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Microdialysis in Drug Development pp 163–178Cite as

Extracellular Amyloid-β Protein Dynamics in Alzheimer’s Disease

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Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 4))

Abstract

Alzheimer’s disease (AD) is caused by the accumulation of the amyloid- (Aβ) peptide within the brain extracellular space. Aβ is produced within neurons then secreted into the extracellular fluid. Normally, Aβ is found as a soluble, monomeric peptide within the brain interstitial fluid (ISF) and cerebrospinal fluid. During the pathogenesis of AD, however, Aβ changes conformation then aggregates into toxic higher ordered species, including soluble oligomers and insoluble plaques, which appear to underlie the etiology of AD. Conversion into these toxic species of Aβ appears to be concentration dependent and, at least partially, occurs within the ISF. Consequently, understanding the metabolic processes that regulate Aβ generation, particularly within the ISF, has implications for understanding pathogenesis as well as treatment. In order to study ISF Aβ metabolism in a physiological setting, several groups have utilized in vivo microdialysis both in animal models of disease as well as human patients. Synaptic transmission, the events that underlie brain function, directly leads to Aβ generation in vivo; suppressing synaptic activity rapidly reduces ISF Aβ levels whereas increasing activity increases Aβ levels. In mouse models of AD, behaviors such as stress and sleep/wake cycles also dynamically modulate ISF Aβ generation. Following traumatic brain injury, cortical ISF Aβ levels in humans is correlated with neurological status and synaptic transmission; comatose patients with initially low synaptic activity have low ISF Aβ levels which rise as neurological status improve. Conversely, in humans 10 % of individuals with temporal lobe epilepsy (TLE) develop Aβ plaques. The absolute concentration of Aβ within the ISF appears directly related to whether a brain region will develop plaques or not. Microdialysis provides a powerful tool to assess brain ISF Aβ levels longitudinally through a wide variety of experimental and behavioral paradigms.

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References

  • Bacskai BJ, Hyman BT (2002) Alzheimer’s disease: what multiphoton microscopy teaches us. Neuroscientist 8:386–390

    Article  PubMed  Google Scholar 

  • Bacskai BJ, Klunk WE, Mathis CA, Hyman BT (2002) Imaging amyloid-beta deposits in vivo. J Cereb Blood Flow Metab 22:1035–1041

    Article  PubMed  CAS  Google Scholar 

  • Beach TG, Walker DG, Potter PE, Sue LI, Fisher A (2001) Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists. Brain Res 905:220–223

    Article  PubMed  CAS  Google Scholar 

  • Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM (2011) Neuronal activity regulates the regional vulnerability to amyloid-beta deposition. Nat Neurosci 14:750–756

    Article  PubMed  CAS  Google Scholar 

  • Brendza RP, Simmons K, Bales KR, Paul SM, Goldberg MP, Holtzman DM (2003) Use of YFP to study amyloid-beta associated neurite alterations in live brain slices. Neurobiol Aging 24:1071–1077

    Article  PubMed  CAS  Google Scholar 

  • Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzman DM (2008) Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science 321:1221–1224

    Article  CAS  Google Scholar 

  • Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu H, Hedden T, Andrews-Hanna JR, Sperling RA, Johnson KA (2009) Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer’s disease. J Neurosci 29:1860–1873

    Article  PubMed  CAS  Google Scholar 

  • Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25:7709–7717

    Article  PubMed  CAS  Google Scholar 

  • Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58:42–51

    Article  PubMed  CAS  Google Scholar 

  • Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM (2005a) Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48:913–922

    Article  PubMed  CAS  Google Scholar 

  • Cirrito JR, May PC, O’Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, DeMattos RB, Holtzman DM (2003) In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci 23:8844–8853

    PubMed  CAS  Google Scholar 

  • Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM (2005b) P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest 115:3285–3290

    Article  PubMed  CAS  Google Scholar 

  • Cirrito JR, Disabato BM, Restivo JL, Verges DK, Goebel WD, Sathyan A, Hayreh D, D’Angelo G, Benzinger T, Yoon H, Kim J, Morris JC, Mintun MA, Sheline YI (2011) Serotonin signaling is associated with lower amyloid-{beta} levels and plaques in transgenic mice and humans. Proc Natl Acad Sci U S A 108:14968–14973

    Article  PubMed  CAS  Google Scholar 

  • 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 163:2164–2169

    Article  PubMed  Google Scholar 

  • Davis AA, Fritz JJ, Wess J, Lah JJ, Levey AI (2010) Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo. J Neurosci 30:4190–4196

    Article  PubMed  CAS  Google Scholar 

  • DeMattos RB, Cirrito JR, Parsadanian M, May PC, O’Dell MA, Taylor JW, Harmony JA, Aronow BJ, Bales KR, Paul SM, Holtzman DM (2004) ApoE and clusterin cooperatively suppress abeta levels and deposition. evidence that ApoE regulates extracellular abeta metabolism in vivo. Neuron 41:193–202

    Article  PubMed  CAS  Google Scholar 

  • Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 127:601–609

    Article  PubMed  CAS  Google Scholar 

  • Farris W, Schutz SG, Cirrito JR, Shankar GM, Sun X, George A, Leissring MA, Walsh DM, Qiu WQ, Holtzman DM, Selkoe DJ (2007) Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. Am J Pathol 171:241–251

    Article  PubMed  CAS  Google Scholar 

  • Fazeli MS, Breen K, Errington ML, Bliss TV (1994) Increase in extracellular NCAM and amyloid precursor protein following induction of long-term potentiation in the dentate gyrus of anaesthetized rats. Neurosci Lett 169:77–80

    Article  PubMed  CAS  Google Scholar 

  • Gordon-Krajcer W, Salinska E, Lazarewicz JW (2002) N-methyl-d-aspartate receptor-mediated processing of beta-amyloid precursor protein in rat hippocampal slices: in vitro–superfusion study. Folia Neuropathol 40:13–17

    PubMed  CAS  Google Scholar 

  • Gouras GK, Relkin NR, Sweeney D, Munoz DG, Mackenzie IR, Gandy S (1997) Increased apolipoprotein E epsilon 4 in epilepsy with senile plaques. Ann Neurol 41:402–404

    Article  PubMed  CAS  Google Scholar 

  • Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–8884

    PubMed  CAS  Google Scholar 

  • Holtzman DM, Morris JC, Goate AM (2011) Alzheimer’s disease: the challenge of the second century. Sci Transl Med 3:77sr71

    Google Scholar 

  • Hong S, Quintero-Monzon O, Ostaszewski BL, Podlisny DR, Cavanaugh WT, Yang T, Holtzman DM, Cirrito JR, Selkoe DJ (2011) Dynamic analysis of amyloid beta-protein in behaving mice reveals opposing changes in ISF versus parenchymal Abeta during age-related plaque formation. J Neurosci 31:15861–15869

    Article  PubMed  CAS  Google Scholar 

  • Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM (2009) Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326:1005–1007

    Article  CAS  Google Scholar 

  • Klunk WE, Bacskai BJ, Mathis CA, Kajdasz ST, McLellan ME, Frosch MP, Debnath ML, Holt DP, Wang Y, Hyman BT (2002) Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative. J Neuropathol Exp Neurol 61:797–805

    PubMed  CAS  Google Scholar 

  • Klyubin I, Walsh DM, Cullen WK, Fadeeva JV, Anwyl R, Selkoe DJ, Rowan MJ (2004) Soluble arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivo. Eur J Neurosci 19:2839–2846

    Article  PubMed  Google Scholar 

  • Koo EH, Squazzo SL (1994) Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem 269:17386–17389

    PubMed  CAS  Google Scholar 

  • Lah JJ, Levey AI (2000) Endogenous presenilin-1 targets to endocytic rather than biosynthetic compartments. Mol Cell Neurosci 16:111–126

    Article  PubMed  CAS  Google Scholar 

  • Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloproteinase. Proc Natl Acad Sci U S A 96:3922–3927

    Article  PubMed  CAS  Google Scholar 

  • Lesne S, Ali C, Gabriel C, Croci N, MacKenzie ET, Glabe CG, Plotkine M, Marchand-Verrecchia C, Vivien D, Buisson A (2005) NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. J Neurosci 25:9367–9377

    Article  PubMed  CAS  Google Scholar 

  • Mackenzie IR, Miller LA (1994) Senile plaques in temporal lobe epilepsy. Acta Neuropathol (Berl) 87:504–510

    Article  CAS  Google Scholar 

  • Magnoni S, Esparza TJ, Conte V, Carbonara M, Carrabba G, Holtzman DM, Zipfel GJ, Stocchetti N, Brody DL (2012) Tau elevations in the brain extracellular space correlate with reduced amyloid-beta levels and predict adverse clinical outcomes after severe traumatic brain injury. Brain 135:1268–1280

    Google Scholar 

  • Marcello E, Gardoni F, Mauceri D, Romorini S, Jeromin A, Epis R, Borroni B, Cattabeni F, Sala C, Padovani A, Di Luca M (2007) Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity. J neurosci 27:1682–1691

    Article  PubMed  CAS  Google Scholar 

  • Marquez-Sterling NR, Lo AC, Sisodia SS, Koo EH (1997) Trafficking of cell-surface beta-amyloid precursor protein: evidence that a sorting intermediate participates in synaptic vesicle recycling. J Neurosci 17:140–151

    PubMed  CAS  Google Scholar 

  • Meyer-Luehmann M, Stalder M, Herzig MC, Kaeser SA, Kohler E, Pfeifer M, Boncristiano S, Mathews PM, Mercken M, Abramowski D, Staufenbiel M, Jucker M (2003) Extracellular amyloid formation and associated pathology in neural grafts. Nat Neurosci 6:370–377

    Article  PubMed  CAS  Google Scholar 

  • Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC (2006) [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67:446–452

    Article  CAS  Google Scholar 

  • Mizuno T, Nakata M, Naiki H, Michikawa M, Wang R, Haass C, Yanagisawa K (1999) Cholesterol-dependent generation of a seeding amyloid beta-protein in cell culture. J Biol Chem 274:15110–15114

    Article  PubMed  CAS  Google Scholar 

  • Morris JC, Price AL (2001) Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J Mol Neurosci 17:101–118

    Article  PubMed  CAS  Google Scholar 

  • Nelson RL, Guo Z, Halagappa VM, Pearson M, Gray AJ, Matsuoka Y, Brown M, Martin B, Iyun T, Maudsley S, Clark RF, Mattson MP (2007) Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3 x TgAD mice. Exp Neurol 205:166–176

    Article  PubMed  CAS  Google Scholar 

  • Newton AJ, Kirchhausen T, Murthy VN (2006) Inhibition of dynamin completely blocks compensatory synaptic vesicle endocytosis. Proc Natl Acad Sci U S A 103:17955–17960

    Article  PubMed  CAS  Google Scholar 

  • Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH (2000) The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 48:913–918

    Article  PubMed  CAS  Google Scholar 

  • Rogers J, Strohmeyer R, Kovelowski CJ, Li R (2002) Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 40:260–269

    Article  PubMed  Google Scholar 

  • Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766

    PubMed  CAS  Google Scholar 

  • Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C et al (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359:325–327

    Article  PubMed  CAS  Google Scholar 

  • Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842

    Article  PubMed  CAS  Google Scholar 

  • Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV (2000) Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106:1489–1499

    Article  PubMed  CAS  Google Scholar 

  • Sloviter RS, Dichter MA, Rachinsky TL, Dean E, Goodman JH, Sollas AL, Martin DL (1996) Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. J Comp Neurol 373:593–618

    Article  PubMed  CAS  Google Scholar 

  • Vassar R et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741

    Article  PubMed  CAS  Google Scholar 

  • Verges DK, Restivo JL, Goebel WD, Holtzman DM, Cirrito JR (2011) Opposing synaptic regulation of amyloid-beta metabolism by NMDA receptors in vivo. J Neurosci 31:11328–11337

    Article  PubMed  CAS  Google Scholar 

  • Wilson RS, Evans DA, Bienias JL, Mendes de Leon CF, Schneider JA, Bennett DA (2003) Proneness to psychological distress is associated with risk of Alzheimer’s disease. Neurology 61:1479–1485

    Article  CAS  Google Scholar 

  • Wilson RS, Barnes LL, Bennett DA, Li Y, Bienias JL, Mendes de Leon CF, Evans DA (2005) Proneness to psychological distress and risk of Alzheimer disease in a biracial community. Neurologys 64:380–382

    Article  CAS  Google Scholar 

  • Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med 9:453–457

    Article  PubMed  CAS  Google Scholar 

  • Yin KJ, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu FF, Turk J, Xu J, Hsu CY, Mills JC, Holtzman DM, Lee JM (2006) Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 26:10939–10948

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Hope Center for Neurological Disorders, and the Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    John R. Cirrito

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  1. John R. Cirrito
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Correspondence to John R. Cirrito .

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  1. Allgemeines Krankenhaus, Department of Clinical Pharmacology, Medical University Vienna, Währinger Gürtel 18-20, Vienna, 1090, Austria

    Markus Müller

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Cirrito, J.R. (2013). Extracellular Amyloid-β Protein Dynamics in Alzheimer’s Disease. In: Müller, M. (eds) Microdialysis in Drug Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4815-0_9

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