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Nerve Growth Factor and Alzheimer's Disease: New Facts for an Old Hypothesis

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Abstract

Understanding sporadic Alzheimer's disease (AD) onset and progression requires an explanation of what triggers the common core of abnormal processing of the amyloid precursor protein and tau processing. In the quest for upstream drivers of sporadic, late-onset AD neurodegeneration, nerve growth factor (NGF) has a central role. Initially connected to AD on a purely correlative basis, because of its neurotrophic actions on basal forebrain cholinergic neurons, two independent lines of research, reviewed in this article, place alterations of NGF processing and signaling at the center stage of a new mechanism, leading to the activation of amyloidogenesis and tau processing. Thus, experimental studies on NGF deficit induced neurodegeneration in transgenic mice, as well as the mechanistic studies on the anti-amyloidogenic actions of NGF/TrkA signaling in primary neuronal cultures demonstrated a novel causal link between neurotrophic signaling deficits and Alzheimer's neurodegeneration. Around these results, a new NGF hypothesis can be built, with neurotrophic deficits of various types representing an upstream driver of the core AD triad pathology. According to the new NGF hypothesis for AD, therapies aimed at reestablishing a correct homeostatic balance between ligands (and receptors) of the NGF pathway appear to have a clear and strong rationale, not just as long-term cholinergic neuroprotection, but also as a truly disease-modifying approach.

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References

  1. Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414

    Article  PubMed  CAS  Google Scholar 

  2. 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 349:704–706

    Article  PubMed  CAS  Google Scholar 

  3. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K et al (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269:973–977

    Article  PubMed  CAS  Google Scholar 

  4. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T et al (1995) Familial Alzheimer's disease in kindreds with missesnse mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376:775–778

    Article  PubMed  CAS  Google Scholar 

  5. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375:754–760

    Article  PubMed  CAS  Google Scholar 

  6. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A et al (1998) Association of missense and 5’-splice-site mutations in Tau with the inherited dementia FTDP-17. Nature 393:702–705

    Article  PubMed  CAS  Google Scholar 

  7. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297(5580):353–356

    Article  PubMed  CAS  Google Scholar 

  8. Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120:545–555

    Article  PubMed  CAS  Google Scholar 

  9. Wisniewski T, Konietzko U (2008) Amyloid-beta immunization for Alzheimer's disease. Lancet Neurol 7:805–811

    Article  PubMed  CAS  Google Scholar 

  10. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW et al (2008) Long term effects of Abeta 42 immunization in Alzheimer's disease: follow-up of a randomized placebo-controlled phase I trial. Lancet 372(9634):216–223

    Article  PubMed  CAS  Google Scholar 

  11. St George-Hyslop PH, Morris JC (2008) Will anti-amyloid therapies work for Alzheimer's disease? Lancet 372:180–182

    Article  PubMed  Google Scholar 

  12. Selkoe DJ (2011) Resolving controversies on the path to Alzheimer's therapeutics. Nat Med 17(9):1060–1065

    Article  PubMed  CAS  Google Scholar 

  13. Benilova I, Karren E, De Strooper B (2012) The toxic A beta oligomers and Alzheimer's disease: an emperor in need of clothes. Nat Neurosci 15:1–9

    Article  CAS  Google Scholar 

  14. Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298:789–791

    Article  PubMed  CAS  Google Scholar 

  15. Golde TE, Schneider LS, Koo EH (2011) Anti Abeta therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron 27:203–213

    Article  CAS  Google Scholar 

  16. Small SA, Duff K (2008) Linking Aβ and Tau in late-onset Alzheimer's disease: a dual pathway hypothesis. Neuron 60:534–542

    Article  PubMed  CAS  Google Scholar 

  17. Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237:1154–1162

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Counts SE, Nadeem M, Wuu J, Ginsberg SD, Saragovi HU, Mufson EJ (2004) Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer's disease. Ann Neurol 56:520–531

    Article  PubMed  CAS  Google Scholar 

  20. Mufson EJ, Ma SY, Cochran EJ, Bennett DA, Beckett LA, Jaffar S, Saragovi HU, Kordower JH (2000) Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer's disease. J Comp Neurol 427:19–30

    Article  PubMed  CAS  Google Scholar 

  21. Fahnestock M, Scott SA, Jette N, Weingartner JA, Crutcher KA (1996) Nerve growth factor mRNA and protein levels measured in the same tissue from normal and Alzheimer's disease parietal cortex. Brain Res Mol Brain Res 42:175–178

    Article  PubMed  CAS  Google Scholar 

  22. Salehi A, Delcroix JD, Mobley WC (2003) Traffic at the intersection of neurotrophic factor signaling and neurodegeneration. Trends Neurosci 26:73–80

    Article  PubMed  CAS  Google Scholar 

  23. Schindowski K, Belarbi K, Buee L (2008) Neurotrophic factors in Alzheimer's disease: role of axonal transport. Genes Brain Behav 7:43–56

    Article  PubMed  CAS  Google Scholar 

  24. Shooter EM (2001) Early days of the nerve growth factor proteins. Annu Rev Neurosci 24:601–629

    Article  PubMed  CAS  Google Scholar 

  25. Bruno MA, Cuello AC (2006) Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci USA 103:6735–6740

    Article  PubMed  CAS  Google Scholar 

  26. Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948

    Article  PubMed  CAS  Google Scholar 

  27. Fahnestock M, Yu G, Coughlin MD (2004) ProNGF: a neurotrophic or an apoptotic molecule? Prog Brain Res 146:101–110

    Article  PubMed  CAS  Google Scholar 

  28. Paoletti F, Covaceuszach S, Konarev PV, Gonfloni S, Malerba F, Schwarz E, Svergun DI, Cattaneo A, Lamba D (2009) Intrinsic structural disorder of mouse proNGF. Proteins 75(4):990–1009

    Article  PubMed  CAS  Google Scholar 

  29. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C et al (2004) Sortilin is essential for proNGFinduced neuronal cell death. Nature 427:843–848

    Article  PubMed  CAS  Google Scholar 

  30. Fahnestock M, Michalski B, Xu B, Coughlin MD (2001) The precursor pro-nerve growth factor is the predominant form of nerve growth factor in brain and is increased in Alzheimer's disease. Mol Cell Neurosci 18:210–220

    Article  PubMed  CAS  Google Scholar 

  31. Bruno MA, Leon WC, Fragoso G, Mushynski WE, Almazan G, Cuello AC (2009) Amyloid β–induced NGF dysmetabolism in Alzheimer disease. J Neuropathol Exp Neurol 68:857–869

    Article  PubMed  CAS  Google Scholar 

  32. Nykjaer A, Willnow TE, Petersen CM (2005) p75NTR—live or let die. Curr Opin Neurobiol 15:49–57

    Article  PubMed  CAS  Google Scholar 

  33. Hempstead BL (2006) Dissecting the diverse actions of pro- and mature neurotrophins. Curr Alzheimer Res 3:19–24

    Article  PubMed  CAS  Google Scholar 

  34. 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 97:6826–6831

    Article  PubMed  CAS  Google Scholar 

  35. Ruberti F, Capsoni S, Comparini A, Di Daniel E, Franzot J, Gonfloni S, Rossi G, Berardi N, Cattaneo A (2000) Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen, and skeletal muscle dystrophy. J Neurosci 20:2589–2601

    PubMed  CAS  Google Scholar 

  36. Berardi N, Braschi C, Capsoni S, Cattaneo A, Maffei L (2007) Environmental enrichment delays the onset of memory deficits and reduces neuropathological hallmarks in a mouse model of Alzheimer-like neurodegeneration. J Alzheimers Dis 11:359–370

    PubMed  CAS  Google Scholar 

  37. De Rosa R, Garcia AA, Braschi C, Capsoni S, Maffei L, Berardi N, Cattaneo A (2005) Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc Natl Acad Sci USA 102:3811–3816

    Article  PubMed  CAS  Google Scholar 

  38. Origlia N, Capsoni S, Domenici L, Cattaneo A (2006) Time window in cholinomimetic ability to rescue long-term potentiation in neurodegenerating antinerve growth factor mice. J Alzheimers Dis 9:59–68

    PubMed  CAS  Google Scholar 

  39. Sola E, Capsoni S, Rosato-Siri M, Cattaneo A, Cherubini E (2006) Failure of nicotine-dependent enhancement of synaptic efficacy at Schaffer-collateral CA1 synapses of AD11 anti-nerve growth factor transgenic mice. Eur J Neurosci 24:1252–1264

    Article  PubMed  Google Scholar 

  40. Capsoni S, Giannotta S, Cattaneo A (2002) Beta-amyloid plaques in a model for sporadic Alzheimer's disease based on transgenic anti-nerve growth factor antibodies. Mol Cell Neurosci 21:15–28

    Article  PubMed  CAS  Google Scholar 

  41. Capsoni S, Giannotta S, Cattaneo A (2002) Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice. Proc Natl Acad Sci USA 99:12432–12437

    Article  PubMed  CAS  Google Scholar 

  42. Capsoni S, Cattaneo A (2006) On the molecular basis linking nerve growth factor (NGF) to Alzheimer's disease. Cell Mol Neurobiol 26:619–633

    Article  PubMed  CAS  Google Scholar 

  43. Cattaneo A, Capsoni S, Paoletti F (2008) Towards noninvasive nerve growth factor therapies for Alzheimer's disease. J Alzheimers Dis 15:255–283

    PubMed  CAS  Google Scholar 

  44. Covaceuszach S, Cassetta A, Konarev PV, Gonfloni S, Rudolph R, Svergun DI, Lamba D, Cattaneo A (2008) Dissecting NGF interactions with TrkA and p75 receptors by structural and functional studies of an anti-NGF neutralizing antibody. J Mol Biol 381:881–896

    Article  PubMed  CAS  Google Scholar 

  45. Capsoni S, Tiveron C, Vignone D, Amato G, Cattaneo A (2010) Dissecting the involvement of tropomyosin-related kinase A and p75 neurotrophin receptor signaling in NGF deficit-induced neurodegeneration. Proc Natl Acad Sci USA 107(27):12299–12304

    Article  PubMed  CAS  Google Scholar 

  46. Lagostena L, Rosato-Siri M, D'Onofrio M, Brandi R, Arisi I, Capsoni S, Franzot J, Cattaneo A, Cherubini E (2010) In the adult hippocampus, chronic nerve growth factor deprivation shifts GABAergic signaling from the hyperpolarizing to the depolarizing direction. J Neurosci 30:885–893

    Article  PubMed  CAS  Google Scholar 

  47. D'Onofrio M, Arisi I, Brandi R, Di Mambro A, Felsani A, Capsoni S, Cattaneo A (2009) Early inflammation and immune response mRNAs in the brain of AD11 anti − NGF mice. Neurobiol Aging 32(6):1007–1022

    Article  PubMed  CAS  Google Scholar 

  48. Parachikova A, Agadjanyan MG, Cribbs DH, Blurton-Jones M, Perreau V, Rogers J, Beach TG, Cotman CW (2007) Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiol Aging 28:1821–1833

    Article  PubMed  CAS  Google Scholar 

  49. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B et al (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178

    Article  PubMed  CAS  Google Scholar 

  50. Capsoni S, Brandi R, Arisi I, D'Onofrio M, Cattaneo A (2011) A dual mechanism linking NGF deprivation and early inflammation to Alzheimer's neurodegeneration in the AD11 anti-NGF mouse model. CNS Neurological Disorders Drug Targets 10(5):635–647, Review

    PubMed  CAS  Google Scholar 

  51. Zlokovic BV (2008) The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201

    Article  PubMed  CAS  Google Scholar 

  52. D'Mello S, Galli C, Ciotti MT, Calissano P (1993) Induction of apoptosis in cerebellar granule neurons by low potassium: inhibition of death by insulin-like growth factor I and cAMP. Proc Natl Acad Sci USA 90:10989–10993

    Article  PubMed  Google Scholar 

  53. Borsello T, Di Luzio A, Ciotti MT, Calissano P, Galli C (2000) Granule neuron DNA damage following deafferentation in adult rats cerebellar cortex: a lesion model. Neuroscience 95:163–171

    Article  PubMed  CAS  Google Scholar 

  54. Cavallaro S, Calissano P (2006) A genomic approach to investigate neuronal apoptosis. Current Alzheimer research 3:4–23

    Article  Google Scholar 

  55. Galli C, Meucci O, Scorziello A, Werge TM, Calissano P, Schettini G (1995) Apoptosis in cerebellar granule cells is blocked by high KCI, Forskolin, and IGF-1 through distinct mechanisms of action: the involvement of intracellular calcium and RNA synthesis. J Neurosci 15:1172–1179

    PubMed  CAS  Google Scholar 

  56. Galli C, Piccini A, Ciotti MT, Castellani L, Calissano P, Zaccheo D, Tabaton M (1998) Increased amyloidogenic secretion in cerebellar granule cells undergoing apoptosis. Proc Natl Acad Sci USA 95:1247–1252

    Article  PubMed  CAS  Google Scholar 

  57. Canu N, Dus L, Barbato C, Ciotti MT, Brancolini C, Rinaldi AM, Novak M, Cattaneo A, Bradbury A, Calissano P (1998) Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis. J Neurosci 18(18):7061–7074

    PubMed  CAS  Google Scholar 

  58. Amadoro G, Serafino AL, Barbato C, Ciotti MT, Sacco A, Calissano P, Canu N (2004) Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons. Cell Death and Differentiation 11:217–230

    Article  PubMed  CAS  Google Scholar 

  59. Amadoro G, Ciotti MT, Costanzi M, Cestari V, Calissano P, Canu N (2006) NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation. Proc Natl Acad Sci USA 103:2892–2897

    Article  PubMed  CAS  Google Scholar 

  60. Atlante A, Amadoro G, Bobba A, De Bari L, Corsetti V, Pappalardo G, Marra E, Calissano P, Passarella S (2008) A peptide containing residues 26-44 of tau protein impairs mitochondrial oxidative phoaphorylation acting at the level of the adenine nucleotide translocator. Biochim BiophisActa 1777:1289–1300

    Article  CAS  Google Scholar 

  61. Bobba A, Atlante A, Giannattasio S, Sgaramella G, Calissano P (1999) Marra E. Early release and subsequent caspase-mediated degradation of cytochrome c in apoptotic cerebellar granule cells. FEBS Lett 457:126–130

    Article  PubMed  CAS  Google Scholar 

  62. Atlante A, De Bari L, Bobba A, Marra E, Calissano P, Passarella S (2003) Cytochrome c, released from cerebellar granule cells undergoing apoptosis or excytotoxic death, can generate protonmotive force and drive ATP synthesis in isolated mitochondria. J Neurochem 86:591–604

    Article  PubMed  CAS  Google Scholar 

  63. Canu N, Barbato C, Ciotti MT, Serafino A, Dus L, Calissano P (2000) Proteasome involvement and accumulation of ubiquitinated proteins in cerebellar granule neurons undergoing apoptosis. J Neurosci 20:589–599

    PubMed  CAS  Google Scholar 

  64. Canu N, Tufi R, Serafino AL, Amadoro G, Ciotti MT, Calissano P (2005) Role of the autophagic-lysosomal system on low potassium-induced apoptosis in cultured cerebellar granule cells. J Neurochem 92(5):1228–1242

    Article  PubMed  CAS  Google Scholar 

  65. De Berardinis MA, Ciotti MT, Amadoro G, Galli C, Calissano P (2001) Transfer of the apoptotic message in sister cultures of cerebellar neurons. NeuroReport 12:2137–2140

    Article  Google Scholar 

  66. Greene LA (1976) Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci USA 73(7):2424–2428

    Article  PubMed  CAS  Google Scholar 

  67. Matrone C, Di Luzio A, Meli G, D'Aguanno S, Severini C, Ciotti MT, Cattaneo A, Calissano P (2008) Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 cells. J Alzheimers Dis 13:81–96

    PubMed  CAS  Google Scholar 

  68. Morrison JH, Hof PR (2002) Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer's disease. Prog Brain Res 136:467–486

    Article  PubMed  CAS  Google Scholar 

  69. Matrone C, Ciotti MT, Mercanti D, Marolda R, Calissano P (2008) NGF and BDNF signaling control amyloidogenic route and Abeta production in hippocampal neurons. Proc Natl Acad Sci USA 105:13139–13144

    Article  PubMed  CAS  Google Scholar 

  70. Amadoro G, Corsetti V, Ciotti MT, Florenzano F, Capsoni S, Amato G, Calissano P (2009) Endogenous Ab causes cell death via early tau hyperphosphorylation. Neurobiology of Aging 32(6):969–990

    Article  PubMed  CAS  Google Scholar 

  71. Shelton SB, Johnson GV (2001) Tau and HMW tau phosphorylation and compartmentalization in apoptotic neuronal PC12 cells. J Neurosci Res 66(2):203–213

    Article  PubMed  CAS  Google Scholar 

  72. Ma QL, Lim GP, Harris-White ME, Yang F, Ambegaokar SS, Ubeda OJ, Glabe CG, Teter B, Frautschy SA, Cole GM (2006) Antibodies against amyloid reduce A oligomers, glycogen synthase kinase-3beta activation and tau phosphorylation in vivo and in vitro. J Neurosci Res 83:374–384

    Article  PubMed  CAS  Google Scholar 

  73. Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Ab immunotherapy leads to learance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332

    Article  PubMed  CAS  Google Scholar 

  74. Magnani E, Fan J, Gasparini L, Golding M, Williams M, Schiavo G, Goedert M, Amos L, Splillantini MG (2007) Interaction of tau protein with the dynactin complex. EMBO J 26:4546–4554

    Article  PubMed  CAS  Google Scholar 

  75. Tatebayashi Y, Haque N, Tung YC, Iqbal K, Grundke-Iqbal I (2004) Role of tau phosphorylation by glycogen synthase kinase-3b in the regulation of organelle transport. J Cell Sci 117:1653–1663

    Article  PubMed  CAS  Google Scholar 

  76. Niewiadomska G, Baksalerska-Pazera M, Riedel G (2006) Cytoskeletal transport in the aging brain: focus on the cholinergic system. Rev Neurosci 17:581–618

    PubMed  CAS  Google Scholar 

  77. Niewiadomska G, Baksalerska-Pazera M, Riedel G (2005) Altered cellular distribution of phospho-tau proteins coincides with impaired retrograde axonal transport in neurons of aged rats. Ann N Y Acad Sci 1048:287–295

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  79. Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642

    Article  PubMed  CAS  Google Scholar 

  80. Matrone C, Marolda R, Ciafrè S, Ciotti MT, Mercanti D, Calissano P (2009) Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation. Proc Natl Acad Sci USA 106:11358–11363

    Article  PubMed  CAS  Google Scholar 

  81. Reynolds CH, Garwood CJ, Wray S, Price C, Kellie S, Perera T, Zvelebil M, Yang A, Sheppard PW, Varndell IM, Hanger DP, Anderton BH (2008) Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases. J Biol Chem 283:18177–18186

    Article  PubMed  CAS  Google Scholar 

  82. Russo C, Dolcini V, Salis S, Venezia V, Violani E, Carlo P, Zambrano N, Russo T, Schettini G (2002) Signal transduction through tyrosine-phosphorylated C-terminal fragments of amyloid precursor protein via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain. J Biol Chem 277:35282–35288

    Article  PubMed  CAS  Google Scholar 

  83. Cruz JC, Tsai LH (2004) Cdk5 deregulation in the pathogenesis of Alzheimer's disease. Trends Mol Med 10(9):452–458, Review

    Article  PubMed  CAS  Google Scholar 

  84. Williamson R, Scales T, Clark BR, Gibb G, Reynolds CH, Kellie S, Bird IN, Varndell IM, Sheppard PW, Everall I, Anderton BH (2002) Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloidbeta peptide exposure: involvement of Src family protein kinases. J Neurosci 22(1):10–20

    PubMed  CAS  Google Scholar 

  85. Zampieri N, Xu CF, Neubert TA, Chao MV (2005) Cleavage of p75 neurotrophin receptor by alpha-secretase and gamma-secretase requires specific receptor domains. J Biol Chem 280(15):14563–14571

    Article  PubMed  CAS  Google Scholar 

  86. Li H, Wolfe MS, Selkoe DJ (2009) Toward structural elucidation of the gammasecretase complex. Structure 17(3):326–334, Review

    Article  PubMed  CAS  Google Scholar 

  87. 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(4):317–323

    Article  PubMed  CAS  Google Scholar 

  88. Sotthibundhu A, Sykes AM, Fox B, Underwood CK, Thangnipon W, Coulson EJ (2009) Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. J Neurosci 28(15):3941–3946

    Article  CAS  Google Scholar 

  89. Corsetti V, Amadoro G, Gentile A, Capsoni S, Ciotti MT, Cencioni MT, Atlante A, Canu N, Rohn TT, Cattaneo A, Calissano P (2008) Identification of a caspasederived N-terminal tau fragment in cellular and animal Alzheimer's disease models. Mol Cell Neurosci 38(3):381–392

    Article  PubMed  CAS  Google Scholar 

  90. Longo FM, Massa SM (2005) Neurotrophin receptor-based strategies for Alzheimer's disease. Curr Alzheimer Res 2(2):167–169, Review

    Article  PubMed  CAS  Google Scholar 

  91. Matrone C, Barbagallo APM, La Rosa LR, Florenzano F, Ciotti MT, Mercanti D, Chao MV, Calissano P, D'Adamio L (2011) APP is phosphorylated by TrkA and regulates NGF/TrkA signaling. J Neurosci 31:11756–11761

    Article  PubMed  CAS  Google Scholar 

  92. Yankner BA, Duffy LK, Kirschner DA (1990) Neurotrophic and neurotoxic effects of βA protein: reversal by tachykinin neuropeptides. Science 250:279–282

    Article  PubMed  CAS  Google Scholar 

  93. Plant LD, Boyle JP, Smith LF, Peers C, Pearson HA (2003) The production of βA peptide is a critical requirement for the visability of central neurons. J Neurosci 23:5531–5535

    PubMed  CAS  Google Scholar 

  94. Puzzo D, Privitera L, Leznik E, Fa M, Staniszewski A, Palmeri A, Arancio O (2008) pM βA positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28:14537–14545

    Article  PubMed  CAS  Google Scholar 

  95. Garcia-Osta A, Alberini C (2009) βA mediates memory formation. Learn Mem 16:267–272

    Article  PubMed  CAS  Google Scholar 

  96. Grimm MO, Grimm HS, Hartmann T (2007) βA as a regulator of lipiod homeostasis. Trends Mol Med 13:337–344

    Article  PubMed  CAS  Google Scholar 

  97. Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E, Slutsky I (2009) βA as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci 12:1567–1576

    Article  PubMed  CAS  Google Scholar 

  98. Giuffrida ML, Caraci F, De Bona P, Pappalardo G, Nicoletti F, Rizzarelli E, Copani A (2010) The moniomer state of βA: where the Alzheimer's disease protein meets physiology. Rev Neurosci 212:83–93

    Google Scholar 

  99. Levi-Montalcini R, Cohen S (1960) Effects of the extract of the mouse submaxillary salivary glands on the sympathetic system of mammals. Ann N Y Acad Sci 85:324–341

    PubMed  CAS  Google Scholar 

  100. Yip HK, Rich KM, Lampe PA, Johnson EM Jr (1984) The effects of nerve growth factor and its antiserum on the postnatal development and survival after injury of sensory neurons in rat dorsal root ganglia. J Neurosci 4(12):2986–2992

    PubMed  CAS  Google Scholar 

  101. Pezet S, McMahon SB (2006) Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 29:507–538

    Article  PubMed  CAS  Google Scholar 

  102. Eriksdotter Jonhagen M, Nordberg A, Amberla K, Backman L, Ebendal T, Meyerson B, Olson L et al (1998) Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement Geriatr Cogn Disord 9:246–257

    Article  PubMed  CAS  Google Scholar 

  103. Apfel SC (2002) Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold? Int Rev Neurobiol 50:393–413

    Article  PubMed  CAS  Google Scholar 

  104. Tuszynski MH, Thal L, Pay M, HS U, Salmon DP, 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. Nat Med 11:551–555

    Article  PubMed  CAS  Google Scholar 

  105. Capsoni S, Covaceuszach S, Ugolini G, Spirito F, Vignone D, Stefanini B, Amato G, Cattaneo A (2009) Delivery of NGF to the brain: intranasal versus ocular administration in anti-NGF transgenic mice. J Alzheimers Dis 16:371–388

    PubMed  CAS  Google Scholar 

  106. Covaceuszach S, Capsoni S, Ugolini G, Spirito F, Vignone D, Cattaneo A (2009) Development of a noninvasive NGFbased therapy for Alzheimer's disease. Curr Alzheimer Res 6:158–170

    Article  PubMed  CAS  Google Scholar 

  107. Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, Mitsubuchi H, Tonoki H, Awaya Y, Matsuda I (1996) Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 13:485–488

    Article  PubMed  CAS  Google Scholar 

  108. Indo Y (2001) Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Hum Mutat 18:462–471

    Article  PubMed  CAS  Google Scholar 

  109. Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G, Holmgren G, Holmberg D, Holmberg M (2004) A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet 13:799–805

    Article  PubMed  CAS  Google Scholar 

  110. Covaceuszach S, Capsoni S, Marinelli S, Pavone F, Ceci M, Ugolini G, Vignone D, Amato G, Paoletti F, Lamba D, Cattaneo A (2010) In vitro receptor binding properties of a “painless” NGF mutein linked to hereditary sensory autonomic neuropathy type V. Biochem Biophys Res Commun 391:824–829

    Article  PubMed  CAS  Google Scholar 

  111. Capsoni S, Covaceuszach S, Marinelli S, Ceci M, Bernardo A, Minghetti L, Ugolini G, Pavone F, Cattaneo A (2011) Taking pain out of NGF: a "painless" NGF mutant, linked to hereditary sensory autonomic neuropathy type V, with full neurotrophic activity. PLoS One 6(2):e17321

    Article  PubMed  CAS  Google Scholar 

  112. Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962

    Article  PubMed  CAS  Google Scholar 

  113. Prescott ED, Julius DA (2003) Modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300:1284–1288

    Article  PubMed  CAS  Google Scholar 

  114. Capsoni S et al (2012) Intranasal painless human nerve growth factor slows amyloid neurodegeneration and prevents memory deficits in APP x PS1 mice. PLoS One 7(5):e37555. doi:10.1371/journal.pone.0037555

    Article  PubMed  CAS  Google Scholar 

  115. Di Maria E, Giorgio E, Uliana V, Bonvicini C, Faravelli F, Cammarata S, Novello MC, Galimberti D, Scarpini E, Zanetti O, Gennarelli M, Tabaton M (2012) Possible influence of a non-synonimous polimorphism located in the NGF precursor on susceptibility to late-onset Alzheimer's disease and mild cognitive impairment. J Alzheimers Dis 16:371–388

    Google Scholar 

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Acknowledgments

The authors wish to thank Progetto Fondazione Roma for supporting the research mentioned in this review, with grants to A.C and P.C. The research was also supported by MIUR (Ministero Universita’ e Ricerca), through grants FIRB (Accordo di Programma 2010, RBAP10L8TY) and PRIN to A.C and P.C. The authors wish to thank Simona Capsoni, Valentina Sposato, and Carmela Matrone for helpful discussions during the preparation of the review, Luca La Rosa for help in drawing figures 4 and 5, and Pamela Bernardo for skilful editorial assistance.

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  1. European Brain Research Institute “Rita Levi-Montalcini”, Via del Fosso di Fiorano 64/65, 00143, Rome, Italy

    Antonino Cattaneo & Pietro Calissano

  2. Scuola Normale Superiore, Piazza dei Cavalieri 7, 56100, Pisa, Italy

    Antonino Cattaneo

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  1. Antonino Cattaneo
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Correspondence to Antonino Cattaneo.

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Cattaneo, A., Calissano, P. Nerve Growth Factor and Alzheimer's Disease: New Facts for an Old Hypothesis. Mol Neurobiol 46, 588–604 (2012). https://doi.org/10.1007/s12035-012-8310-9

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  • DOI: https://doi.org/10.1007/s12035-012-8310-9

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