Skip to main content

Advertisement

SpringerLink
Log in

Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Aβ) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

A fascinating yet perhaps overlooked trait of the p75 neurotrophin receptor (p75NTR) is its ability to bind ligands with no obvious neurotrophic function. Using cultured basal forebrain (BF) neurons, this study demonstrates selective internalization of amyloid β (Aβ) 1–42 in conjunction with p75NTR (labelled with IgG192-Cy3) by cholinergic cells. Active under resting conditions, this process was enhanced by high K+ stimulation and was insensitive to inhibitors of regulated synaptic activity—tetrodotoxin or botulinum neurotoxins (BoNT type/A and/B). Blockade of sarco-endoplasmic reticulum (SERCA) Ca2+ ATPase with thapsigargin and CPA or chelation of Ca2+ with EGTA-AM strongly suppressed the endocytosis of p75NTR, implicating the role of ER released Ca2+. The uptake of IgG192-Cy3 was also reduced by T-type Ca2+ channel blocker mibefradil but not Cd2+, an indiscriminate blocker of high voltage-activated Ca2+ currents. A strong co-localization of IgG192-Cy3 with late endosome (Rab7) or lysosome (Lamp1) qualifier proteins suggest these compartments as the primary destination for internalized IgG192 and Aβ. Selective uptake and labeling of BF cholinergic cells with IgG192-Cy3 injected into the prefrontal cortex was verified also in vivo. The significance of these findings in relation to Aβ clearance in the cerebral cortex and pathophysiology of Alzheimer’s disease is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Allen SJ, Watson JJ, Dawbarn D (2011) The neurotrophins and their role in Alzheimer's disease. Curr Neuropharmacol 9(4):559–573

    Google Scholar 

  • Almeida CG, Takahashi RH, Gouras GK (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci 26:4277–4288

    Article  CAS  PubMed  Google Scholar 

  • Arevalo MA, Roldan PM, Chacon PJ, Rodriguez-Tebar A (2009) Amyloid beta serves as an NGF-like neurotrophic factor or acts as a NGF antagonist depending on its concentration. J Neurochem 111:1425–1433

    Article  CAS  PubMed  Google Scholar 

  • Auld DS, Day JC, Mennicken F, Quirion R (2000) Pharmacological characterization of endogenous acetylcholine release from primary septal cultures. J Pharmacol Exp Ther 292:692–697

    CAS  PubMed  Google Scholar 

  • Baldwin AN, Shooter EM (1995) Zone mapping of the binding domain of the rat low affinity nerve growth factor receptor by the introduction of novel N-glycosylation sites. J Biol Chem 270:4594–4602

    Article  CAS  PubMed  Google Scholar 

  • Buckner RL, Andrews-Hanna JR, Schacter DL (2008) The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci 1124:1–38

    Article  PubMed  Google Scholar 

  • Butowt R, von Bartheld CS (2009) Fates of neurotrophins after retrograde axonal transport: phosphorylation of p75NTR is a sorting signal for delayed degradation. J Neurosci 29:10715–10729

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Buzsaki G, Gage FH (1989) The cholinergic nucleus basalis: a key structure in neocortical arousal. Exs 57:159–171

    CAS  PubMed  Google Scholar 

  • Cantalupo G, Alifano P, Roberti V, Bruni CB, Bucci C (2001) Rab-interacting lysosomal protein (RILP): the Rab7 effector required for transport to lysosomes. EMBO J 20:683–693

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chakravarthy B, Menard M, Ito S, Gaudet C, Dal Pra I, Armato U, Whitfield J (2012) Hippocampal membrane-associated p75NTR levels are increased in Alzheimer’s disease. J Alzheimers Dis 30:675–684

    CAS  PubMed  Google Scholar 

  • Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309

    Article  CAS  PubMed  Google Scholar 

  • Coulson EJ, May LM, Osborne SL, Reid K, Underwood CK, Meunier FA, Bartlett PF, Sah P (2008) p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate. J Neurosci 28:315–324

    Article  CAS  PubMed  Google Scholar 

  • Coulson EJ, May LM, Sykes AM, Hamlin AS (2009) The role of the p75 neurotrophin receptor in cholinergic dysfunction in Alzheimer’s disease. Neuroscientist 15:317–323

    Article  CAS  PubMed  Google Scholar 

  • Counts SE, Mufson EJ (2005) The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease. J Neuropathol Exp Neurol 64:263–272

    CAS  PubMed  Google Scholar 

  • Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ (2002) Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 277:32046–32053

    Article  CAS  PubMed  Google Scholar 

  • Dean C, Liu H, Dunning FM, Chang PY, Jackson MB, Chapman ER (2009) Synaptotagmin-IV modulates synaptic function and long-term potentiation by regulating BDNF release. Nat Neurosci 12:767–776

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dechant G, Barde YA (2002) The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat Neurosci 5:1131–1136

    Article  CAS  PubMed  Google Scholar 

  • Ertel SI, Ertel EA (1997) Low-voltage-activated T-type Ca2+ channels. Trends Pharmacol Sci 18:37–42

    Article  CAS  PubMed  Google Scholar 

  • Ertel SI, Ertel EA, Clozel JP (1997) T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. Cardiovasc Drugs Ther 11:723–739

    Article  CAS  PubMed  Google Scholar 

  • Etheredge JA, Murchison D, Abbott LC, Griffith WH (2007) Functional compensation by other voltage-gated Ca2+ channels in mouse basal forebrain neurons with Ca(V)2.1 mutations. Brain Res 1140:105–119

    Article  CAS  PubMed  Google Scholar 

  • Gad H, Low P, Zotova E, Brodin L, Shupliakov O (1998) Dissociation between Ca2+-triggered synaptic vesicle exocytosis and clathrin-mediated endocytosis at a central synapse. Neuron 21:607–616

    Article  CAS  PubMed  Google Scholar 

  • Geula C, Mesulam MM, Saroff DM, Wu CK (1998) Relationship between plaques, tangles, and loss of cortical cholinergic fibers in Alzheimer disease. J Neuropathol Exp Neurol 57:63–75

    Article  CAS  PubMed  Google Scholar 

  • Ginsberg SD, Che S, Wuu J, Counts SE, Mufson EJ (2006) Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer’s disease. J Neurochem 97:475–487

    Article  CAS  PubMed  Google Scholar 

  • Griffith WH, Taylor L, Davis MJ (1994) Whole-cell and single-channel calcium currents in guinea pig basal forebrain neurons. J Neurophysiol 71:2359–2376

    CAS  PubMed  Google Scholar 

  • Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  PubMed  Google Scholar 

  • Hartig W, Seeger J, Naumann T, Brauer K, Bruckner G (1998) Selective in vivo fluorescence labelling of cholinergic neurons containing p75(NTR) in the rat basal forebrain. Brain Res 808:155–165

    Article  CAS  PubMed  Google Scholar 

  • Hartmann M, Heumann R, Lessmann V (2001) Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J 20:5887–5897

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hasselmo ME, Giocomo LM (2006) Cholinergic modulation of cortical function. J Mol Neurosci 30:133–135

    Article  CAS  PubMed  Google Scholar 

  • Hefti F, Weiner WJ (1986) Nerve growth factor and Alzheimer’s disease. Ann Neurol 20:275–281

    Article  CAS  PubMed  Google Scholar 

  • Herreros J, Ng T, Schiavo G (2001) Lipid rafts act as specialized domains for tetanus toxin binding and internalization into neurons. Mol Biol Cell 12:2947–2960

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Huang CS, Zhou J, Feng AK, Lynch CC, Klumperman J, DeArmond SJ, Mobley WC (1999) Nerve growth factor signaling in caveolae-like domains at the plasma membrane. J Biol Chem 274:36707–36714

    Article  CAS  PubMed  Google Scholar 

  • Huerta PT, Lisman JE (1995) Bidirectional synaptic plasticity induced by a single burst during cholinergic theta oscillation in CA1 in vitro. Neuron 15:1053–1063

    Article  CAS  PubMed  Google Scholar 

  • Huotari J, Helenius A (2011) Endosome maturation. EMBO J 30:3481–3500

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, Eskelinen EL (2004) Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117:4837–4848

    Article  PubMed  Google Scholar 

  • Kacza J, Grosche J, Seeger J, Brauer K, Bruckner G, Hartig W (2000) Laser scanning and electron microscopic evidence for rapid and specific in vivo labelling of cholinergic neurons in the rat basal forebrain with fluorochromated antibodies. Brain Res 867:232–238

    Article  CAS  PubMed  Google Scholar 

  • Lacy DB, Stevens RC (1997) Recombinant expression and purification of the botulinum neurotoxin type A translocation domain. Protein Expr Purif 11:195–200

    Article  CAS  PubMed  Google Scholar 

  • LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8:499–509

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lalli G, Schiavo G (2002) Analysis of retrograde transport in motor neurons reveals common endocytic carriers for tetanus toxin and neurotrophin receptor p75NTR. J Cell Biol 156:233–239

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Langui D, Girardot N, El Hachimi KH, Allinquant B, Blanchard V, Pradier L, Duyckaerts C (2004) Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. Am J Pathol 165:1465–1477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lawrence JJ (2008) Cholinergic control of GABA release: emerging parallels between neocortex and hippocampus. Trends Neurosci 31:317–327

    Article  CAS  PubMed  Google Scholar 

  • Lawrence JJ, Grinspan ZM, Statland JM, McBain CJ (2006) Muscarinic receptor activation tunes mouse stratum oriens interneurones to amplify spike reliability. J Physiol 571:555–562

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lytton J, Westlin M, Hanley MR (1991) Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem 266:17067–17071

    CAS  PubMed  Google Scholar 

  • McKinney M, Jacksonville MC (2005) Brain cholinergic vulnerability: relevance to behavior and disease. Biochem Pharmacol 70:1115–1124

    Article  CAS  PubMed  Google Scholar 

  • Mesulam MM (1990) Human brain cholinergic pathways. Prog Brain Res 84:231–241

    Article  CAS  PubMed  Google Scholar 

  • Mesulam M (2004) The cholinergic lesion of Alzheimer’s disease: pivotal factor or side show? Learn Mem 11:43–49

    Article  PubMed  Google Scholar 

  • Mudd LM, Torres J, Lopez TF, Montague J (1998) Effects of growth factors and estrogen on the development of septal cholinergic neurons from the rat. Brain Res Bull 45:137–142

    Article  CAS  PubMed  Google Scholar 

  • Mufson EJ, Ginsberg SD, Ikonomovic MD, DeKosky ST (2003) Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction. J Chem Neuroanat 26(4):233–242

    Google Scholar 

  • Mullins C, Bonifacino JS (2001) The molecular machinery for lysosome biogenesis. BioEssays 23:333–343

    Article  CAS  PubMed  Google Scholar 

  • Murchison D, Griffith WH (1995) Low-voltage activated calcium currents increase in basal forebrain neurons from aged rats. J Neurophysiol 74:876–887

    CAS  PubMed  Google Scholar 

  • Naumann T, Casademunt E, Hollerbach E, Hofmann J, Dechant G, Frotscher M, Barde YA (2002) Complete deletion of the neurotrophin receptor p75NTR leads to long-lasting increases in the number of basal forebrain cholinergic neurons. J Neurosci 22:2409–2418

    CAS  PubMed  Google Scholar 

  • Nazer B, Hong S, Selkoe DJ (2008) LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-beta peptide in a blood-brain barrier in vitro model. Neurobiol Dis 30:94–102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nitsch RM, Slack BE, Wurtman RJ, Growdon JH (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258:304–307

    Article  CAS  PubMed  Google Scholar 

  • Nixon RA (2007) Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 120:4081–4091

    Article  CAS  PubMed  Google Scholar 

  • O’Leary VB, Ovsepian SV, Raghunath A, Huo Q, Lawrence GW, Smith L, Dolly JO (2011) Innocuous full-length botulinum neurotoxin targets and promotes the expression of lentiviral vectors in central and autonomic neurons. Gene Ther 18:656–665

    Article  PubMed  Google Scholar 

  • Ovsepian SV (2008) Differential cholinergic modulation of synaptic encoding and gain control mechanisms in rat hippocampus. Neurosci Res 61:92–98

    Article  CAS  PubMed  Google Scholar 

  • Ovsepian SV, Dolly JO (2011) Dendritic SNAREs add a new twist to the old neuron theory. Proc Natl Acad Sci USA 108:19113–19120

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ovsepian SV, Friel DD (2012) Enhanced synaptic inhibition disrupts the efferent code of cerebellar Purkinje neurons in leaner Cav2.1 Ca2+ channel mutant mice. Cerebellum 11:666–680

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ovsepian SV, Anwyl R, Rowan MJ (2004) Endogenous acetylcholine lowers the threshold for long-term potentiation induction in the CA1 area through muscarinic receptor activation: in vivo study. Eur J Neurosci 20:1267–1275

    Article  PubMed  Google Scholar 

  • Ovsepian SV, Dolly JO, Zaborszky L (2012) Intrinsic voltage dynamics govern the diversity of spontaneous firing profiles in basal forebrain noncholinergic neurons. J Neurophysiol 108:406–418

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patel AN, Jhamandas JH (2012) Neuronal receptors as targets for the action of amyloid-beta protein (Abeta) in the brain. Expert Rev Mol Med 14:e2

    Article  PubMed  Google Scholar 

  • Saavedra L, Mohamed A, Ma V, Kar S, de Chaves EP (2007) Internalization of beta-amyloid peptide by primary neurons in the absence of apolipoprotein E. J Biol Chem 282:35722–35732

    Article  CAS  PubMed  Google Scholar 

  • Salinas S, Schiavo G, Kremer EJ (2010) A hitchhiker’s guide to the nervous system: the complex journey of viruses and toxins. Nat Rev Microbiol 8:645–655

    Article  CAS  PubMed  Google Scholar 

  • Shupliakov O (2009) The synaptic vesicle cluster: a source of endocytic proteins during neurotransmitter release. Neuroscience 158:204–210

    Article  CAS  PubMed  Google Scholar 

  • Smith LA (1998) Development of recombinant vaccines for botulinum neurotoxin. Toxicon 36:1539–1548

    Article  CAS  PubMed  Google Scholar 

  • Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ (2008) Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28:3941–3946

    Article  CAS  PubMed  Google Scholar 

  • Swaab DF (1991) Brain aging and Alzheimer’s disease, “wear and tear” versus “use it or lose it”. Neurobiol Aging 12:317–324

    Article  CAS  PubMed  Google Scholar 

  • Takahashi RH, Nam EE, Edgar M, Gouras GK (2002a) Alzheimer beta-amyloid peptides: normal and abnormal localization. Histol Histopathol 17:239–246

    CAS  PubMed  Google Scholar 

  • Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK (2002b) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Taniuchi M, Johnson EM Jr (1985) Characterization of the binding properties and retrograde axonal transport of a monoclonal antibody directed against the rat nerve growth factor receptor. J Cell Biol 101:1100–1106

    Article  CAS  PubMed  Google Scholar 

  • Tsien RW, Lipscombe D, Madison DV, Bley KR, Fox AP (1988) Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci 11:431–438

    Article  CAS  PubMed  Google Scholar 

  • Ullrich O, Reinsch S, Urbe S, Zerial M, Parton RG (1996) Rab11 regulates recycling through the pericentriolar recycling endosome. J Cell Biol 135:913–924

    Article  CAS  PubMed  Google Scholar 

  • Van der Zee CE, Ross GM, Riopelle RJ, Hagg T (1996) Survival of cholinergic forebrain neurons in developing p75NGFR-deficient mice. Science 274:1729–1732

    Article  PubMed  Google Scholar 

  • Wang YJ, Wang X, Lu JJ, Li QX, Gao CY, Liu XH, Sun Y, Yang M, Lim Y, Evin G, Zhong JH, Masters C, Zhou XF (2011) p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. J Neurosci 31:2292–2304

    Article  CAS  PubMed  Google Scholar 

  • Wayman CP, McFadzean I, Gibson A, Tucker JF (1996) Two distinct membrane currents activated by cyclopiazonic acid-induced calcium store depletion in single smooth muscle cells of the mouse anococcygeus. Br J Pharmacol 117:566–572

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yaar M, Zhai S, Pilch PF, Doyle SM, Eisenhauer PB, Fine RE, Gilchrest BA (1997) Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J Clin Invest 100:2333–2340

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yaar M, Zhai S, Fine RE, Eisenhauer PB, Arble BL, Stewart KB, Gilchrest BA (2002) Amyloid beta binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J Biol Chem 277:7720–7725

    Article  CAS  PubMed  Google Scholar 

  • Yan Z, Feng J (2004) Alzheimer’s disease: interactions between cholinergic functions and beta-amyloid. Curr Alzheimer Res 1:241–248

    Article  CAS  PubMed  Google Scholar 

  • Zaborszky L (2002) The modular organization of brain systems. Basal forebrain: the last frontier. Prog Brain Res 136:359–372

    Article  PubMed  Google Scholar 

  • Zeng F, Lu JJ, Zhou XF, Wang YJ (2011) Roles of p75NTR in the pathogenesis of Alzheimer’s disease: a novel therapeutic target. Biochem Pharmacol 82:1500–1509

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Program for Research in Third Level Institutions Cycle 4 grant from the Irish Higher Educational Authority for the Neuroscience section of ‘Targeted-driven therapeutics and theranostics’ (to Saak V. Ovsepian and J. Oliver Dolly), NIH/NINDS NS023945 grant (to Laszlo Zaborszky) and Deutsche Forschungsgemeinschaft within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy) (Jochen Herms). Authors thank Liam Ryan for expressing and purifying BoNT/A and/B.

Author information

Authors and Affiliations

  1. International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Republic of Ireland

    Saak V. Ovsepian, Inga Antyborzec, Valerie B. O’Leary & J. Oliver Dolly

  2. Department of Translational Brain Research, DZNE, Munich, Germany

    Saak V. Ovsepian, Inga Antyborzec & Jochen Herms

  3. Institute of Radiation Biology, Helmholtz Zentrum Munchen, Neuherberg, Germany

    Valerie B. O’Leary

  4. Centre for Molecular and Behavioural Neuroscience, The State University of New Jersey Rutgers, Newark, NJ, USA

    Laszlo Zaborszky

Authors
  1. Saak V. Ovsepian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Inga Antyborzec
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valerie B. O’Leary
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laszlo Zaborszky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jochen Herms
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Oliver Dolly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Saak V. Ovsepian or J. Oliver Dolly.

Additional information

S. V. Ovsepian and I. Antyborzec contributed equally to this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (MOV 5241 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ovsepian, S.V., Antyborzec, I., O’Leary, V.B. et al. Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Aβ) peptide, guiding it to lysosomes for degradation in basal forebrain cholinergic neurons. Brain Struct Funct 219, 1527–1541 (2014). https://doi.org/10.1007/s00429-013-0583-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-013-0583-x

Keywords

Search

Navigation