Axonal Transport of Neurotrophic Signals: An Achilles' Heel for Neurodegeneration?

  • Ahmad Salehi
  • Chengbiao Wu
  • Ke Zhan
  • William C. Mobley
Part of the Research and Perspectives in Alzheimer's Disease book series (ALZHEIMER)


The most effective treatments for neurodegenerative disorders, including Alzheimer's disease, will come from studies of the pathogenesis of age-related cognitive failure and understanding of the underlying mechanisms. Given the marked similarities in pathological and clinical phenotypes between Alzheimer's disease and Down syndrome, studies of the pathogenesis of one can be expected to complement and support those in the other. Alzheimer's disease and Down syndrome are characterized by dysfunction and loss of several biochemically and anatomically defined neuronal populations. The pathological involvement of hippocampus, in particular, is an early feature of both disorders, as is the degeneration of neurons whose axons innervate this region. Long, thin and poorly myelinated axons project from a number of subcortical and brain stem nuclei to modulate hippocampally mediated cognitive functions. In studies on mouse models of Down's syndrome, we uncovered evidence for the involvement of a particular neuronal population heavily innervating the hippocampus. In an extensive series of experiments, we found evidence that failed retrograde transport of nerve growth factor signaling in cholinergic neurons of the basal forebrain is linked to their vulnerability and that these changes are caused by increased gene dose and overexpression of the gene for amyloid precursor protein. These findings raise the possibility that intracellular trafficking defects created by changes in amyloid precursor protein expression or processing make an important contribution to pathogenesis and set the stage for studies to explore the molecular mechanisms of degeneration of cholinergic neurons and to define new therapeutic targets for these neurons. An important unanswered question is whether or not similar mechanisms operate within other vulnerable populations, innervating hippocampus to cause de-afferentation and dysfunction of this critical brain region.


Nerve Growth Factor Down Syndrome Dentate Gyrus Axonal Transport Retrograde Transport 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Belichenko PV, Masliah E, Kleschevnikov AM, Villar AJ, Epstein CJ, Salehi A, Mobley WC (2004) Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome. J Comp Neurol 480:281–298CrossRefPubMedGoogle Scholar
  2. Belichenko PV, Kleschevnikov AM, Salehi A, Garner C, Mobley W (2007) Synaptic and cognitive abnormalities in mouse models of Down syndrome: exploring genotype-phenotype relationships. J Comp Neurol 504:329–345CrossRefPubMedGoogle Scholar
  3. Borelli KG, Gargaro AC, dos Santos JM, Brandao ML (2005) Effects of inactivation of seroton-ergic neurons of the median raphe nucleus on learning and performance of contextual fear conditioning. Neurosci Lett 387:105–110PubMedCrossRefGoogle Scholar
  4. Braak E, Griffing K, Arai K, Bohl J, Bratzke H, Braak H (1999) Neuropathology of Alzheimer's disease: what is new since A. Alzheimer? Eur Arch\Psych Clin Neurosci 249 S3:14–22CrossRefGoogle Scholar
  5. Capsoni S, Ugolini G, Comparini A, Ruberti F, Berardi N, Cattaneo A (2000) Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci USA 97:6826–6831CrossRefPubMedGoogle Scholar
  6. Cataldo AM, Petanceska S, Peterhoff CM, Terio NB, Epstein CJ, Villar A, Carlson EJ, Staufenbiel M, Nixon RA (2003) App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of Down syndrome. J Neurosci 23:6788–6792PubMedGoogle Scholar
  7. Celada P, Siuciak JA, Tran TM, Altar CA, Tepper JM (1996) Local infusion of brain-derived neu-rotrophic factor modifies the firing pattern of dorsal raphe serotonergic neurons. Brain Res 712:293–298CrossRefPubMedGoogle Scholar
  8. Chapman RS, Hesketh LJ (2000) Behavioral phenotype of individuals with Down syndrome. Mental Retardation Dev Disabilities Res Rev 6:84–95CrossRefGoogle Scholar
  9. Chen Y, Dyakin VV, Branch CA, Ardekani B, Yang D, Guilfoyle DN, Peterson J, Peterhoff C, Ginsberg SD, Cataldo AM, Nixon RA (2008) In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model. Neurobiol Aging doi:10.1016Google Scholar
  10. Compton DM, Dietrich KL, Smith JS, Davis BK (1995) Spatial and non-spatial learning in the rat following lesions to the nucleus locus coeruleus. Neuroreport 7:177–182PubMedGoogle Scholar
  11. Cooper JD, Salehi A, Delcroix JD, Howe CL, Belichenko PV, Chua-Couzens J, Kilbridge JF, Carlson EJ, Epstein CJ, Mobley WC (2001) Failed retrograde transport of NGF in a mouse model of Down's syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc Natl Acad Sci USA 98:10439–10444CrossRefPubMedGoogle Scholar
  12. Cui B, Wu C, Chen L, Ramirez A, Bearer EL, Li WP, Mobley WC, Chu S (2007) One at a time, live tracking of NGF axonal transport using quantum dots. Proc Natl Acad Sci USA 104:13666–13671CrossRefPubMedGoogle Scholar
  13. Delcroix JD, Valletta JS, Wu C, Hunt SJ, Kowal AS, Mobley WC (2003) NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals. Neuron 39:69–84CrossRefPubMedGoogle Scholar
  14. Delcroix JD, Valletta J, Wu C, Howe CL, Lai CF, Cooper JD, Belichenko PV, Salehi A, Mobley WC (2004) Trafficking the NGF signal: implications for normal and degenerating neurons. Prog Brain Res 146:3–23PubMedGoogle Scholar
  15. Ginty DD, Segal RA (2002) Retrograde neurotrophin signaling: Trk-ing along the axon. Curr Opin Neurobiol 12:268–274CrossRefPubMedGoogle Scholar
  16. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349:704–706CrossRefPubMedGoogle Scholar
  17. Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML (2000) The DNA sequence of human chromosome 21. Nature 405:311–319CrossRefPubMedGoogle Scholar
  18. Heerssen HM, Segal RA (2002) Location, location, location: a spatial view of neurotrophin signal transduction. Trends Neurosci 25:160–165CrossRefPubMedGoogle Scholar
  19. Hohng S, Ha T (2004) Near-complete suppression of quantum dot blinking in ambient conditions. J Am ChemSoc 126:1324–1325CrossRefGoogle Scholar
  20. Holtzman DM, Li Y, Parada LF, Kinsman S, Chen CK, Valletta JS, Zhou J, Long JB, Mobley WC (1992) p140trk mRNA marks NGF-responsive forebrain neurons: evidence that trk gene expression is induced by NGF. Neuron 9:465–478CrossRefPubMedGoogle Scholar
  21. Howe CL, Mobley WC (2005) Long-distance retrograde neurotrophic signaling. Curr Opin Neurobiol 15:40–48CrossRefPubMedGoogle Scholar
  22. Moreau PH, Cosquer B, Jeltsch H, Cassel JC, Mathis C (2008) Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice. Hippocampus 18:610–622CrossRefPubMedGoogle Scholar
  23. Morrison JH, Hof PR (2002) Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer's disease. Prog Brain Res 136:467–486CrossRefPubMedGoogle Scholar
  24. Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T (1999) Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Prog Neurobiol 57:451–484CrossRefPubMedGoogle Scholar
  25. Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ, Barber PCButler AC (1998) Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann Neurol 43:380–383CrossRefPubMedGoogle Scholar
  26. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cup-ples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nature Genet 39:168–177CrossRefPubMedGoogle Scholar
  27. Roizen NJ, Patterson D (2003) Down's syndrome. Lancet 361:1281–1289CrossRefPubMedGoogle Scholar
  28. Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg TCampion D (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature Genet 38:24–26CrossRefPubMedGoogle Scholar
  29. Sago H, Carlson EJ, Smith DJ, Rubin EM, Crnic LS, Huang TT, Epstein CJ (2000) Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Ped Res 48:606–613CrossRefGoogle Scholar
  30. Salehi A, Pohlman B, Mobley WC (2008) Down syndrome/trisomy 21. Encycl Neurosci, in press.Google Scholar
  31. Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC (2006) Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51:29–42CrossRefPubMedGoogle Scholar
  32. Salehi A, Kleschevnikov AM, Mobley W (2007a) Cholinergic neurodegeneration in Alzheimer's disease: basis for nerve growth factor therapy. In: Cuello AC.(ed) Pharmacological mechanisms in Alzheimer's therapeutics. Springer 64–104Google Scholar
  33. Salehi A, Faizi M, Belichenko PV, Mobley WC (2007b) Using mouse models to explore genotype-phenotype relationship in Down syndrome. Mental Retardation De Disabilities Res Rev 13:207–214CrossRefGoogle Scholar
  34. Schmidt V, Sporbert A, Rohe M, Reimer T, Rehm A, Andersen OMWillnow TE (2007) SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1. J Biol Chem 282:32956–32964CrossRefPubMedGoogle Scholar
  35. Shahidi S, Motamedi F, Naghdi N (2004) Effect of reversible inactivation of the supramammillary nucleus on spatial learning and memory in rats. Brain Res 1026:267–274CrossRefPubMedGoogle Scholar
  36. Sofroniew MV, Howe CL, Mobley WC (2001) Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 24:1217–1281CrossRefPubMedGoogle Scholar
  37. Taylor AM, Rhee SW, Jeon NL (2006) Microfluidic chambers for cell migration and neuroscience research. Methods Mol Biol 321:167–77PubMedGoogle Scholar
  38. Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G, Tong G, Potkin SG, Fallon J, Hansen L, Mufson EJ, Kordower JH, Gall C, Conner J (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Med 11:551–555CrossRefPubMedGoogle Scholar
  39. Wessendorf MW (1991) Fluoro-Gold: composition, and mechanism of uptake. Brain Res 553:135– 148CrossRefPubMedGoogle Scholar
  40. Wisniewski KE, Dalton AJ, McLachlan C, Wen GY, Wisniewski HM (1985) Alzheimer's disease in Down's syndrome: clinicopathologic studies. Neurology 35:957–961PubMedGoogle Scholar
  41. Wu C, Ramirez A, Cui B, Ding J, Delcroix JD, Valletta JS, Liu JJ, Yang Y, Chu S, Mobley WC (2007) A functional dynein-microtubule network is required for NGF signaling through the Rap1/MAPK pathway. Traffic 8:1503–1520CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Ahmad Salehi
    • 1
  • Chengbiao Wu
    • 1
  • Ke Zhan
  • William C. Mobley
    1. 1.Dept of NeurologyStanford University School of MedicineStanfordUSA

    Personalised recommendations