Top

Published in:

Open Access 01-05-2021 | Alzheimer's Disease | Neurology and Preclinical Neurological Studies - Review Article

The connections of Locus Coeruleus with hypothalamus: potential involvement in Alzheimer’s disease

Authors: Filippo Sean Giorgi, Alessandro Galgani, Stefano Puglisi-Allegra, Carla Letizia Busceti, Francesco Fornai

Published in: Journal of Neural Transmission | Issue 5/2021

Abstract

The hypothalamus and Locus Coeruleus (LC) share a variety of functions, as both of them take part in the regulation of the sleep/wake cycle and in the modulation of autonomic and homeostatic activities. Such a functional interplay takes place due to the dense and complex anatomical connections linking the two brain structures. In Alzheimer’s disease (AD), the occurrence of endocrine, autonomic and sleep disturbances have been associated with the disruption of the hypothalamic network; at the same time, in this disease, the occurrence of LC degeneration is receiving growing attention for the potential roles it may have both from a pathophysiological and pathogenetic point of view. In this review, we summarize the current knowledge on the anatomical and functional connections between the LC and hypothalamus, to better understand whether the impairment of the former may be responsible for the pathological involvement of the latter, and whether the disruption of their interplay may concur to the pathophysiology of AD. Although only a few papers specifically explored this topic, intriguingly, some pre-clinical and post-mortem human studies showed that aberrant protein spreading and neuroinflammation may cause hypothalamus degeneration and that these pathological features may be linked to LC impairment. Moreover, experimental studies in rodents showed that LC plays a relevant role in modulating the hypothalamic sleep/wake cycle regulation or neuroendocrine and systemic hormones; in line with this, the degeneration of LC itself may partly explain the occurrence of hypothalamic-related symptoms in AD.

Accorroni A, Giorgi FS, Donzelli R, Lorenzini L, Prontera C, Saba A, Vergallo A, Tognoni G, Siciliano G, Baldacci F, Bonuccelli U, Clerico A, Zucchi R (2017) Thyroid hormone levels in the cerebrospinal fluid correlate with disease severity in euthyroid patients with Alzheimer’s disease. Endocrine 55(3):981–984. https://doi.org/10.1007/s12020-016-0897-6.CrossRefPubMed

Ammar AA, Södersten P, Johnson AE (2001) Locus coeruleus noradrenergic lesions attenuate intraoral intake. NeuroReport. https://doi.org/10.1097/00001756-200110080-00023CrossRefPubMed

Andersen KB, Allan KH, Sommerauer M, Fedorova TD, Knudsen K, Vang K, Van Den Berge N et al (2020) Altered sensorimotor cortex noradrenergic function in idiopathic rem sleep behaviour disorder – a PET study. Parkinsonism Relat Disord. https://doi.org/10.1016/j.parkreldis.2020.05.013CrossRefPubMed

Anselmo-Franci JA, Franci CR, Krulich L, Antunes-Rodrigues J, McCann SM (1997) Locus coeruleus lesions decrease norepinephrine input into the medial preoptic area and medial basal hypothalamus and block the LH, FSH and prolactin preovulatory surge. Brain Res. https://doi.org/10.1016/S0006-8993(97)00613-6CrossRefPubMed

Aral H, Kosaka K, Iizuka R (1984) Changes of biogenic amines and their metabolites in postmortem brains from patients with alzheimer-type dementia. J Neurochem. https://doi.org/10.1111/j.1471-4159.1984.tb00913.xCrossRef

Aston-Jones G, Cohen JD (2005) An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 28(1):403–450. https://doi.org/10.1146/annurev.neuro.28.061604.135709CrossRefPubMed

Baldo BA, Daniel RA, Berridge CW, Kelley AE (2003) Overlapping distributions of orexin/hypocretin- and dopamine-β-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J Comp Neurol. https://doi.org/10.1002/cne.10783CrossRefPubMed

Baloyannis SJ, Mavroudis I, Mitilineos D, Baloyannis IS, Costa VG (2015) The hypothalamus in Alzheimer’s disease: a golgi and electron microscope study. Am J Alzheimer’s Dis Other Dement. https://doi.org/10.1177/1533317514556876CrossRef

Banki CM, Karmacsi L, Bissette G, Nemeroff CB (1992) Cerebrospinal fluid neuropeptides in dementia. Biol Psychiatry. https://doi.org/10.1016/0006-3223(92)90132-JCrossRefPubMed

Banks D, Harris MC (1984) Lesions of the locus coeruleus abolish baroreceptor-induced depression of supraoptic neurones in the rat. J Physiol. https://doi.org/10.1113/jphysiol.1984.sp015425CrossRefPubMedPubMedCentral

Bekar LK, Wei HS, Nedergaard M (2012) The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand. J Cereb Blood Flow Metab. https://doi.org/10.1038/jcbfm.2012.115CrossRefPubMedPubMedCentral

Berridge CW, Schmeichel BE, España RA (2012) Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev. https://doi.org/10.1016/j.smrv.2011.12.003CrossRefPubMedPubMedCentral

Betts MJ, Cardenas-Blanco A, Kanowski M, Spottke A, Teipel SJ, Kilimann I, Jessen F, Düzel E (2019) Locus coeruleus MRI contrast is reduced in Alzheimer’s disease dementia and correlates with CSF Aβ levels. Alzheimer’s Dement Diagn Assess Dis Monit. https://doi.org/10.1016/j.dadm.2019.02.001CrossRef

Blanco-Centurion C, Gerashchenko D, Salin-Pascual RJ, Shiromani PJ (2004) Effects of hypocretin2-saporin and antidopamine-β-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone. Eur J Neurosci. https://doi.org/10.1111/j.0953-816X.2004.03366.xCrossRefPubMedPubMedCentral

Bluet-Pajot MT, Mounier F, Durand D, Kordon C, Llorens-Cortes C, Videau C, Epelbaum J (1992) 6-Hydroxydopamine lesions of the locus coeruleus induce a paradoxical increase in growth hormone secretion in male rats. J Neuroendocrinol. https://doi.org/10.1111/j.1365-2826.1992.tb00338.xCrossRefPubMed

Bonaz B, Martin L, Beurriand E, Hostein J, Feuerstein C (1992a) Involvement of hypothalamic noradrenergic systems in the modulation of intestinal motility in rats. Brain Res. https://doi.org/10.1016/S0006-8993(10)80045-9CrossRefPubMed

Bonaz B, Martin L, Beurriand E, Hostein J, Feuerstein C (1992b) Locus ceruleus modulates migrating myoelectric complex in rats. Am J Physiol Gastrointest Liver Physiol. https://doi.org/10.1152/ajpgi.1992.262.6.g1121CrossRef

Bowden DM, German DC, Poynter WD (1978) An autoradiographic, semistereotaxic mapping of major projections from locus coeruleus and adjacent nuclei in macaca mulatta. Brain Res. https://doi.org/10.1016/0006-8993(78)90861-2CrossRefPubMed

Bowen RL, Perry G, Xiong C, Smith MA, Atwood CS (2015) A clinical study of lupron depot in the treatment of women with Alzheimer’s disease: preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose lupron over 48 weeks. J Alzheimer’s Dis 44(2):549–560. https://doi.org/10.3233/JAD-141626CrossRef

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259CrossRef

Braak H, Del Tredici K (2011) Alzheimer’s pathogenesis: is there neuron-to-neuron propagation? Acta Neuropathol 121(5):589–595. https://doi.org/10.1007/s00401-011-0825-zCrossRefPubMed

Braak H, Del Tredici K, Rüb U, De Vos RAI, Jansen Steur ENH, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24(2):197–211. https://doi.org/10.1016/S0197-4580(02)00065-9CrossRefPubMed

Braak H, Thal DR, Ghebremedhin E, Del Tredici K (2011) Stages of the pathologic process in alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol 70(11):960–969. https://doi.org/10.1097/NEN.0b013e318232a379CrossRef

Brumberg J, Tran-Gia J, Lapa C, Isaias IU, Samnick S (2019) PET imaging of noradrenaline transporters in Parkinson’s disease: focus on scan time. Ann Nucl Med. https://doi.org/10.1007/s12149-018-1305-5CrossRefPubMed

Burke WJ, Coronado PG, Schmitt CA, Gillespie KM, Chung HD (1994) Blood pressure regulation in Alzheimer’s disease. J Auton Nerv Syst 48(1):65–71. https://doi.org/10.1016/0165-1838(94)90160-0CrossRefPubMed

Callen DJA, Black SE, Gao F, Caldwell CB, Szalai JP (2001) Beyond the hippocampus: MRI volumetry confirms widespread limbic atrophy in AD. Neurology. https://doi.org/10.1212/WNL.57.9.1669CrossRefPubMed

Campbell RE, Herbison AE (2007) Definition of brainstem afferents to gonadotropin-releasing hormone neurons in the mouse using conditional viral tract tracing. Endocrinology. https://doi.org/10.1210/en.2007-0854CrossRefPubMedPubMedCentral

Cedarbaum JM, Aghajanian GK (1978) Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique. J Comp Neurol. https://doi.org/10.1002/cne.901780102CrossRefPubMed

Chalermpalanupap T, Weinshenker D, Rorabaugh JM (2017) Down but not out: the consequences of pretangle tau in the locus coeruleus. Neural Plast 2017:7829507. https://doi.org/10.1155/2017/7829507CrossRefPubMedPubMedCentral

Chen HF, Chang-Quan H, You C, Wang ZR, Hui W, Liu QX, Si-Qing H (2013) The circadian rhythm of arterial blood pressure in Alzheimer disease (AD) patients without hypertension. Blood Press 22(2):101–105. https://doi.org/10.3109/08037051.2012.733508CrossRefPubMed

Claudio Cuello A, Pentz R, Hall H (2019) The brain NGF metabolic pathway in health and in Alzheimer’s pathology. Front Neurosci. https://doi.org/10.3389/fnins.2019.00062CrossRefPubMed

Congdon EE, Sigurdsson EM (2018) Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol. https://doi.org/10.1038/s41582-018-0013-zCrossRefPubMedPubMedCentral

Coon EA, Cutsforth-Gregory JK, Benarroch E (2018) Neuropathology of autonomic dysfunction in synucleinopathies. Mov Disord. https://doi.org/10.1002/mds.27186CrossRefPubMed

Counts SE, Mufson EJ (2012) Locus Coeruleus. In: Mai JK, Paxinos G (eds) The human nervous system, 3rd edn, pp 427–440. https://doi.org/10.1016/B978-0-12-374236-0.10012-4.

Csernansky JG, Dong H, Fagan AM, Wang L, Xiong C, Holtzman DM, Morris JC (2006) Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry. https://doi.org/10.1176/ajp.2006.163.12.2164CrossRefPubMedPubMedCentral

Dehay B, Bourdenx M, Gorry P, Przedborski S, Vila M, Hunot S, Singleton A et al (2015) Targeting α-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol. https://doi.org/10.1016/S1474-4422(15)00006-XCrossRefPubMedPubMedCentral

de la Torre JC (2017) Are major dementias triggered by poor blood flow to the brain? Theoretical considerations. J Alzheimers Dis. 2017;57(2):353–371. https://doi.org/10.3233/JAD-161266CrossRefPubMed

Doppler CEJ, Smit JAM, Hommelsen M, Seger A, Horsager J, Kinnerup MB, Hansen AK et al (2021) Microsleep disturbances are associated with noradrenergic dysfunction in Parkinson’s disease. Sleep. https://doi.org/10.1093/sleep/zsab040CrossRefPubMed

Dotti C, Taleisnik S (1982) Inhibition of the release of LH and ovulation by activation of the noradrenergic system. Effect of interrupting the ascending pathways. Brain Res. https://doi.org/10.1016/0006-8993(82)90062-2CrossRefPubMed

Dotti C, Taleisnik S (1984) Beta-adrenergic receptors in the premammillary nucleus mediate the inhibition of LH release evoked by locus ceruleus stimulation. Neuroendocrinology. https://doi.org/10.1159/000123858CrossRefPubMed

Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, Dekosky ST et al (2014) Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. https://doi.org/10.1016/S1474-4422(14)70090-0CrossRefPubMed

Endroczi E, Marton I, Radnai Z, Biro J (1978) Effect of the depletion of brain noradrenaline of the plasma FSH and growth hormone levels in ovariectomized rats. Acta Endocrinol. https://doi.org/10.1530/acta.0.0870055CrossRef

Espinoza García AS, Martínez Moreno AG, Reyes CZ (2021) The role of ghrelin and leptin in feeding behavior: genetic and molecular evidence. Endocrinol Diabetes y Nutr. https://doi.org/10.1016/j.endinu.2020.10.011CrossRef

Farley IJ, Hornykiewicz O (1977) Noradrenaline distribution in subcortical areas of the human brain. Brain Res. https://doi.org/10.1016/0006-8993(77)90214-1CrossRefPubMed

Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E (2002) Noradrenergic regulation of inflammatory gene expression in brain. Neurochem Int 41(5):357–365CrossRef

Flanagan LM, Dohanics J, Verbalis JG, Stricker EM (1992) Gastric motility and food intake in rats after lesions of hypothalamic paraventricular nucleus. Am J Physiol Regul Integr Comp Physiol. https://doi.org/10.1152/ajpregu.1992.263.1.r39CrossRef

Follesa P, Mocchetti I (1993) Regulation of basic fibroblast growth factor and nerve growth factor MRNA by beta-adrenergic receptor activation and adrenal steroids in rat central nervous system. Mol Pharmacol 43(2):132–138PubMed

Foote SL, Berridge CW (2019) New developments and future directions in understanding locus coeruleus – norepinephrine (LC-NE) function. Brain Res. https://doi.org/10.1016/j.brainres.2018.09.033CrossRefPubMed

Fornai F, Ferrucci M (2017) Anatomia Funzionale Della Formazione Reticolare Nel Tronco Encefalico Dell’uomo. Pisa University Press, Pisa

Fornai F, Bassi L, Torracca MT, Alessandrì MG, Scalori V, Corsini GU (1996) Region- and neurotransmitter-dependent species and strain differences in DSP-4-induced monoamine depletion in rodents. Neurodegeneration 5(3):241–249. https://doi.org/10.1006/neur.1996.0032CrossRefPubMed

Franci JAA, Antunes-Rodrigues J (1985) Effect of locus ceruleus lesion on luteinizing hormone secretion under different experimental conditions. Neuroendocrinology. https://doi.org/10.1159/000124152CrossRefPubMed

Fritschy JM, Grzanna R (1991) Selective effects of DSP-4 on locus coeruleus axons: are there pharmacologically different types of noradrenergic axons in the central nervous system? Prog Brain Res 88:257–268. https://doi.org/10.1016/S0079-6123(08)63815-7CrossRefPubMed

Galgani A, Lombardo F, Della Latta D, Martini N, Bonuccelli U, Fornai F, Giorgi FS (2020) Locus coeruleus magnetic resonance imaging in neurological diseases. Curr Neurol Neurosci Rep 21(1):2. https://doi.org/10.1007/s11910-020-01087-7CrossRefPubMedPubMedCentral

García-Lorenzo D, Longo-Dos Santos C, Ewenczyk C, Leu-Semenescu S, Gallea C, Quattrocchi G, Pita Lobo P et al (2013) The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease. Brain 136(7):2120–2129. https://doi.org/10.1093/brain/awt152CrossRefPubMedPubMedCentral

German DC, Manaye KF, White CL, Woodward DJ, McIntire DD, Smith WK, Kalaria RJ, Mann DMA (1992) Disease-specific patterns of locus coeruleus cell loss. Ann Neurol 32(5):667–676. https://doi.org/10.1002/ana.410320510CrossRefPubMed

Giorgi FS, Ferrucci M, Lazzeri G, Pizzanelli C, Lenzi P, Alessandrl MG, Murri L, Fornai F (2003) A damage to locus coeruleus neurons converts sporadic seizures into self-sustaining limbic status epilepticus. Eur J Neurosci 17(12):2593–2601. https://doi.org/10.1046/j.1460-9568.2003.02692.xCrossRefPubMed

Giorgi FS, Ryskalin L, Ruffoli R, Biagioni F, Limanaqi F, Ferrucci M, Busceti CL, Bonuccelli U, Fornai F (2017) The neuroanatomy of the reticular nucleus locus coeruleus in Alzheimer’s disease. Front Neuroanat 11(September):80. https://doi.org/10.3389/fnana.2017.00080CrossRefPubMedPubMedCentral

Giorgi FS, Galgani A, Puglisi-Allegra S, Limanaqi F, Busceti CL, Fornai F (2020a) Locus coeruleus and neurovascular unit: from its role in physiology to its potential role in Alzheimer’s disease pathogenesis. J Neurosci Res. https://doi.org/10.1002/jnr.24718CrossRefPubMed

Giorgi FS, Biagioni F, Galgani A, Pavese N, Lazzeri G, Fornai F (2020b) Locus coeruleus modulates neuroinflammation in Parkinsonism and dementia. Int J Mol Sci. https://doi.org/10.3390/ijms21228630CrossRefPubMedPubMedCentral

Grossberg AJ, Zhu X, Leinninger GM, Levasseur PR, Braun TP, Myers MG, Marks DL (2011) Inflammation-induced lethargy is mediated by suppression of orexin neuron activity. J Neurosci. https://doi.org/10.1523/JNEUROSCI.2311-11.2011CrossRefPubMedPubMedCentral

Harper DG, Stopa EG, McKee AC, Satlin A, Harlan PC, Goldstein R, Volicer L (2001) Differential circadian rhythm disturbances in men with Alzheimer disease and frontotemporal degeneration. Arch Gen Psychiatry 58(4):353–360. https://doi.org/10.1001/archpsyc.58.4.353CrossRefPubMed

Harper DG, Stopa EG, Kuo-Leblanc V, McKee AC, Asayama K, Volicer L, Kowall N, Satlin A (2008) Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia. Brain. https://doi.org/10.1093/brain/awn049CrossRefPubMedPubMedCentral

Hawthorn J, Ang VTY, Jenkins JS (1985) Effects of lesions in the hypothalamic paraventricular, supraoptic and suprachiasmatic nuclei on vasopressin and oxytocin in rat brain and spinal cord. Brain Res. https://doi.org/10.1016/0006-8993(85)91093-5CrossRefPubMed

Heneka MT, Gavrilyuk V, Landreth GE, O’Banion MK, Weinberg G, Feinstein DL (2003) Noradrenergic depletion increases inflammatory responses in brain: effects on I$κ$B and HSP70 expression. J Neurochem 85(2):387–398CrossRef

Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, Sastre M et al (2006) Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 26(5):1343–1354. https://doi.org/10.1523/jneurosci.4236-05.2006CrossRefPubMedPubMedCentral

Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D et al (2010) Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107(13):6058–6063. https://doi.org/10.1073/pnas.0909586107CrossRefPubMed

Heneka MT, Carson MJ, el Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405. https://doi.org/10.1016/S1474-4422(15)70016-5CrossRefPubMedPubMedCentral

Hiller AJ, Ishii M (2018) Disorders of body weight, sleep and circadian rhythm as manifestations of hypothalamic dysfunction in Alzheimer’s disease. Front Cell Neurosci. https://doi.org/10.3389/fncel.2018.00471CrossRefPubMedPubMedCentral

Holden KF, Lindquist K, Tylavsky FA, Rosano C, Harris TB, Yaffe K (2009) Serum leptin level and cognition in the elderly: findings from the health ABC study. Neurobiol Aging 30(9):1483–1489. https://doi.org/10.1016/j.neurobiolaging.2007.11.024CrossRefPubMed

Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones A, Kilduff TS, van den Pol AN (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol. https://doi.org/10.1002/(SICI)1096-9861(19991213)415:2%3c145::AID-CNE1%3e3.0.CO;2-2CrossRefPubMed

Hou L, Sun F, Sun W, Zhang L, Wang Q (2019) Lesion of the locus coeruleus damages learning and memory performance in paraquat and Maneb-induced mouse Parkinson’s disease model. Neuroscience. https://doi.org/10.1016/j.neuroscience.2019.09.006CrossRefPubMedPubMedCentral

Hughes TM, Lockhart SN, Smagula SF (2018) Blood pressure’s role in Alzheimer disease pathology. Am J Geriatr Psychiatry. https://doi.org/10.1016/j.jagp.2017.09.019CrossRefPubMed

Iba M, McBride JD, Guo JL, Zhang B, Trojanowski JQ, Lee VMY (2015) Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections. Acta Neuropathol 130(3):349–362CrossRef

Idiaquez J, Roman GC (2011) Autonomic dysfunction in neurodegenerative dementias. J Neurol Sci. https://doi.org/10.1016/j.jns.2011.02.033CrossRefPubMed

Isaias IU, Trujillo P, Summers P, Marotta G, Mainardi L, Pezzoli G, Zecca L, Costa A (2016) Neuromelanin imaging and dopaminergic loss in Parkinson’s disease. Front Aging Neurosci. https://doi.org/10.3389/fnagi.2016.00196CrossRefPubMedPubMedCentral

Ishii M, Iadecola C (2015) Metabolic and non-cognitive manifestations of Alzheimers disease: the hypothalamus as both culprit and target of pathology. Cell Metab. https://doi.org/10.1016/j.cmet.2015.08.016CrossRefPubMedPubMedCentral

Ishii M, Wang G, Racchumi G, Dyke JP, Iadecola C (2014) Transgenic mice overexpressing amyloid precursor protein exhibit early metabolic deficits and a pathologically low leptin state associated with hypothalamic dysfunction in arcuate neuropeptide y neurons. J Neurosci. https://doi.org/10.1523/JNEUROSCI.0872-14.2014CrossRefPubMedPubMedCentral

Isik AT, Kocyigit SE, Smith L, Aydin AE, Soysal P (2019) A comparison of the prevalence of orthostatic hypotension between older patients with Alzheimer’s disease, lewy body dementia, and without dementia. Exp Gerontol 124(September):110628. https://doi.org/10.1016/j.exger.2019.06.001CrossRefPubMed

Jaffer A, Searson A, Russell VA, Taljaard JJF (1990) The effect of selective noradrenergic denervation on thyrotropin secretion in the rat. Neurochem Res. https://doi.org/10.1007/BF00969178CrossRefPubMed

Jardanhazi-Kurutz D, Kummer MP, Terwel D, Vogel K, Thiele A, Heneka MT (2011) Distinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in APP/PS1 transgenic mice. Neuroscience 176:396–407. https://doi.org/10.1016/j.neuroscience.2010.11.052CrossRefPubMed

Javitch JA, Strittmatter SM, Snyder SH (1985) Differential visualization of dopamine and norepinephrine uptake sites in rat brain using [3H]mazindol autoradiography. J Neurosci. https://doi.org/10.1523/jneurosci.05-06-01513.1985CrossRefPubMedPubMedCentral

Jeong SM, Han K, Kim D, Rhee SY, Jang W, Shin DW (2020) Body mass index, diabetes, and the risk of Parkinson’s disease. Mov Disord. https://doi.org/10.1002/mds.27922CrossRefPubMed

Jimenez A, Pegueroles J, Carmona-Iragui M, Vilaplana E, Montal V, Alcolea D, Videla L et al (2017) Weight loss in the healthy elderly might be a non-cognitive sign of preclinical Alzheimer’s disease. Oncotarget. https://doi.org/10.18632/oncotarget.22218CrossRefPubMedPubMedCentral

Kalinin S, Feinstein DL, Xu H, Huesa G, Pelligrino DA, Galea E (2006) Degeneration of noradrenergic bres from the locus coeruleus causes tight-junction disorganisation in the rat brain. Reactions 24:3393–3400. https://doi.org/10.1111/j.1460-9568.2006.05223.xCrossRef

Kang SS, Liu X, Ahn EH, Xiang J, Manfredsson FP, Yang X, Luo HR, Liles LC, Weinshenker D, Ye K (2020) Norepinephrine metabolite DOPEGAL activates AEP and pathological tau aggregation in locus coeruleus. J Clin Investig 130(1):422–437. https://doi.org/10.1172/JCI130513CrossRefPubMed

Kasanuki K, Iseki E, Kondo D, Fujishiro H, Minegishi M, Sato K, Katsuse O, Hino H, Kosaka K, Arai H (2014) Neuropathological investigation of hypocretin expression in brains of dementia with lewy bodies. Neurosci Lett. https://doi.org/10.1016/j.neulet.2014.03.020CrossRefPubMed

Kelly SC, He B, Perez SE, Ginsberg SD, Mufson EJ, Counts SE (2017) Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease. Acta Neuropathol Commun 5(1):8. https://doi.org/10.1186/s40478-017-0411-2CrossRefPubMedPubMedCentral

Kelly SC, McKay EC, Beck JS, Collier TJ, Dorrance AM, Counts SE (2019) Locus coeruleus degeneration induces forebrain vascular pathology in a transgenic rat model of Alzheimer’s disease. J Alzheimer’s Dis 70(2):369–386. https://doi.org/10.3233/JAD-190090CrossRef

Kovacs GG, Lukic MJ, Irwin DJ, Arzberger T, Respondek G, Lee EB, Coughlin D et al (2020) Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol. https://doi.org/10.1007/s00401-020-02158-2CrossRefPubMedPubMedCentral

Krout KE, Kawano J, Mettenleiter TC, Loewy AD (2002) CNS inputs to the suprachiasmatic nucleus of the rat. Neuroscience. https://doi.org/10.1016/S0306-4522(01)00551-6CrossRefPubMed

Lechan RM, Toni R (2000) Functional anatomy of the hypothalamus and pituitary. In: Feingold KR, Anawalt B, Boyce A et al (eds) Endotext. MDText.com, Inc., South Dartmouth, MA

Lecrux C, Hamel E (2016) Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states. Philos Trans R Soc Lond Ser B Biol Sci 371(1705):350. https://doi.org/10.1098/rstb.2015.0350CrossRef

Liu KY, Marijatta F, Hämmerer D, Acosta-Cabronero J, Düzel E, Howard RJ (2017) Magnetic resonance imaging of the human locus coeruleus: a systematic review. Neurosci Biobehav Rev. https://doi.org/10.1016/j.neubiorev.2017.10.023CrossRefPubMedPubMedCentral

Liu KY, Kievit RA, Tsvetanov KA, Betts MJ, Düzel E, Rowe JB, Tyler LK et al (2020) Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences. Nat Commun 11(1):1712. https://doi.org/10.1038/s41467-020-15410-wCrossRefPubMedPubMedCentral

Luppi PH, Aston-Jones G, Akaoka H, Chouvet G, Jouvet M (1995) Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and phaseolus vulgaris leucoagglutinin. Neuroscience. https://doi.org/10.1016/0306-4522(94)00481-JCrossRefPubMed

Mahoney CE, Cogswell A, Koralnik IJ, Scammell TE (2019) The neurobiological basis of narcolepsy. Nat Rev Neurosci. https://doi.org/10.1038/s41583-018-0097-xCrossRefPubMedPubMedCentral

Manaye KF, McIntire DD, Mann DMA, German DC (1995) Locus coeruleus cell loss in the aging human brain: a non-random process. J Comp Neurol 358(1):79–87. https://doi.org/10.1002/cne.903580105CrossRefPubMed

Manly JJ, Merchant CA, Jacobs DM, Small SA, Bell K, Ferin M, Mayeux R (2000) Endogenous estrogen levels and Alzheimer’s disease among postmenopausal women. Neurology 54(4):833–837. https://doi.org/10.1212/WNL.54.4.833CrossRefPubMed

Mann DMA, Lincoln J, Yates PO, Stamp JE, Toper S (1980) Changes in the monoamine containing neurones of the human CNS in senile dementia. Br J Psychiatry. https://doi.org/10.1192/bjp.136.6.533CrossRefPubMed

Mann DM, Yates PO, Hawkes J (1982) The noradrenergic system in Alzheimer and multi-infarct dementias. J Neurol Neurosurg Psychiatry 45(2):113–119CrossRef

Mann DM, Yates PO, Marcyniuk B (1984) A comparison of changes in the nucleus basalis and locus caeruleus in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 47(2):201–203CrossRef

Mann DMA, Yates PO, Marcyniuk B (1985) Changes in Alzheimer’s disease in the magnocellular neurones of the supraoptic and paraventricular nuclei of the hypothalamus and their relationship to the noradrenergic deficit. Clin Neuropathol 4(3):127–134PubMed

Martins-Afférri MP, Ferreira-Silva IA, Franci CR, Anselmo-Franci JA (2003) LHRH release depends on locus coeruleus noradrenergic inputs to the medial preoptic area and median eminence. Brain Res Bull. https://doi.org/10.1016/S0361-9230(03)00190-4CrossRefPubMed

Marwarha G, Ghribi O (2012) Leptin signaling and Alzheimer’s disease. Am J Neurodegener Dis 1(3):245–265PubMedPubMedCentral

Matsuura K, Maeda M, Yata K, Ichiba Y, Yamaguchi T, Kanamaru K, Tomimoto H (2013) Neuromelanin magnetic resonance imaging in Parkinson’s disease and multiple system atrophy. Eur Neurol 70(1–2):70–77. https://doi.org/10.1159/000350291CrossRefPubMed

McCall JG, Siuda ER, Bhatti DL, Lawson LA, McElligott ZA, Stuber GD, Bruchas MR (2017) Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior. Elife 6(July):e18247. https://doi.org/10.7554/eLife.18247CrossRefPubMedPubMedCentral

Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM (2004) Free testosterone and risk for Alzheimer disease in older men. Neurology 62(2):188–193. https://doi.org/10.1212/WNL.62.2.188CrossRefPubMed

Musiek ES, Xiong DD, Holtzman DM (2015) Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med. https://doi.org/10.1038/emm.2014.121CrossRefPubMedPubMedCentral

Oh J, Eser RA, Ehrenberg AJ, Morales D, Petersen C, Kudlacek J, Dunlop SR et al (2019) Profound degeneration of wake-promoting neurons in Alzheimer’s disease. Alzheimer’s Dement. https://doi.org/10.1016/j.jalz.2019.06.3916CrossRef

Ozben T, Ozben S (2019) Neuro-inflammation and anti-inflammatory treatment options for Alzheimer’s disease. Clin Biochem. https://doi.org/10.1016/j.clinbiochem.2019.04.001CrossRefPubMed

Paxinos G, Franklin KBJ (2001) The mouse brain in stereotactic coordinates. Compact 2nd edn. Academic Press, New York

Peever J, Fuller PM (2017) The biology of REM sleep. Curr Biol. https://doi.org/10.1016/j.cub.2017.10.026CrossRefPubMed

Pellegrini C, Antonioli L, Colucci R, Blandizzi C, Fornai M (2018) Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases? Acta Neuropathol. https://doi.org/10.1007/s00401-018-1856-5CrossRefPubMed

Pellegrini C, Daniele S, Antonioli L, Benvenuti L, D’Antongiovanni V, Piccarducci R, Pietrobono D et al (2020) Prodromal intestinal events in Alzheimer’s disease (AD): colonic dysmotility and inflammation are associated with enteric AD-related protein deposition. Int J Mol Sci 21(10):3523. https://doi.org/10.3390/ijms21103523CrossRefPubMedCentral

Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HG, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. https://doi.org/10.1523/jneurosci.18-23-09996.1998CrossRefPubMedPubMedCentral

Poe GR, Foote S, Eschenko O, Johansen JP, Bouret S, Aston-Jones G, Harley CW et al (2020) Locus coeruleus: a new look at the blue spot. Nat Rev Neurosci. https://doi.org/10.1038/s41583-020-0360-9CrossRefPubMedPubMedCentral

Prinz PN, Vitaliano PP, Vitiello MC, Bokan J, Raskind M, Peskind E, Gerber C (1982) Sleep, EEG and mental function changes in senile dementia of the Alzheimer’s type. Neurobiol Aging 3(4):361–370. https://doi.org/10.1016/0197-4580(82)90024-0CrossRefPubMed

Reyes BAS, Valentino RJ, Xu G, Van Bockstaele EJ (2005) Hypothalamic projections to locus coeruleus neurons in rat brain. Eur J Neurosci. https://doi.org/10.1111/j.1460-9568.2005.04197.xCrossRefPubMed

Rodovalho GV, Franci CR, Morris M, Anselmo-Franci JA (2006) Locus coeruleus lesions decrease oxytocin and vasopressin release induced by hemorrhage. Neurochem Res. https://doi.org/10.1007/s11064-005-9015-5CrossRefPubMed

Roizen MF, Kobayashi RM, Muth EA, Jacobowitz DM (1976) Biochemical mapping of noradrenergic projections of axons in the dorsal noradrenergic bundle. Brain Res. https://doi.org/10.1016/0006-8993(76)90637-5CrossRefPubMed

Samuels E, Szabadi E (2008) 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. https://doi.org/10.2174/157015908785777229CrossRefPubMedPubMedCentral

Saper CB (2012) Hypothalamus. In: Mai JK, Paxinos G (eds) The human nervous system, 3rd edn. Academic Press, London, pp 550–585

Saper CB (2013) The central circadian timing system. Curr Opin Neurobiol. https://doi.org/10.1016/j.conb.2013.04.004CrossRefPubMedPubMedCentral

Sawchenko PE, Swanson LC, Grzanna E, Howe PRC, Bloom SR, Polak JM (1985) Colocalization of neuropeptide y immunoreactivity in brainstem catecholaminergic neurons that project to the paraventricular nucleus of the hypothalamus. J Comp Neurol. https://doi.org/10.1002/cne.902410203CrossRefPubMed

Scheibel AB, Duong TH, Tomiyasu U (1987) Denervation microangiopathy in senile dementia, Alzheimer type. Alzheimer Dis Assoc Disord. https://doi.org/10.1097/00002093-198701000-00004CrossRefPubMed

Schwartz MD, Nguyen AT, Warrier DR, Palmerston JB, Thomas AM, Morairty SR, Neylan TC, Kilduff TS (2016) Locus coeruleus and tuberomammillary nuclei ablations attenuate hypocretin/orexin antagonist-mediated REM sleep. ENeuro. https://doi.org/10.1523/ENEURO.0018-16.2016CrossRefPubMedPubMedCentral

Seki K, Yoshida S, Jaiswal M (2018) Molecular mechanism of noradrenaline during the stress-induced major depressive disorder. Neural Regen Res. https://doi.org/10.4103/1673-5374.235019CrossRefPubMedPubMedCentral

Shih CD, Chan SHH, Chan JYH (1995) Participation of hypothalamic paraventricular nucleus in locus ceruleus- induced baroreflex suppression in rats. Am J Physiol Heart Circ Physiol. https://doi.org/10.1152/ajpheart.1995.269.1.h46CrossRef

Sobrinho CR, Canteras NS (2011) A study of the catecholaminergic inputs to the dorsal premammillary nucleus. Neurosci Lett. https://doi.org/10.1016/j.neulet.2011.07.006CrossRefPubMed

Sommerauer M, Fedorova TD, Hansen AK, Knudsen K, Otto M, Jeppesen J, Frederiksen Y et al (2018) Evaluation of the noradrenergic system in Parkinson’s disease: an 11 C-MeNER PET and neuromelanin MRI study. Brain. https://doi.org/10.1093/brain/awx348CrossRefPubMed

St Louis EK, Boeve BF (2017) REM sleep behavior disorder: diagnosis, clinical implications, and future directions. Mayo Clin Proc. https://doi.org/10.1016/j.mayocp.2017.09.007CrossRefPubMedPubMedCentral

Swaab DF, Goudsmit E, Hofman MA, Ravid R, Kremer HPH (1992) The human hypothalamus in development, sexual differentiation, aging and Alzheimer’s disease. Prog Brain Res 91(3):465–472. https://doi.org/10.1016/S0079-6123(08)62369-9CrossRefPubMed

Swanson LW (1976) An autoradiographic study of the efferent connections of the preoptic region in the rat. J Comp Neurol. https://doi.org/10.1002/cne.901670207CrossRefPubMed

Szabadi E (2013) Functional neuroanatomy of the central noradrenergic system. J Psychopharmacol 27(8):659–693. https://doi.org/10.1177/0269881113490326CrossRefPubMed

Szafarczyk A, Alonso G, Ixart G (1985) Diurnal-stimulated and stress-induced ACTH release in rats mediated by ventral noradrenergic bundle. Am J Physiol Endocrinol Metab. https://doi.org/10.1152/ajpendo.1985.249.2.e219CrossRef

Tan ZS, Vasan RS (2009) Thyroid function and Alzheimer’s disease. J Alzheimer’s Dis. https://doi.org/10.3233/JAD-2009-0991CrossRef

Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58(12):1791–1800. https://doi.org/10.1212/WNL.58.12.1791CrossRefPubMed

Theofilas P, Ehrenberg AJ, Dunlop S, di Lorenzo Alho AT, Nguy A, Leite REP, Rodriguez RD et al (2017) 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 Dement 13(3):236–246. https://doi.org/10.1016/j.jalz.2016.06.2362CrossRefPubMed

Tortorella S, Rodrigo-Angulo ML, Núñez A, Garzón M (2013) Synaptic interactions between perifornical lateral hypothalamic area, locus coeruleus nucleus and the oral pontine reticular nucleus are implicated in the stage succession during sleep-wakefulness cycle. Front Neurosci. https://doi.org/10.3389/fnins.2013.00216CrossRefPubMedPubMedCentral

Uschakov A, Gong H, McGinty D, Szymusiak R (2007) Efferent projections from the median preoptic nucleus to sleep- and arousal-regulatory nuclei in the rat brain. Neuroscience. https://doi.org/10.1016/j.neuroscience.2007.05.055CrossRefPubMedPubMedCentral

Vest RS, Pike CJ (2013) Gender, sex steroid hormones, and Alzheimer’s disease. Horm Behav. https://doi.org/10.1016/j.yhbeh.2012.04.006CrossRefPubMed

Weinshenker D (2018) Long road to ruin: noradrenergic dysfunction in neurodegenerative disease. Trends Neurosci. https://doi.org/10.1016/j.tins.2018.01.010CrossRefPubMedPubMedCentral

Whitwell JL, Weigand SD, Shiung MM, Boeve BF, Ferman TJ, Smith GE, Knopman DS et al (2007) Focal atrophy in dementia with lewy bodies on MRI: a distinct pattern from Alzheimer’s disease. Brain. https://doi.org/10.1093/brain/awl388CrossRefPubMedPubMedCentral

Wilson RS, Nag S, Boyle PA, Hizel LP, Yu L, Buchman AS, Schneider JA, Bennett DA (2013) Neural reserve, neuronal density in the locus ceruleus, and cognitive decline. Neurology 80(13):1202–1208. https://doi.org/10.1212/WNL.0b013e3182897103CrossRefPubMedPubMedCentral

Wu H, Dunnett S, Ho YS, Chung Chang RC (2019) The role of sleep deprivation and circadian rhythm disruption as risk factors of Alzheimer’s disease. Front Neuroendocrinol. https://doi.org/10.1016/j.yfrne.2019.100764CrossRefPubMed

Yong-Hong L, Xiao-Dong P, Chang-Quan H, Bo Y, Qing-Xiu L (2013) Hypothalamic-pituitary-thyroid axis in patients with Alzheimer disease (AD). J Investig Med. https://doi.org/10.2310/JIM.0b013e318280aafbCrossRefPubMed

Yoon YS, Lee JS, Lee HS (2013) Retrograde study of CART- or NPY-neuronal projection from the hypothalamic arcuate nucleus to the dorsal raphe and/or the locus coeruleus in the rat. Brain Res. https://doi.org/10.1016/j.brainres.2013.04.039CrossRefPubMed

Yu X, Ji C, Shao A (2020) Neurovascular unit dysfunction and neurodegenerative disorders. Front Neurosci 14(April):334. https://doi.org/10.3389/fnins.2020.00334CrossRefPubMedPubMedCentral

Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D (2013) Hypothalamic programming of systemic ageing involving IKK-β, NF-ΚB and GnRH. Nature. https://doi.org/10.1038/nature12143CrossRefPubMedPubMedCentral

Zhu Y, Fenik P, Zhan G, Somach R, Xin R, Veasey S (2016) Intermittent short sleep results in lasting sleep wake disturbances and degeneration of locus coeruleus and orexinergic neurons. Sleep 39(8):1601–1611. https://doi.org/10.5665/sleep.6030CrossRefPubMedPubMedCentral

Zhu Y, Zhan G, Fenik P, Brandes M, Bell P, Francois N, Shulman K, Veasey S (2018) Chronic sleep disruption advances the temporal progression of tauopathy in P301S mutant mice. J Neurosci 38(48):10255–10270. https://doi.org/10.1523/JNEUROSCI.0275-18.2018CrossRefPubMedPubMedCentral

Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12(12):723–738. https://doi.org/10.1038/nrn3114CrossRefPubMedPubMedCentral

Title: The connections of Locus Coeruleus with hypothalamus: potential involvement in Alzheimer’s disease
Authors: Filippo Sean Giorgi
Alessandro Galgani
Stefano Puglisi-Allegra
Carla Letizia Busceti
Francesco Fornai
Publication date: 01-05-2021
Publisher: Springer Vienna
Keywords: Alzheimer's Disease
Alzheimer's Disease
Published in: Journal of Neural Transmission / Issue 5/2021
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-021-02338-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The connections of Locus Coeruleus with hypothalamus: potential involvement in Alzheimer’s disease

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2021

Evaluation of multi-feature auditory deviance detection in Parkinson’s disease: a mismatch negativity study

Tractography patterns of pedunculopontine nucleus deep brain stimulation

Cortical copper transporter expression in schizophrenia: interactions of risk gene dysbindin-1

Significance of cerebral amyloid angiopathy and other co-morbidities in Lewy body diseases

Association of early and later depressive symptoms with functional outcome after ischemic stroke

Endocannabinoid and dopaminergic system: the pas de deux underlying human motivation and behaviors