Skip to main content
SpringerLink
Log in

Cycles of Aberrant Synaptic Sprouting and Neurodegeneration in Alzheimer's and Dementia with Lewy Bodies

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common neuro-degenerative disorders affecting the elderly. The cognitive and motor deficits in these diseases are associated with the disruption of neuritic substructure, loss of synaptic contacts in selectively vulnerable circuitries, and aberrant sprouting. Where as in AD, accumulation of misfolded forms of Aβtriggers neurodegeneration, in DLB accumulation of α-synuclein might play a central role. The mechanisms by which oligomeric forms of these proteins might lead to cycles of synapse loss and aberrant sprouting are currently under investigation. Several possibilities are being considered, including mitochondrial damage, caspase activation, lysosomal leakage, fragmentation of the Golgi apparatus, interference with synaptic vesicle transport and function, and interference with gene transcription and signaling. Among them, recent lines of research support the possibility that alterations in signaling pathways such extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 relevant to synaptic plasticity and cell survival might play a pivotal role. A wide range of cellular functions are affected by the accumulation of misfolded Aβ and α-synuclein; thus it is possible that a more fundamental cellular alteration may underlie the mechanisms of synaptic pathology in these disorders. Among them, one possibility is that scaffold proteins, such as caveolin and JNK-interacting protein (JIP), which are necessary to integrate signaling pathways, are affected, leading to cycles of synapse loss and aberrant sprouting. This is significant because both caveolar dysfunction and altered axonal plasticity might be universally important in the pathogenesis of various neurodegenerative disorders, and therefore these signaling pathways might be common therapeutic targets for these devastating diseases.

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

Similar content being viewed by others

REFERENCES

  1. Eccles, J. 1984. The cerebral neocortex: A theory of its operation. Pages 1-38, in Jones, E. and Peters, A. (eds.), Cerebral Cortex, Vol. 2, Functional Properties of Cortical Cells, New York, Plenum.

    Google Scholar 

  2. Patterson, P. 1992. Process outgrowth and the specificity of connections. Pages 388-427, in Sunderland, H. Z. (ed.), An Introduction to Molecular Neurobiology, Sunderland, MA, Sinauer Associates, Inc.

    Google Scholar 

  3. Cotman, C. W., Matthews, D. A., Taylor, D., and Lynch, G. 1973. Synaptic rearrangement in the dentate gyrus: Histochemical evidence of adjustments after lesions in immature and adult rats. Proc. Natl. Acad. Sci. USA 70:3473-3477.

    PubMed  Google Scholar 

  4. Cotman, C., Gentry, C., and Steward, O. 1977. Synaptic replacement in the dentate gyrus after unilateral entorhinal lesion: Electron microscopic analysis of the extent of replacement of synapses by the remaining entorhinal cortex. J. Neurocytol. 6:455-464.

    PubMed  Google Scholar 

  5. Cotman, C. and Nadler, J. 1978. Reactive synaptogenesis in the hippocampus. Pages 227-271, in Cotman, C. (ed.), Neuronal Plasticity, New York, Raven.

    Google Scholar 

  6. Cotman, C. and Anderson, K. 1987. Synaptic plasticity and functional stabilization in the hippocampal formation: Possible role in Alzheimer's disease. Adv. Neurol. 47:313-335.

    Google Scholar 

  7. Crain, B., Cotman, C., Taylor, D., and Lynch, G. 1973. A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat. Brain Res. 63:195-204.

    PubMed  Google Scholar 

  8. Parnavelas, J. G., Lynch, G., Brecha, N., Cotman, C. W., and Globus, A. 1974. Spine loss and regrowth in hippocampus following deafferentation. Nature 248:71-73.

    PubMed  Google Scholar 

  9. Matthews, D., Cotman, C., and Lynch, G. 1976. An electron microscopic study of lesion-induced synaptogenesis in the dentate gyrus of the adult rat: II. Reappearance of morphologically normal synaptic contacts. Brain Res. 115:23-41.

    PubMed  Google Scholar 

  10. Masliah, E., Fagan, A., Terry, R., DeTeresa, R., Mallory, M., and Gage, F. 1991. Reactive synaptogenesis assessed by synaptophysin immunoreactivity is associated with GAP-43 in the dentate gyrus of the adult rat. Exp. Neurol. 113:131-142.

    PubMed  Google Scholar 

  11. Cotman, C., Cummings, B., and Whitson, J. 1991. The role of misdirect plasticity in plaque biogenesis and Alzheimer's disease pathology. Pages 222-233, in Hefti, F., Brachet, P., Will, B., and Christen, Y. (eds.), Growth Factors and Alzheimer's Disease, New York, Springer-Verlag.

    Google Scholar 

  12. Cotman, C., Cummings, B., and Pike, C. 1993. Molecular cascades in adaptive versus pathological plasticity. Pages 217-240, in Gorio, A. (ed.), Neurodegeneration, New York, Raven.

    Google Scholar 

  13. Geddes, J., Anderson, K., and Cotman, C. 1986. Senile plaques as aberrant sprout stimulating structures. Exp. Neurol. 94:767-776.

    PubMed  Google Scholar 

  14. Galasko, D., Hansen, L., Katzman, R., Wiederholt, W., Masliah, E., Terry, R., Hill, L., Lessin, P., and Thal, L. 1994. Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch. Neurol. 51:888-895.

    PubMed  Google Scholar 

  15. Katzman, R. Alzheimer's disease is a degenerative disorder. 1989. Neurobiol. Aging 10:581-582; 588–590.

    PubMed  Google Scholar 

  16. Khachaturian, Z. 1985. Diagnosis of Alzheimer's disease. Arch. Neurol. 42:1097-1105.

    PubMed  Google Scholar 

  17. Terry, R., Hansen, L., and Masliah, E. 1994. Structural basis of the cognitive alterations in Alzheimer disease. Pages 179-196, in Terry, R. and Katzman, R. (eds.), Alzheimer Disease, New York, Raven.

    Google Scholar 

  18. Gearing, M., Mirra, S., Hedreen, J., Sumi, S., Hansen, L., and Heyman, A. 1995. Neuropathology confirmation of the clinical diagnosis of Alzheimer's disease: CERAD: X. Neurology 45:461-466.

    PubMed  Google Scholar 

  19. Masliah, E., Rockenstein, E., Veinbergs, I., Sagara, Y., Mallory, M., Hashimoto, M., and Mucke, L. 2001. β amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's and Parkinson's disease. Proc. Natl. Acad. Sci. USA 98:12245-12250.

    PubMed  Google Scholar 

  20. McKeith, I., Galasko, D., Kosaka, K., Perry, E., Dickson, D., Hansen, L., Salmon, D., Lowe, J., Mirra, S., Byrne, E., Quinn, N., Edwardson, J., Ince, P., Bergeron, C., Burns, A., Miller, B., Lovestone, S., Collerton, D., Jansen, E., de Vos R., Wilcock, G., Jellinger, K., and Perry, R. 1996. Clinical and pathological diagnosis of dementia with Lewy bodies (DLB): Report of the CDLB International Workshop. Neurology 47:1113-1124.

    PubMed  Google Scholar 

  21. Kurosinski, P., Guggisberg, M., and Gotz, J. 2002. Alzheimer's and Parkinson's disease: Overlapping or synergistic pathologies? Trends Mol. Med. 8:3-5.

    PubMed  Google Scholar 

  22. Hansen, L. 1997. The Lewy body variant of Alzheimer disease. J. Neural. Transm. 51:111-121.

    Google Scholar 

  23. Dickson, D., Davies, P., Mayeux, R., Crystal, H., Horoupian, D., Thompson, A., and Goldman, J. 1987. Diffuse Lewy body disease: Neuropathological and biochemical studies of six patients. Acta Neuropathol. 75:8-15.

    PubMed  Google Scholar 

  24. Kosaka, K., Yoshimura, M., Ikeda, K., and Budka, H. 1984. Diffuse type of Lewy body disease: Progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree—A new disease? Clin. Neuropathol. 3:183-192.

    Google Scholar 

  25. Hurtig, H., Trojanowski, J., Galvin, J., Ewbank, D., Schmidt, M., Clark, C., Glosser, G., Stern, M., Gollomp, S., and Arnold, S. 2000. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. Neurology 54:1916-1921.

    PubMed  Google Scholar 

  26. Kotzbauer, P. T., Trojanowski, J. O., and Lee, V. M. 2001. Lewy body pathology in Alzheimer's disease. J. Mol. Neurosci. 17:225-232.

    PubMed  Google Scholar 

  27. Lotharius, J. and Brundin, P. 2002. Pathogenesis of Parkinson's disease: Dopamine, vesicles and alpha-synuclein. Nat. Rev. Neurosci. 3:932-942.

    PubMed  Google Scholar 

  28. Masliah, E. and LiCastro, F. 2000. Neuronal and synaptic loss, reactive gliosis, microglial response, and induction of the complement cascade in Alzheimer's disease. Pages 131-146, in Clark, C. and Trojanowski, J. Neurodegenerative Dementias, New York, McGraw-Hill.

    Google Scholar 

  29. Braak, E., Braak, H., and Mandelkow, E. 1994. A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta. Neuropathol. (Berl.) 87:554-567.

    Google Scholar 

  30. Braak, H. and Braak, E. 1991. Neuropathological stageing of Alzheimer-related changes. Acta. Neuropathol. 82:239-259.

    PubMed  Google Scholar 

  31. Masliah, E. 1995. The natural evolution of the neurodegenerative alterations in Alzheimer's disease. Neurobiol. Aging 16:280-282.

    Google Scholar 

  32. Masliah, E., Mallory, M., Alford, M., DeTeresa, R., Hansen, L. A., McKeel, D. W., Jr., and Morris, J. C. 2001. Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease. Neurology 56:127-129.

    PubMed  Google Scholar 

  33. Masliah, E., Mallory, M., Hansen, L., DeTeresa, R., Alford, M., and Terry, R. 1994. Synaptic and neuritic alterations during the progression of Alzheimer's disease. Neurosci. Lett. 174:67-72.

    PubMed  Google Scholar 

  34. Terry, R., Masliah, E., Salmon, D., Butters, N., DeTeresa, R., Hill, R., Hansen, L., and Katzman, R. 1991. Physical basis of cognitive alterations in Alzheimer disease: Synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30:572-580.

    PubMed  Google Scholar 

  35. DeKosky, S. and Scheff, S. 1990. Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity. Ann. Neurol. 27:457-464.

    PubMed  Google Scholar 

  36. Arriagada, P., Growdon, J., Hedley-Whyte, E., and Hyman, B. 1992. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42:631-639.

    PubMed  Google Scholar 

  37. Martin, L., Pardo, C., Cork, L., and Price, D. 1994. Synaptic pathology and glial responses to neuronal injury precede the formation of senile plaques and amyloid deposits in the aging cerebral cortex. Am. J. Pathol. 145:1358-1381.

    PubMed  Google Scholar 

  38. Mucke, L., Masliah, E., Yu, G.-Q., Mallory, M., Rockenstein, E., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., and McConlogue, L. 2000. High-level neuronal expression of Abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation. J. Neurosci. 20:4050-4058.

    PubMed  Google Scholar 

  39. Hof, P. and Morrison, J. 1994. The cellular basis of cortical disconnection in Alzheimer disease and related dementing conditions. Pages 197-230, in Terry, R., Katzman, R., and Bick, K. (eds.), Alzheimer Disease, New York, Raven.

    Google Scholar 

  40. Masliah, E. and Salmon, D. 1999. Neuropathological correlates of dementia in Alzheimer's disease: Cerebral cortex. Pages 513-551, in Peters, A. and Morrison, J. (eds.), Neurodegenerative and Age-Related Changes in Structure and Function of Cerebral Cortex, Vol. 14, New York, Plenum.

    Google Scholar 

  41. Samuel, W., Masliah, E., and Terry, R. 1994. Hippocampal connectivity and Alzheimer's dementia: Effects of pathology in a two-component model. Neurology 44:2081-2088.

    PubMed  Google Scholar 

  42. Wakabayashi, K., Honer, W., and Masliah, E. 1994. Synapse alterations in the hippocampal-entorhinal formation in Alzheimer's disease with and without Lewy body disease. Brain Res. 667:24-32.

    PubMed  Google Scholar 

  43. Masliah, E. 1998. Mechanisms of synaptic pathology in Alzheimer's disease. J. Neural. Transm. 53(suppl):147-158.

    Google Scholar 

  44. Lassmann, H., Weiler, R., Fischer, P., Bancher, C., Jellinger, K., Floor, E., Danielczyk, W., Seitelberger, F., and Winkler, H. 1992. Synaptic pathology in Alzheimer's disease: Immunological data for markers of synaptic and large dense-core vesicles. Neurosci. 46:1-8.

    Google Scholar 

  45. Blennow, K., Bogdanovic, N., Alafuzoff, I., Ekman, R., and Davidsson, P. 1996. Synaptic pathology in Alzheimer's disease: Relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. J. Neural. Transm. 103:603-618.

    PubMed  Google Scholar 

  46. Weiler, R., Lassmann, H., Fischer, P., Jellinger, K., and Winkler, H. 1990. A high ratio of chromogranin A to synaptin/synaptophysin is a common feature of brains in Alzheimer and Pick disease. FEBS Lett. 263:337-339.

    PubMed  Google Scholar 

  47. Zhan, S., Beyreuther, K., and Schmitt, H. 1993. Quantitative assessment of the synaptophysin immuno-reactivity of the cortical neuropil in various neurodegenerative disorders with dementia. Dementia 4:66-74.

    PubMed  Google Scholar 

  48. Dickson, D., Crystal, H., Bevona, C., Honer, W., Vincent, I., and Davies, P. 1995. Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol. Aging 16:285-304.

    PubMed  Google Scholar 

  49. Anderson, B. 1995. Dendritic correlates of dementia severity in Alzheimer's disease. Med. Sci. Res. 23:597-599.

    Google Scholar 

  50. Bertoni-Freddari, C., Fattoretti, P., Delfino, A., Solazzi, M., Giorgetti, B., Ulrich, J., and Meier-Ruge, W. 2002. Deafferentative synaptopathology in physiological aging and Alzheimer's disease. Ann. N Y Acad. Sci. 977:322-326.

    PubMed  Google Scholar 

  51. Scheff, S. and Price, D. 1993. Synapse loss in the temporal lobe in Alzheimer's disease. Ann. Neurol. 33:190-199.

    PubMed  Google Scholar 

  52. Scheff, S. W. and Price, D. A. 2001. Alzheimer's disease-related synapse loss in the cingulate cortex. J. Alzheimers Dis. 3:495-505.

    PubMed  Google Scholar 

  53. Scheff, S., Sparks, D., and Price, D. 1993. Quantitative assessment of synaptic density in the entorhinal cortex in Alzheimer's disease. Ann. Neurol. 34:356-361.

    PubMed  Google Scholar 

  54. Davies, C., Mann, D., Sumpter, P., and Yates, P. 1987. A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease. J. Neurol. Sci. 78:151-164.

    PubMed  Google Scholar 

  55. Hamos, J., DeGennaro, L., and Drachman, D. 1989. Synaptic loss in Alzheimer's disease and other dementias. Neurology 39:355-361.

    PubMed  Google Scholar 

  56. Masliah, E. and Terry, R. 1994. The role of synaptic pathology in the mechanisms of dementia in Alzheimer's disease. Clin. Neurosci. 1:192-198.

    Google Scholar 

  57. Masliah, E., Terry, R., DeTeresa, R., and Hansen, L. 1989. Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease. Neurosci. Lett. 103:234-239.

    PubMed  Google Scholar 

  58. Masliah, E., Mallory, M., DeTeresa, R., Alford, M., and Hansen, L. 1993. Differing patterns of aberrant neuronal sprouting in Alzheimer's disease with and without Lewy bodies. Brain Res. 617:258-266.

    PubMed  Google Scholar 

  59. Samuel, W., Hansen, L., Galasko, D., Masliah, E., and Katzman, R. 1996. Neocortical Lewy body density correlates with dementia in the Lewy body variant of Alzheimer's disease. J. Neuropathol. Exp. Neurol. 55:44-52.

    PubMed  Google Scholar 

  60. Hansen, L., Daniel, S., Wilcock, G., and Lowe, S. 1988. Neocortical synaptophysin in Lewy body disease: Relationship to Alzheimer's disease and dementia. J. Neurol. Neurosurg. Psychiatry 64:653-656.

    Google Scholar 

  61. Nishimura, M., Tomimoto, H., Suenaga, T., Nakamura, S., Namba, Y., Ikeda, K., Akiguchi, I., and Kimura, J. 1994. Synaptophysin and chromogranin A immunoreactivities of Lewy bodies in Parkinson's disease brains. Brain Res. 634:339-344.

    PubMed  Google Scholar 

  62. Wakabayashi, K., Matsumoto, K., Takayama, K., Yoshimoto, M., and Takahashi, H. 1997. NACP, a presynaptic protein, immunore-activity in Lewy bodies in Parkinson's disease. Neurosci. Lett. 239:45-48.

    PubMed  Google Scholar 

  63. Takeda, A., Mallory, M., Sundsmo, M., Honer, W., Hansen, L., and Masliah, E. 1998. Abnormal accumulation of NACP/α-synuclein in neurodegenerative disorders. Am. J. Pathol. 152:367-372.

    PubMed  Google Scholar 

  64. Spillantini, M., Schmidt, M., Lee, V.-Y., Trojanowski, J., Jakes, R., and Goedert, M. 1997. α-Synuclein in Lewy bodies. Nature 388:839-840.

    PubMed  Google Scholar 

  65. Iwai, A., Masliah, E., Yoshimoto, M., De Silva, R., Ge, N., Kittel, A., and Saitoh, T. 1994. The precursor protein of non-Aβ component of Alzheimer's disease amyloid (NACP) is a presynaptic protein of the central nervous system. Neuron 14:467-475.

    Google Scholar 

  66. Masliah, E., Terry, R., Alford, M., DeTeresa, R., and Hansen, L. 1991. Cortical and subcortical patterns of synaptophysin-like immunoreactivity in Alzheimer disease. Am. J. Pathol. 138:235-246.

    PubMed  Google Scholar 

  67. Masliah, E., Hansen, L., Albright, T., Mallory, M., and Terry, R. 1991. Immunoelectron microscopic study of synaptic pathology in Alzheimer disease. Acta Neuropathol. 81:428-433.

    PubMed  Google Scholar 

  68. Masliah, E., Honer, W., Mallory, M., Voigt, M., Kushner, P., and Terry, R. 1994. Topographical distribution of synaptic-associated proteins in the neuritic plaques of Alzheimer disease hippocampus. Acta Neuropathol. 87:135-142.

    PubMed  Google Scholar 

  69. Marksteiner, J., Kaufmann, W. A., Gurka, P., and Humpel, C. 2002. Synaptic proteins in Alzheimer's disease. J. Mol. Neurosci. 18:53-63.

    PubMed  Google Scholar 

  70. Gonatas, N., Anderson, W., and Evangelista, I. 1967. The contribution of altered synapses in the senile plaque: An electron microscopic study in Alzheimer's disease. J. Neuropathol. Exp. Neurol. 26:25-39.

    PubMed  Google Scholar 

  71. Gonatas, N. and Gambetti, P. 1970. The pathology of the synapse in Alzheimer's disease. In Wolstenholmes G.E.W. and London, OM. (eds.), Ciba Foundation Symposium on Alzheimer's disease and related conditions, St. Louis, MO, J & A Churchill, pp. 169-183.

    Google Scholar 

  72. Jones, D. and Harris, R. 1995. An analysis of contemporary morphological concepts of synaptic remodelling in the CNS: Perforated synapses revisited. Rev. Neurosci. 6:177-219.

    PubMed  Google Scholar 

  73. Dickson, D., Farlo, J., Davies, P., Crystal, H., Fuld, P., and Yen, S. 1988. Alzheimer disease: A double immunohistochemical study of senile plaques. Am. J. Pathol. 132:86-101.

    PubMed  Google Scholar 

  74. Terry, R., Gonatas, N., and Weiss, M. 1964. Ultrastructural studies in Alzheimer's presenile dementia. Am. J. Pathol. 44:269-297.

    PubMed  Google Scholar 

  75. Masliah, E., Sisk, A., Mallory, M., Mucke, L., Schenk, D., and Games, D. 1996. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F β-amyloid precursor protein and Alzheimer's disease. J. Neurosci. 16:5795-5811.

    PubMed  Google Scholar 

  76. Masliah, E., Mallory, M., Hansen, L., Alford, M., Albright, T., DeTeresa, R., Terry, R., Baudier, J., and Saitoh, T. 1991. Patterns of aberrant sprouting in Alzheimer disease. Neuron 6:729-739.

    PubMed  Google Scholar 

  77. Cummings, B., Su, J., Geddes, J., Van Norstrand, W., Wagner, S., Cunningham, D., and Cotman, C. 1992. Aggregation of the amyloid precursor protein within degenerating neurons and dystrophic neurites in Alzheimer's disease. Neurosci. 48:763-777.

    Google Scholar 

  78. Six, J., Lubke, U., Lenders, M.-B., Vandermeeren, M., Mercken, M., Villanova, M., Van de Voorde, A., Gheuenst, J., Martin, J.-J., and Cras, P. 1992. Neurite sprouting and cytoskeletal pathology in Alzheimer's disease: A comparative study with monoclonal antibodies to growth-associated protein B-50 (GAP43) and paired helical filaments. Neurodegeneration 1:247-255.

    Google Scholar 

  79. Cork, L. and Price, D. 1990. Relationships of abnormal neuronal processes and amyloid in plaques in aged monkeys. J. Neuropathol. Exp. Neurol. 49:309.

  80. Cork, L., Masters, C., Beyreuther, K., and Price, D. 1990. Development of senile plaques: Relationships of neuronal abnormalities and amyloid deposits. Am. J. Pathol. 137:1383-1392.

    PubMed  Google Scholar 

  81. Arai, H., Schmidt, M., Lee, V.-Y., Hurtig, H., Greenberg, B., Adler, C., and Trojanowski, J. 1992. Epitope analysis of senile plaque components in the hippocampus of patients with Parkinson's disease. Neurology 42:1315-1322.

    PubMed  Google Scholar 

  82. Koo, E., Lansbury, P. J., and Kelly, J. 1999. Amyloid diseases: Abnormal protein aggregation in neurodegeneration. Proc. Natl. Acad. Sci. USA 96:9989-9990.

    PubMed  Google Scholar 

  83. Selkoe, D. J., Yamazaki, T., Citron, M., Podlisny, M. B., Koo, E. H., Teplow, D. B., and Haass, C. 1996. The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Ann. N Y Acad. Sci. 777:57-64.

    PubMed  Google Scholar 

  84. Koo, E., Park, L., and Selkoe, D. 1993. Amyloid β-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth. Proc. Natl. Acad. Sci. USA 90:4749-4752.

    Google Scholar 

  85. Schubert, W., Prior, R., Weidemann, A., Dircksen, H., Multhaup, G., Masters, C., and Beyreuther, K. 1991. Localization of Alzheimer β-A4 amyloid at presynaptic terminals. Brain Res. 563:184-194.

    PubMed  Google Scholar 

  86. Masliah, E., Mallory, M., Hansen, L., Alford, M., DeTeresa, R., Terry, R., Baudier, J., and Saitoh, T. 1992. Localization of amyloid precursor protein in GAP43-immunoreactive aberrant sprouting neurites in Alzheimer's disease. Brain Res. 574:312-316.

    PubMed  Google Scholar 

  87. Beer, J., Weidemann, A., Fischer, P., Bunke, D., Masters, C., and Beyreuther, K. 1989. Synaptic localization of the A4 protein precursor of the amyloid of Alzheimer's disease. Soc. Neurosci. Abstr. 15:547.

  88. Masliah, E., Hansen, L., Mallory, M., Albright, T., and Terry, R. 1991. Abnormal brain spectrin immunoreactivity in sprouting neurons in Alzheimer disease. Neurosci. Lett. 129:1-5.

    PubMed  Google Scholar 

  89. Masliah, E., Mallory, M., DeTeresa, R., Alford, M., Terry, R., and Hansen, L. 1992. Alzheimer's disease (AD) with and without Lewy bodies (LB): Differing patterns of aberrant neuronal sprouting. Neurology 42:444.

  90. Masliah, E., Rockenstein, E., Veinbergs, I., Sagara, Y., Mallory, M., Hashimoto, M., and Mucke, L. 2001. Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc. Natl. Acad. Sci. USA 98:12245-12250.

    PubMed  Google Scholar 

  91. Palop, J., Jones, B., Kekonius, L., Essrich, C., Chin, J., Yu, C-G., Raber, J., Masliah, E., and Mucke, L. 2003. Depletion of calcium-dependent neuronal proteins by amyloid proteins is tightly linked to Alzheimer's disease-related cognitive impairments. Proc. Natl. Acad. Sci. USA, July 24 [E-pub ahead of print].

  92. Masliah, E., Mallory, M., Alford, M., Ge, N., and Mucke, L. 1995.Abnormal synaptic regeneration in hAPP695 transgenic and APOE knockout mice. Pages 405-414, in Iqbal, K., Mortimer, J., Winblad, B., and Wisniewski, H. (eds.), Research Advances in Alzheimer's Disease and Related Disorders, New York, John Wiley & Sons Ltd.

    Google Scholar 

  93. Trapp, B., Hauer, P., Haney, C., and Wirak, D. 1992. APP is expressed in fetal brain and is associated with neuronal development. J. Neuropathol. Exp. Neurol. 51:358.

  94. Masliah, E., Mallory, M., Ge, N., and Saitoh, T. 1992. Amyloid precursor protein is localized in growing neurites of neonatal rat brain. Brain Res. 593:323-328.

    PubMed  Google Scholar 

  95. Yankner, B., Duffy, L., and Kirschner, D. 1990. Neurotrophic and neurotoxic effects of amyloid β protein: Reversal by tachykinin neuropeptides. Science 250:279-282.

    PubMed  Google Scholar 

  96. Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S., and Malinow, R. 2003. APP processing and synaptic function. Neuron 37:925-937.

    PubMed  Google Scholar 

  97. Mileusnic, R., Lancashire, C. L., Johnston, A. N., and Rose, S. P. 2000. APP is required during an early phase of memory formation. Eur. J. Neurosci. 12:4487-4495.

    PubMed  Google Scholar 

  98. Masliah, E., Raber, J., Aford, M. Mallory, M., Mattson, M. P., Yang, D., Wong, D., and Mucke, L. 1998. Amyloid protein precursor stimulates excitory amino acid transport. Implication for roles in neuroprotection and pathogenesis. J. Biol. Chem. 273:12548-12554.

    PubMed  Google Scholar 

  99. Masliah, E., Alford, M., Adame, A., Rockenstein, E., Galasko, D., Salmon, D., Hansen, L., and Thal, L. 2003. Abetal-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD. Neurology. (in press).

  100. Grace, E. A., Rabiner, C. A., and Busciglio, J. 2002. Characterization of neuronal dystrophy induced by fibrillar amyloid beta: Implications for Alzheimer's disease. Neuroscience 114:265-273.

    PubMed  Google Scholar 

  101. Chartier-Harlin, M.-C., Crawford, F., Houlden, H., Warren, A., Hughes, D., Fidani, L., Goate, A., Rossor, M., Roques, P., Hardy, J., and Mullan, M. 1991. Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353:844-846.

    PubMed  Google Scholar 

  102. Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Guiffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Williamson, R., Rossor, M., Owen, M., and Hardy, J. 1991. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349:704.

  103. Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C., Perez-Tur, J., Hutton, M., Buee, L., Harigaya, Y., Yager, D., Morgan, D., Gordon, M., Holcomb, L., Refolo, L., Zenk, B., Hardy, J., and Younkin, S. 1996. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710-713.

    PubMed  Google Scholar 

  104. Younkin, S. G. 1997. The AAP and PS1/2 mutations linked to early onset familial Alzheimer's disease increase the extracellular concentration and A beta 1-42 (43). Rinsho Shinkeigaku 37:1099.

  105. Haas, C., Hung, A. Y., Citron, M., Teplow, D. B., and Selkoe, D. J. 1995. Beta-amyloid, protein processing and Alzheimer's disease. Arzneimittelforschung 45:398-402.

    PubMed  Google Scholar 

  106. Esler, W. P. and Wolfe, M. S. 2001. A portrait of Alzheimer secretases: New features and familiar faces. Science 293:1449-1454.

    PubMed  Google Scholar 

  107. Sinha, S., Anderson, J., John, V., McConlogue, L., Basi, G., Thorsett, E., and Schenk, D. 2000. Recent advances in the understanding of the processing of APP to beta amyloid peptide. Ann. N Y Acad. Sci. 920:206-208.

    PubMed  Google Scholar 

  108. Sinha, S., Anderson, J. P., Barbour, R., Basi, G. S., Caccavello, R., Davis, D., Doan, M., Dovey, H. F., Frigon, N., Hong, J., Jacobson-Croak, K., Jewett, N., Keim, P., Knops, J., Lieberburg, I., Power, M., Tan, H., Tatsuno, G., Tung, J., Schenk, D., Seubert, P., Suomensaari, S. M., Wang, S., Walker, D., and John, V., et al. 1999. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537-540.

    PubMed  Google Scholar 

  109. Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., Fuller, J., Edenson, S., Lile, J., Jarosinski, M. A., Biere, A. L., Curran, E., Burgess, T., Louis, J. C., Collins, F., Treanor, J., Rogers, G., and Citron, M. 1999. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735-741.

    PubMed  Google Scholar 

  110. Holsinger, R. M., McLean, C. A., Beyreuther, K., Masters, C. L., and Evin, G. 2002. Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann. Neurol. 51:783-786.

    PubMed  Google Scholar 

  111. Huse, J. T., Liu, K., Pijak, D. S., Carlin, D., Lee, V. M., and Doms, R. W. 2002. Beta-secretase processing in the trans-Golgi network preferentially generates truncated amyloid species that accumulate in Alzheimer's disease brain. J. Biol. Chem. 277:16278-16284.

    PubMed  Google Scholar 

  112. Rossner, S., Apelt, J., Schliebs, R., Perez-Polo, J. R., and Bigl, V. 2001. Neuronal and glial beta-secretase (BACE) protein expression in transgenic Tg2576 mice with amyloid plaque pathology. J. Neurosci. Res. 64:437-446.

    PubMed  Google Scholar 

  113. Fukumoto, H., Cheung, B. S., Hyman, B. T., and Irizarry, M. C. 2002. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch. Neurol. 59:1381-1389.

    PubMed  Google Scholar 

  114. Takahashi, R. H., Milner, T. A., Li, F., Nam, E. E., Edgar, M. A., Yamaguchi. H., Beal, M. F., Xu, H., Greengard, P., and Gouras, G. K. 2002. Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am. J. Pathol. 161:1869-1879.

    PubMed  Google Scholar 

  115. Yao, P. J., Zhu, M., Pyun, E., Brooks, A. I., Therianos, S., Meyers, V. E., and Coleman, P. D. 2003. Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer's disease. Neurobiol. Dis. 12:97-109.

    PubMed  Google Scholar 

  116. Chan, S. L., Furukawa, K., and Mattson, M. P. 2002. Presenilins and APP in neuritic and synaptic plasticity: Implications for the pathogenesis of Alzheimer's disease. Neuromol. Med. 2:167-196.

    Google Scholar 

  117. Mattson, M. P. 2002. Apoptosis in neurodegenerative disorders. Nat. Rev. Mol. Cell. Biol. 1:120-129.

    Google Scholar 

  118. Mattson, M. P. 2002. Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer's disease. J. Neurovirol. 8:539-550.

    PubMed  Google Scholar 

  119. Golbe, L. 1999. Alpha-synuclein and Parkinson's disease. Mov. Disord. 14:6-9.

    PubMed  Google Scholar 

  120. Hashimoto, M. and Masliah, E. 1999. Alpha-synuclein in Lewy body disease and Alzheimer's disease. Brain Pathol. 9:707-720.

    PubMed  Google Scholar 

  121. Wakabayashi, K., Yoshioto, M., Tsuji, S., and Takahashi, H. 1998. Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci. Lett. 249:180-182.

    PubMed  Google Scholar 

  122. Trojanowski, J., Goedert, M., Iwatsubo, T., and Lee, V. 1998. Fatal attractions: Abnormal protein aggregation and neuron death in Parkinson's disease and lewy body dementia. Cell Death Differ. 5:832-837.

    PubMed  Google Scholar 

  123. Lansbury, P. T. J. 1999. Evolution of amyloid: What normal protein folding may tell us about fibrillogenesis and disease. PNAS. 96:3342-3344.

    PubMed  Google Scholar 

  124. Ueda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Otero, D., Kondo, J., Ihara, Y., and Saitoh, T. 1993. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 90:11282-11286.

    PubMed  Google Scholar 

  125. Polymeropoulos, M., Lavedan, C., Leroy, E., Ide, S., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., Stenroos, E., Chandrasekharappa, S., Athanassiadou, A., Papapetropulos, T., Johnson, W., Lazzarini, A., Duvoisin, R., Di Iorio, G., Golbe. L., and Nussbaum, R. 1997. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276:2045-2047.

    PubMed  Google Scholar 

  126. Kruger, R., Kuhn, W., Muller, T., Woitalla, D., Graeber, M., Kosel, S., Przuntek, H., Epplen, J., Schols, L., and Reiss, O. 1998. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18:106-108.

    PubMed  Google Scholar 

  127. Hashimoto, M., Hernandez-Ruiz, S., Hsu, L., Sisk, A., Xia, Y., Takeda, A., Sundsmo, M., and Masliah, E. 1998. Human recombinant NACP/α-synuclein is aggregated and fibrillated in vitro: Relevance for Lewy body disease. Brain Res. 799:301-306.

    PubMed  Google Scholar 

  128. Conway, K., Harper, J., and Lansbury, P. 1998. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med. 4:1318-1320.

    PubMed  Google Scholar 

  129. El-Agnaf, O., Jakes, R., Curran, M., and Wallace, A. 1998. Effects of the mutations Ala30 to Pro and Ala 53 to Thr on the physical and morphological properties of α-synuclein protein implicated in Parkinson's disease. FEBS Lett. 440:67-70.

    PubMed  Google Scholar 

  130. Masliah, E., Rockenstein, E., Veinbergs, I., Mallory, M., Hashimoto, M., Takeda, A., Sagara, Y., Sisk, A., and Mucke, L. 2000. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: Implications for neurodegenerative disorders. Science 287:1265-1269.

    PubMed  Google Scholar 

  131. Feany, M. and Bender, W. 2002. A Drosophila model of Parkinson's disease. Nature 404:394-398.

    Google Scholar 

  132. Giasson, B. I., Duda, J. E., Quinn, S. M., Zhang, B., Trojanowski, J. Q., and Lee, V. M. 2002. Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521-533.

    PubMed  Google Scholar 

  133. Lee, M. K., Stirling, W., Xu, Y., Xu, X., Qui, D., Mandir, A. S., Dawson, T. M., Copeland, N. G., Jenkins, N. A., and Price, D. L. 2002. Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 \to Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc. Natl. Acad. Sci. USA 99:8968-8973.

    PubMed  Google Scholar 

  134. Hsu, L. J., Sagara, Y., Arroyo, A., Rockenstein, E., Sisk, A., Mallory, M., Wong, J., Takenouchi, T., Hashimoto, M., and Masliah, E. 2000. α-Synuclein promotes mitochondrial deficiencies and oxidative stress. Am. J. Pathol. 157:401-410.

    PubMed  Google Scholar 

  135. Kanda, S., Bishop, J. F., Eglitis, M. A., Yang, Y., and Mouradian, M. M. 2000. Enhanced vulnerability to oxidative stress by alpha-synuclein mutations and C-terminal truncation. Neuroscience 97:279-284.

    PubMed  Google Scholar 

  136. Tabrizi, S. J., Orth, M., Wilkinson, J. M., Taanman, J. W., Warner, T. T., Cooper, J. M., and Schapira, A. H. 2000. Expression of mutant alpha-synuclein causes increased susceptibility to dopamine toxicity. Hum. Mol. Genet. 9:2683-2689.

    PubMed  Google Scholar 

  137. Kirik, D., Rosenblad, C., Burger, C., Lundberg, C., Johansen, T. E., Muzyczka, N., Mandel, R. J., and Bjorklund, A. 2002. Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci. 22:2780-2791.

    PubMed  Google Scholar 

  138. Xu, J., Kao, S. Y., Lee, F. I., Song, W., Jin, L. W., and Yankner, B. A. 2002. Dopamine-dependent neurotoxicity of alpha-synuclein: A mechanism for selective neurodegeneration in Parkinson disease. Nat. Med. 8:600-606.

    PubMed  Google Scholar 

  139. Takenouchi, T., Hashimoto, M., Hsu, L., Mackowski, B., Rockenstein, E., Mallory, M., and Masliah, E. 2001. Reduced neuritic outgrowth and cell adhesion in neuronal cells transfected with human α-synuclein. Mol. Cell Neurosci. 17:141-150.

    PubMed  Google Scholar 

  140. Hashimoto, M., Sagara, Y., Everall, I. P., Mallory, M., Everson, A., Langford, D., and Masliah, E. 2002. Fibroblast growth factor 1 regulates signaling via the glycogen synthase kinase-3β pathway: Implications for neuroprotection. J. Biol. Chem. 277:32985-32991.

    PubMed  Google Scholar 

  141. Meredith, G. E., Totterdell, S., Petroske, E., Santa Cruz, K., Callison, R. C. J., and Lau, Y. S. 2002. Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson's disease. Brain Res. 956:156-165.

    PubMed  Google Scholar 

  142. Gosavi, N., Lee, H. J., Lee, J. S., Patel, S., and Lee, S. J. 2002. Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion. J. Biol. Chem. 277:48984-48992.

    PubMed  Google Scholar 

  143. Cabin, D. E., Shimazu, K., Murphy, D. P., Cole, N. B., Gottschalk, W., McIlwain, K. L., Orrison, B., Chen, A., Ellis, C. E., Paylor, R., Lu, B., and Nussbaum, R. L. 2002. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J. Neurosci. 22:8797-8807.

    PubMed  Google Scholar 

  144. Hashimoto, M., Hsu, L. J., Rockenstein, E., Takenouchi, T., Mallory, M., and Masliah, E. 2002. α-Synuclein protects against oxidative stress via inactivation of the C-jun N-terminal kinase stress signaling pathway in neuronal cells. J. Biol. Chem. 277:11465-11472.

    PubMed  Google Scholar 

  145. Ostrerova, N., Petrucelli, L., Farrer, M., Mehta, M., Choi, P., Hardy, J., and Wolozin, B. 1999. Alpha-synuclein shares physical and functional homology with 14-3-3 proteins. J. Neurosci. 19:5782-5791.

    PubMed  Google Scholar 

  146. Iwata, A., Maruyama, M., Kanazawa, I., and Nukina, N. 2001. Alpha-synuclein affects the MAPK pathway and accelerates cell death. J. Biol. Chem. 276:45320-45329.

    PubMed  Google Scholar 

  147. Ahn, B., Rhim, H., Kim, S., Sung, Y., Lee, M. Y., Choi, J., Wolozin, B., Chang, J., Lee, Y., Kwon, T., Chung, K., Yoon, S., Hahn, S., Kim, M., Jo, Y., and Min, D. 2002. α-Synuclein interacts with phospholipase D isozymes and inhibits pervana-date-induced phospholipase D activation in human embryonic kidney-293 cells. J. Biol. Chem. 277:12334-12342.

    PubMed  Google Scholar 

  148. Impey, S., Obrietan, K., and Storm, D. 1999. Making new connections: Role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 23:11-14.

    PubMed  Google Scholar 

  149. Cox, M. E. and Parsons, S. J. 1997. Roles for protein kinase C and mitogen-activated protein kinase in nicotine-induced secretion from bovine adrenal chromaffin cells. J. Neurochem. 69:1119-1130.

    PubMed  Google Scholar 

  150. Bloch-Shilderman, E., Jiang, H., Abu-Raya, S., Linial, M., and Lazarovici, P. 2001. Involvement of extracellular signal-regulated kinase (ERK) in pardaxin-induced dopamine release from PC12 cells. J. Pharmacol. Exp. Ther. 296:704-711.

    PubMed  Google Scholar 

  151. Abeliovich, A., Schmitz, Y., Farinas, I., Choi-Lundberg, D., Ho, W. H., Castillo, P. E., Shinsky, N., Verdugo, J. M., Armanini, M., Ryan, A., Hynes, M., Phillips, H., Sulzer, D., and Rosenthal, A. 2000. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239-252.

    PubMed  Google Scholar 

  152. Iwata, A., Miura, S., Kanazawa, I., Sawada, M., and Nukina, N. 2001. Alpha-synuclein forms a complex with transcription factor Elk-1. J. Neurochem. 77:239-252.

    PubMed  Google Scholar 

  153. Hashimoto, M., Takenouchi, T., Rockenstein, E., and Masliah, E. 2003. α-Synuclein up-regulates expression of caveolin-1 and down-regulates extracellular signal-regulated kinase activity in B103 neuroblastoma cells: Role in the pathogenesis of Parkinson's disease. J. Neurochem. 85:1468-1479.

    PubMed  Google Scholar 

  154. Smart, E. J., Graf, G. A., McNiven, M. A., Sessa, W. C., Engelman, J. A., Scherer, P. E., Okamoto, T., and Lisanti, M. P. 1999. Caveolins, liquid-ordered domains, and signal transduction. Mol. Cell Biol. 9:7289-7304.

    Google Scholar 

  155. Braun, J. E. and Madison, D. V. 2000. A novel SNAP25-caveolin complex correlates with the onset of persistent synaptic potentiation. J. Neurosci. 20:5997-6006.

    PubMed  Google Scholar 

  156. Okamoto, T., Schlegel, A., Scherer, P. E., and Lisanti, M. P. 1998. Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J. Biol. Chem. 273:5419-5422.

    PubMed  Google Scholar 

  157. Kurzchalia, T. V. and Parton, R. G. 1999. Membrane microdomains and caveolae. Curr. Opin. Cell. Biol. 11:424-431.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosciences, University of California, San Diego, La Jolla, California

    Makoto Hashimoto & Eliezer Masliah

Authors
  1. Makoto Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eliezer Masliah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eliezer Masliah.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hashimoto, M., Masliah, E. Cycles of Aberrant Synaptic Sprouting and Neurodegeneration in Alzheimer's and Dementia with Lewy Bodies. Neurochem Res 28, 1743–1756 (2003). https://doi.org/10.1023/A:1026073324672

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026073324672

Search

Navigation