1177/1759091417696161
Cao S. Fisher D.W. Rodriguez G. Yu T. Dong H. Comparisons of neuroinflammation, microglial activation, and degeneration of the locus coeruleus-norepinephrine system in APP/PS1 and aging mice J. Neuroinflammation 2021 18 1 16 10.1186/s12974-020-02054-2 33407625
Rho H.-J. Kim J.-H. Lee S.-H. Function of Selective Neuromodulatory Projections in the Mammalian Cerebral Cortex: Comparison Between Cholinergic and Noradrenergic Systems Front. Neural Circuits 2018 12 47 10.3389/fncir.2018.00047 29988373
O’Donnell J. Zeppenfeld D. McConnell E. Pena S. Nedergaard M. Norepinephrine: A Neuromodulator That Boosts the Function of Multiple Cell Types to Optimize CNS Performance Neurochem. Res. 2012 37 2496 2512 10.1007/s11064-012-0818-x
Feinstein D.L. Galea E. Reis D.J. Norepinephrine Suppresses Inducible Nitric Oxide Synthase Activity in Rat Astroglial Cultures J. Neurochem. 1993 60 1945 1948 10.1111/j.1471-4159.1993.tb13425.x 7682604
Braun D. Madrigal J.L.M. Feinstein U.L. Noradrenergic Regulation of Glial Activation: Molecular Mechanisms and Therapeutic Implications Curr. Neuropharmacol. 2014 12 342 352 10.2174/1570159X12666140828220938
Russo C.D. Boullerne A.I. Gavrilyuk V. Feinstein D.L. Inhibition of microglial inflammatory responses by norepinephrine: Effects on nitric oxide and interleukin-1β production J. Neuroinflammation 2004 1 9 10.1186/1742-2094-1-9
Feinstein D.L. Heneka M.T. Gavrilyuk V. Russo C.D. Weinberg G. Galea E. Noradrenergic regulation of inflammatory gene expression in brain Neurochem. Int. 2002 41 357 365 10.1016/S0197-0186(02)00049-9
Mori K. Ozaki E. Zhang B. Yang L. Yokoyama A. Takeda I. Maeda N. Sakanaka M. Tanaka J. Effects of norepinephrine on rat cultured microglial cells that express α1, α2, β1 and β2 adrenergic receptors Neuropharmacology 2002 43 1026 1034 10.1016/S0028-3908(02)00211-3
Madrigal J.L. Dello Russo C. Gavrilyuk V. Feinstein D.L. Effects of Noradrenaline on Neuronal NOS2 Expression and Viability Antioxid. Redox Signal. 2006 8 885 892 10.1089/ars.2006.8.885
Evans A.K. Ardestani P.M. Yi B. Park H.H. Lam R.K. Shamloo M. Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer’s Disease Neurobiol. Dis. 2020 146 105089 10.1016/j.nbd.2020.105089
Liu Y.U. Ying Y. Li Y. Eyo U.B. Chen T. Zheng J. Umpierre A.D. Zhu J. Bosco D.B. Dong H. et al. Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling Nat. Neurosci. 2019 22 1771 1781 10.1038/s41593-019-0511-3 31636449
Stowell R.D. Sipe G.O. Dawes R.P. Batchelor H.N. Lordy K.A. Whitelaw B.S. Stoessel M.B. Bidlack J.M. Brown E. Sur M. et al. Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex Nat. Neurosci. 2019 22 1782 1792 10.1038/s41593-019-0514-0 31636451
Mercan D. Heneka M.T. Norepinephrine as a modulator of microglial dynamics Nat. Neurosci. 2019 22 1745 1746 10.1038/s41593-019-0526-9 31636450
David M.C.B. Del Giovane M. Liu K.Y. Gostick B. Rowe J.B. Oboh I. Howard R. Malhotra P. Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: Systematic review and meta-analysis J. Neurol. Neurosurg. Psychiatry 2022 93 1080 1090 10.1136/jnnp-2022-329136
Al-Majed A. Bakheit A.H. Alharbi R.M. Abdel Aziz H.A. Chapter Two—Mirtazapine Profiles of Drug Substances, Excipients and Related Methodology Brittain H.G. Academic Press Cambridge, MA, USA 2018 Volume 43 209 254
Correia A.S. Vale N. Antidepressants in Alzheimer’s Disease: A Focus on the Role of Mirtazapine Pharmaceuticals 2021 14 930 10.3390/ph14090930
Raji M.A. Brady S.R. Mirtazapine for Treatment of Depression and Comorbidities in Alzheimer Disease Ann. Pharmacother. 2001 35 1024 1027 10.1345/aph.10371
Cakir S. Kulaksizoglu I.B. The efficacy of mirtazapine in agitated patients with Alzheimer’s disease: A 12-week open-label pilot study Neuropsychiatr. Dis. Treat. 2008 4 963 966 10.2147/NDT.S3201
Banerjee S. Hellier J. Dewey M. Romeo R. Ballard C. Baldwin R. Bentham P. Fox C. Holmes C. Katona C. et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): A randomised, multicentre, double-blind, placebo-controlled trial Lancet 2011 378 403 411 10.1016/S0140-6736(11)60830-1
Banerjee S. Banerjee S. High J. Stirling S. Shepstone L. Swart A.M. Telling T. Henderson C. Ballard C. Bentham P. et al. Study of mirtazapine for agitated behaviours in dementia (SYMBAD): A randomised, double-blind, place-bo-controlled trial Lancet 2021 398 1487 1497 10.1016/S0140-6736(21)01210-1
Manzoor S. Hoda N. A comprehensive review of monoamine oxidase inhibitors as Anti-Alzheimer’s disease agents: A review Eur. J. Med. Chem. 2020 206 112787 10.1016/j.ejmech.2020.112787
Emilsson L. Saetre P. Balciuniene J. Castensson A. Cairns N. Jazin E.E. Increased monoamine oxidase messenger RNA expression levels in frontal cortex of Alzheimer’s disease patients Neurosci. Lett. 2002 326 56 60 10.1016/S0304-3940(02)00307-5 12052537
Behl T. Kaur D. Sehgal A. Singh S. Sharma N. Zengin G. Andronie-Cioara F.L. Toma M.M. Bungau S. Bumbu A.G. et al. Role of Monoamine Oxidase Activity in Alzheimer’s Disease: An Insight into the Therapeutic Potential of In-hibitors Molecules 2021 26 3724 10.3390/molecules26123724 34207264
Gulyás B. Pavlova E. Kasa P. Gulya K. Bakota L. Varszegi S. Keller E. Horvath M.C. Nag S. Hermecz I. et al. Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-l-deprenyl using whole hem-isphere autoradiography Neurochem. Int. 2011 58 60 68 10.1016/j.neuint.2010.10.013 21075154
Sano M. Ernesto C. Thomas R.G. Klauber M.R. Schafer K. Grundman M. Woodbury P. Growdon J. Cotman C.W. Pfeiffer E. et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study N. Engl. J. Med. 1997 336 1216 1222 10.1056/NEJM199704243361704
Magni G. Meibach R. Lazabemide for the long-term treatment of Alzheimer’s disease Eur. Neuropsychopharmacol. 1999 9 142 10.1016/S0924-977X(99)80017-0
Piccinin G.L. Finali G. Piccirilli M. Neuropsychological effects of L-deprenyl in Alzheimer’s type dementia Clin Neuropharmacol 1990 13 147 163 10.1097/00002826-199004000-00004 2109658
Bönisch H. Brüss M. The Noradrenaline Transporter of the Neuronal Plasma Membranea Ann. N. Y. Acad. Sci. 1994 733 193 202 10.1111/j.1749-6632.1994.tb17269.x
Wong D.T. Threlkeld P.G. Best K.L. Bymaster F.P. A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain J. Pharmacol. Exp. Ther. 1982 222 61 65
Bymaster F.P. Katner J.S. Nelson D.L. Hemrick-Luecke S.K. Threlkeld P.G. Heiligenstein J.H. Morin S.M. Gehlert D.R. Perry K.W. Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat a Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder Neuropsychopharmacology 2002 27 699 711 10.1016/S0893-133X(02)00346-9
Kielbasa W. Kalvass J.C. Stratford R. Microdialysis Evaluation of Atomoxetine Brain Penetration and Central Nervous System Pharmacokinetics in Rats Drug Metab. Dispos. 2008 37 137 142 10.1124/dmd.108.023119
Mohs R.C. Shiovitz T.M. Tariot P.N. Porsteinsson A.P. Baker K.D. Feldman P.D. Atomoxetine Augmentation of Cholinesterase Inhibitor Therapy in Patients With Alzheimer Disease: 6-Month, Randomized, Double-Blind, Placebo-Controlled, Parallel-Trial Study Am. J. Geriatr. Psychiatry 2009 17 752 759 10.1097/JGP.0b013e3181aad585 19700948
Levey A.I. Qiu D. Zhao L. Hu W.T. Duong D.M. Higginbotham L. Dammer E.B. Seyfried N.T. Wingo T.S. Hales C.M. et al. A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment Brain 2022 145 1924 1938 10.1093/brain/awab452 34919634
Vargas-Caballero M. Warming H. Walker R. Holmes C. Cruickshank G. Patel B. Vagus Nerve Stimulation as a Potential Therapy in Early Alzheimer’s Disease: A Review Front. Hum. Neurosci. 2022 16 e866434 10.3389/fnhum.2022.866434 35572001
Kenny B.J. Bordoni B. Neuroanatomy, Cranial Nerve 10 (Vagus Nerve) StatPearls StatPearls Publishing Treasure Island, FL, USA 2022
Rosas-Ballina M. Olofsson P.S. Ochani M. Valdés-Ferrer S.I. Levine Y.A. Reardon C. Tusche M.W. Pavlov V.A. Andersson U. Chavan S. et al. Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit Science 2011 334 98 101 10.1126/science.1209985 21921156
Breit S. Kupferberg A. Rogler G. Hasler G. Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders Front Psychiatry 2018 9 44 10.3389/fpsyt.2018.00044
Hulsey D.R. Riley J.R. Loerwald K.W. Rennaker II R.L. Kilgard M.P. Hays S.A. Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimula-tion Exp. Neurol. 2017 289 21 30 10.1016/j.expneurol.2016.12.005
Pisapia J. Baltuch G. Vagus nerve stimulation Neuromodulation in Psychiatry John Wiley Hoboken, NJ, USA 2015 325 334 10.1002/9781118801086.ch17
Roosevelt R.W. Smith D.C. Clough R.W. Jensen R.A. Browning R.A. Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat Brain Res. 2006 1119 124 132 10.1016/j.brainres.2006.08.048
Manta S. Dong J. Debonnel G. Blier P. Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation J. Psychiatry Neurosci. 2009 34 272 280
Follesa P. Biggio F. Gorini G. Caria S. Talani G. Dazzi L. Puligheddu M. Marrosu F. Biggio G. Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain Brain Res. 2007 1179 28 34 10.1016/j.brainres.2007.08.045
Sun L. Peräkylä J. Holm K. Haapasalo J. Lehtimäki K. Ogawa K.H. Peltola J. Hartikainen K.M. Vagus nerve stimulation improves working memory performance J. Clin. Exp. Neuropsychol. 2017 39 954 964 10.1080/13803395.2017.1285869
Jacobs H.I.L. Priovoulos N. Riphagen J.M. Poser B.A. Napadow V. Uludag K. Sclocco R. Ivanov D. Verhey F.R.J. Transcutaneous vagus nerve stimulation increases locus coeruleus function and memory performance in older individuals: Featured research and focused topic sessions: Interventions targeting the noradrenergic system in Alzheimer’s and neurodegenerative disease Alzheimer’s Dement. 2020 16 e044766
Sjögren M.J.C. Cognition-Enhancing Effect of Vagus Nerve Stimulation in Patients with Alzheimer’s Disease: A Pilot Study J. Clin. Psychiatry 2002 63 972 980 10.4088/JCP.v63n1103 12444809
Merrill C.A. Jonsson M.A.G. Minthon L. Ejnell H. Silander H.C.-s. Blennow K. Karlsson M. Nordlund A. Rolstad S. Warkentin S. et al. Vagus Nerve Stimulation in Patients with Alzheimer’s Disease: Additional Follow-Up Results of a Pilot Study Through 1 Year J. Clin. Psychiatry 2006 67 1171 1178 10.4088/JCP.v67n0801 16965193
Hoang K. Watt H. Golemme M. Perry R.J. Ritchie C. Wilson D. Pickett J. Fox C. Howard R. Malhotra P.A. Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): Study protocol for a randomised clinical trial and COVID-19 amendments Trials 2022 23 1 13 10.1186/s13063-022-06190-3 35915506
Noradrenergic Add-on Therapy with Guanfacine (NorAD) Available online: https://clinicaltrials.gov/ct2/show/NCT03116126 (accessed on 14 November 2022)
David M. Malhotra P.A. New approaches for the quantification and targeting of noradrenergic dysfunction in Alz-heimer’s disease Ann. Clin. Transl. Neurol. 2022 9 582 596 10.1002/acn3.51539 35293158
Implantable Vagus Nerve Stimulation Modulation of Coeruleus-Norepinephrine Network for Mild-Moderate AD Patients Available online: https://clinicaltrials.gov/ct2/show/NCT05575271 (accessed on 14 November 2022)
Modulating the Locus Coeruleus Function Available online: https://clinicaltrials.gov/ct2/show/NCT04877782 (accessed on 14 November 2022)
The Wandering Nerve: Gateway to Boost Alzheimer’s Disease Related Cognitive Performance (WALLe) Available online: https://clinicaltrials.gov/ct2/show/NCT04908358 (accessed on 14 November 2022)