Abstract
Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders that share progressive dementia as the common major clinical symptom. Damages to memory-related brain structures are the likely pathological correlate, and in both illnesses deposition of amyloidogenic proteins are present mainly within these limbic structures. Amyloid-β–positive plaques and phospho-tau–positive neurofibrillary tangles are the main feature of AD and α-synuclein–positive Lewy bodies and Lewy neurites are found in DLB. Interestingly the associated proteins also interfere with synaptic function and synaptic plasticity. Here, we propose that the same neuronal circuits are disturbed within the hippocampal formation in AD and DLB and that in both diseases the associated proteins might lead to changes in synaptic plasticity and function. Thus both classic neuropathological changes and cellular dysfunctions might contribute to the cognitive impairments in AD and DLB.
Similar content being viewed by others
REFERENCES
Alzheimer, A. 1907. übereine eigenartige Erkrankung der Hirnrinde. Allg. Z. Psychiatr. Psych.-Gerichtl. Med. 64:146-148.
Glenner, G. G. and Wong, C. W. 1984. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120:885-890.
Hyman, B. T., Van Horsen, G. W., Damasio, A. R., and Barnes, C. L. 1984. Alzheimer's disease: Cell-specific pathology isolates the hippocampal formation. Science 225: 1168-1170.
Iqbal, K., Grundke-Iqbal, I., Zaidi, T., Merz, P. A., Wen, G. Y., Shaikh, S. S., Wisniewski, H. M., Alafuzoff, I., and Winblad, B. 1986. Defective brain microtubule assembly in Alzheimer's disease. Lancet 2:421-426.
Yankner, B. A., Dawes, L. R., Fisher, S., Villa-Komaroff, L., Oster-Granite, M. L., and Neve, R. L. 1989. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 245:417-420.
Van Hoesen, G. W. and Hyman, B. T. 1990. Hippocampal formation: Anatomy and the patterns of pathology in Alzheimer's disease. Prog. Brain. Res. 83:445-457.
Braak, H. and Braak, E. 1991. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berl.) 82: 239-259.
Goedert, M., Spillantini, M. G., and Crowther, R. A. 1991. Tau proteins and neurofibrillary degeneration. Brain Pathol. 1:279-286.
Arriagada, P. V., Marzloff, K., and Hyman, B. T. 1992. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease. Neurology 42:1681-1688.
Selkoe, D. J. 1994. Alzheimer's disease: A central role for amyloid. J. Neuropathol. Exp. Neurol. 53:438-447.
Trojanowski, J. Q., Shin, R. W., Schmidt, M. L., and Lee, V. M. 1995. Relationship between plaques, tangles, and dystrophic processes in Alzheimer's disease. Neurobiol. Aging 16:335-340; discussion 341-335.
Hardy, J. 1997. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 20:154-159.
Parkinson, J. 1817. An Essy on the Shaking Palsy, London, Neely and Jones.
Lewy, F. 1912. Pages 920-933, in M.A. Lewandowski, G. (eds.), Handbuch der Neurologie, Berlin, Springer Verlag.
Ueda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D. A., Kondo, J., Ihara, Y., and Saitoh, T. 1993. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 90:11282-11286.
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. 1997. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276:2045-2047.
Spillantini, M. G., Schmidt, M. L., Lee, V. M., Trojanowski, J. Q., Jakes, R., and Goedert, M. 1997. Alpha-synuclein in Lewy bodies. Nature 388:839-840.
Irizarry, M. C., Growdon, W., Gomez-Isla, T., Newell, K., George, J. M., Clayton, D. F., and Hyman, B. T. 1998. Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain alpha-synuclein immunoreactivity. J. Neuropathol. Exp. Neurol. 57:334-337.
Kruger, R., Kuhn, W., Muller, T., Woitalla, D., Graeber, M., Kosel, S., Przuntek, H., Epplen, J. T., Schols, L., and Riess, O. 1998. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat. Genet. 18:106-108.
Clayton, D. F. and George, J. M. 1999. Synucleins in synaptic plasticity and neurodegenerative disorders. J. Neurosci. Res. 58:120-129.
Baba, M., Nakajo, S., Tu, P. H., Tomita, T., Nakaya, K., Lee, V. M., Trojanowski, J. Q., and Iwatsubo, T. 1998. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am. J. Pathol. 152:879-884.
Gomez-Tortosa, E., Ingraham, A. O., Irizarry, M. C., and Hyman, B. T. 1998. Dementia with Lewy bodies. J. Am. Geriatr. Soc. 46:1449-1458.
Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M., and Goedert, M. 1998. Alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc. Natl. Acad. Sci. USA 95:6469-6473.
Rosene, D. L. and Van Hoesen, G. W. 1987. The hippocampal formation of the primate brain. Pages 345-456, in Peters, A. and Jones, E. G. (eds.), Cerebral Cortex, New York, Plenum Press.
Squire, L. R. and Zola-Morgan, S. 1991. The medial temporal lobe memory system. Science 253:1380-1386.
Van Hoesen, G. W. and Pandya, D. N. 1975. Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices of the rhesus monkey: III. Efferent connections. Brain Res. 95:39-59.
Steward, O. 1976. Topographic organization of the projections from the entorhinal area to the hippocampal formation of the rat. J. Comp. Neurol. 167:285-314.
Van Hoesen, G. W., Rosene, D. L., and Mesulam, M. M. 1979. Subicular input from temporal cortex in the rhesus monkey. Science 205:608-610.
Van Hoesen, G. W. 1985. Neural systems of the non-human primate forebrain implicated in memory. Ann. N Y Acad. Sci. 444:97-112.
Lynch, G., Matthews, D. A., Mosko, S., Parks, T., and Cotman, C. W. 1972. Induced acetylcholinesterase-rich layer in rat dentate gyrus following entorhinal lesions. Brain Res. 42:311-318.
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.
Storm-Mathisen, J. 1974. Choline acetyltransferase and acetylcholinesterase in fascia dentata following lesion of the entorhinal afferents. Brain Res. 80:181-197.
Hyman, B. T., Kromer, L. J., and Van Hoesen, G. W. 1987. Reinnervation of the hippocampal perforant pathway zone in Alzheimer's disease. Ann. Neurol. 21:259-267.
Cotman, C. W. and Nieto-Sampedro, M. 1982. Brain function, synapse renewal, and plasticity. Annu. Rev. Psychol. 33:371-401.
Cotman, C. W. and Nieto-Sampedro, M. 1984. Cell biology of synaptic plasticity. Science 225:1287-1294.
Cotman, C. W., Nieto-Sampedro, M., and Gibbs, R. B. 1984. Enhancing the self-repairing potential of the CNS after injury. Cent. Nerv. Syst. Trauma 1:3-14.
Cotman, C. W. and Anderson, K. J. 1988. Synaptic plasticity and functional stabilization in the hippocampal formation: Possible role in Alzheimer's disease. Adv. Neurol. 47:313-335.
Hyman, B. T., Van Hoesen, G. W., Kromer, L. J., and Damasio, A. R. 1986. Perforant pathway changes and the memory impairment of Alzheimer's disease. Ann. Neurol. 20:472-481.
Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R., and Van Hoesen, G. W. 1991. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb. Cortex 1:103-116.
Van Hoesen, G. W., Hyman, B. T., and Damasio, A. R. 1991. Entorhinal cortex pathology in Alzheimer's disease. Hippocampus 1:1-8.
Geddes, J. W., Monaghan, D. T., Cotman, C. W., Lott, I. T., Kim, R. C., and Chui, H. C. 1985. Plasticity of hippocampal circuitry in Alzheimer's disease. Science 230:1179-1181.
Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., and Hyman, B. T. 1992. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42:631-639.
Hyman, B. T., Van Hoesen, G. W., Wolozin, B. L., Davies, P., Kromer, L. J., and Damasio, A. R. 1988. Alz-50 antibody recognizes Alzheimer-related neuronal changes. Ann. Neurol. 23:371-379.
Knowles, R. B., Wyart, C., Buldyrev, S. V., Cruz, L., Urbanc, B., Hasselmo, M. E., Stanley, H. E., and Hyman, B. T. 1999. Plaque-induced neurite abnormalities: Implications for disruption of neural networks in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 96:5274-5279.
Cotman, C. W. 1998. Apoptosis decision cascades and neuronal degeneration in Alzheimer's disease. Neurobiol. Aging 19: S29-S32.
Wilson, C. A., Doms, R. W., and Lee, V. M. 1999. Intracellular APP processing and A beta production in Alzheimer disease. J. Neuropathol. Exp. Neurol. 58:787-794.
Yankner, B. A. 1996. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron 16:921-932.
Hyman, B. T., Marzloff, K., and Arriagada, P. V. 1993. The lack of accumulation of senile plaques or amyloid burden in Alzheimer's disease suggests a dynamic balance between amyloid deposition and resolution. J. Neuropathol. Exp. Neurol. 52:594-600.
Gomez-Isla, T., Price, J. L., McKeel, D. W., Jr., Morris, J. C., Growdon, J. H., and Hyman, B. T. 1996. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J. Neurosci. 16:4491-4500.
Stephan, A., Laroche, S., and Davis, S. 2001. Generation of aggregated beta-amyloid in the rat hippocampus impairs synaptic transmission and plasticity and causes memory deficits. J. Neurosci. 21:5703-5714.
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. 1998. Diffusible, nonfibrillar ligands derived from Abeta l-142 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95:6448-6453.
Hartley, D. M., Walsh, D. M., Ye, C. P., Diehl, T., Vasquez, S., Vassilev, P. M., Teplow, D. B., and Selkoe, D. J. 1999. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J. Neurosci. 19:8876-8884.
Holcomb, L. A., Gordon, M. N., Jantzen, P., Hsiao, K., Duff, K., and Morgan, D. 1999. Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: Lack of association with amyloid deposits. Behav. Genet. 29:177-185.
Hsia, A. Y., Masliah, E., McConlogue, L., Yu, G. Q., Tatsuno, G., Hu, K., Kholodenko, D., Malenka, R. C., Nicoll, R. A., and Mucke, L. 1999. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl. Acad. Sci. USA 96:3228-3233.
Lue, L. F., Kuo, Y. M., Roher, A. E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., and Rogers, J. 1999. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 155: 853-862.
McLean, C. A., Cherny, R. A., Fraser, F. W., Fuller, S. J., Smith, M. J., Beyreuther, K., Bush, A. I., and Masters, C. L. 1999. Soluble pool of Abeta amyloid as a determinant of severity of neu-rodegeneration in Alzheimer's disease. Ann. Neurol. 46:860-866.
Mucke, L., Masliah, E., Yu, G. Q., Mallory, M., Rockenstein, E. M., 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.
Klein, W. L., Krafft, G. A., and Finch, C. E. 2001. Targeting small abeta oligomers: The solution to an Alzheimer's disease conundrum? Trends Neurosci. 24:219-224.
Walsh, D. M., Hartley, D. M., Condron, M. M., Selkoe, D. J., and Teplow, D. B. 2001. In vitro studies of amyloid beta-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692—>Gly) Alzheimer's disease. Biochem. J. 355:869-877.
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Rowan, M. J., and Selkoe, D. J. 2002. Amyloid-beta oligomers: Their production, toxicity and therapeutic inhibition. Biochem. Soc. Trans. 30:552-557.
Buell, S. J. and Coleman, P. D. 1979. Dendritic growth in the aged human brain and failure of growth in senile dementia. Science 206:854-856.
Scheibel, A. B. and Tomiyasu, U. 1978. Dendritic sprouting in Alzheimer's presenile dementia. Exp. Neurol. 60:1-8.
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's disease. Neuron 6:729-739.
Seabrook, G. R., Smith, D. W., Bowery, B. J., Easter, A., Reynolds, T., Fitzjohn, S. M., Morton, R. A., Zheng, H., Dawson, G. R., Sirinathsinghji, D. J., et al. 1999. Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38:349-359.
Mucke, L., Masliah, E., Johnson, W. B., Ruppe, M. D., Alford, M., Rockenstein, E. M., Forss-Petter, S., Pietropaolo, M., Mallory, M., and Abraham, C. R. 1994. Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice. Brain Res. 666:151-167.
Chapman, P. F., White, G. L., Jones, M. W., Cooper-Blacketer, D., Marshall, V. J., Irizarry, M., Younkin, L., Good, M. A., Bliss, T. V., Hyman, B. T., et al. 1999. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat. Neurosci. 2:271-276.
Chen, Q. S., Wei, W. Z., Shimahara, T., and Xie, C. W. 2002. Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus. Neurobiol. Learn. Mem. 77: 354-371.
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., and Selkoe, D. J. 2002. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535-539.
McKeith, I. G., Galasko, D., Kosaka, K., Perry, E. K., Dickson, D. W., Hansen, L. A., Salmon, D. P., Lowe, J., Mirra, S. S., Byrne, E. J., et al. 1996. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 47:1113-1124.
McLean, P. J., Gomez-Tortosa, E., Irizarry, M., and Hyman, B. T. 2002. Dementia with Lewy bodies. Pages 267-282, in A. K. Asbury, G. M. McKahnn, W. I. McDonald, P. J. Goadsby, and J. C. McArthur (eds.), Diseases of the Nervous System: Clinical Neuroscience and Therapeutic Principles, ed. 3, Cambridge, U. K., Cambridge University Press.
Lippa, C. F., Smith, T. W., and Swearer, J. M. 1994. Alzheimer's disease and Lewy body disease: A comparative clinicopathological study. Ann. Neurol. 35:81-88.
Gomez-Isla, T., Growdon, W. B., McNamara, M., Newell, K., Gomez-Tortosa, E., Hedley-Whyte, E. T., and Hyman, B. T. 1999. Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies. Neurology 53:2003-2009.
Gomez-Tortosa, E., Newell, K., Irizarry, M. C., Sanders, J. L., and Hyman, B. T. 2000. Alpha-synuclein immunoreactivity in dementia with Lewy bodies: Morphological staging and comparison with ubiquitin immunostaining. Acta Neuropathol. (Berl.) 99:352-357.
Harding, A. J., Lakay, B., and Halliday, G. M. 2002. Selective hippocampal neuron loss in dementia with Lewy bodies. Ann. Neurol. 51:125-128.
Buldyrev, S. V., Cruz, L., Gomez-Isla, T., Gomez-Tortosa, E., Havlin, S., Le, R., Stanley, H. E., Urbanc, B., and Hyman, B. T. 2000. Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias. Proc. Natl. Acad. Sci. USA 97:5039-5043.
Dickson, D. W., Ruan, D., Crystal, H., Mark, M. H., Davies, P., Kress, Y., and Yen, S. H. 1991. Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease: Light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD. Neurology 41:1402-1409.
Pellise, A., Roig, C., Barraquer-Bordas, L. I., and Ferrer, I. 1996. Abnormal, ubiquitinated cortical neurites in patients with diffuse Lewy body disease. Neurosci. Lett. 206:85-88.
Gomez-Tortosa, E., Irizarry, M. C., Gomez-Isla, T., and Hyman, B. T. 2000. Clinical and neuropathological correlates of dementia with Lewy bodies. Ann. N Y Acad. Sci. 920:9-15.
Galvin, J. E., Uryu, K., Lee, V. M., and Trojanowski, J. Q. 1999. Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. Proc. Natl. Acad. Sci. USA 96:13450-13455.
Clayton, D. F. and George, J. M. 1998. The synucleins: A family of proteins involved in synaptic function, plasticity, neurodegen-eration and disease. Trends Neurosci. 21:249-254.
Gai, W. P., Yuan, H. X., Li, X. Q., Power, J. T., Blumbergs, P. C., and Jensen, P. H. 2000. In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies. Exp. Neurol. 166:324-333.
Goedert, M. 2001. Alpha-synuclein and neurodegenerative diseases. Nat. Rev. Neurosci. 2:492-501.
Kuzuhara, S., Mori, H., Izumiyama, N., Yoshimura, M., and Ihara, Y. 1988. Lewy bodies are ubiquitinated: A light and electron microscopic immunocytochemical study. Acta Neuropathol. (Berl.) 75:345-353.
Ii, K., Ito, H., Tanaka, K., and Hirano, A. 1997. Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. J. Neuropathol. Exp. Neurol. 56:125-131.
Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M., and Bonini, N. M. 2002. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295:865-868.
McLean, P. J., Kawamata, H., Shariff, S., Hewett, J., Sharma, N., Ueda, K., Breakefield, X. O., and Hyman, B. T. 2002. TorsinA and heat shock proteins act as molecular chaperones: Suppression of alpha-synuclein aggregation. J. Neurochem. 83:846-854.
Galvin, J. E., Lee, V. M., Baba, M., Mann, D. M., Dickson, D. W., Yamaguchi, H., Schmidt, M. L., Iwatsubo, T., and Trojanowski, J. O. 1997. Monoclonal antibodies to purified cortical Lewy bodies recognize the mid-size neurofilament subunit. Ann. Neurol. 42:595-603.
Masliah, E., Iwai, A., Mallory, M., Ueda, K., and Saitoh, T. 1996. Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer's disease. Am. J. Pathol. 148:201-210.
Perrin, R. J., Woods, W. S., Clayton, D. F., and George, J. M. 2000. Interaction of human alpha-synuclein and Parkinson's disease variants with phospholipids: Structural analysis using site-directed mutagenesis. J. Biol. Chem. 275:34393-34398.
Crowther, R. A., Jakes, R., Spillantini, M. G., and Goedert, M. 1998. Synthetic filaments assembled from C-terminally truncated alpha-synuclein. FEBS Lett. 436:309-312.
El-Agnaf, O. M., Jakes, R., Curran, M. D., Middleton, D., Ingenito, R., Bianchi, E., Pessi, A., Neill, D., and Wallace, A. 1998. Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of beta-sheet and amyloid-like filaments. FEBS Lett. 440:71-75.
Narhi, L., Wood, S. J., Steavenson, S., Jiang, Y., Wu, G. M., Anafi, D., Kaufman, S. A., Martin, F., Sitney, K., Denis, P., et al. 1999. Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation. J. Biol. Chem. 274:9843-9846.
Giasson, B. I., Murray, I. V., Trojanowski, J. Q., and Lee, V. M. 2001. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J. Biol. Chem. 276:2380-2386.
Conway, K. A., Harper, J. D., and Lansbury, P. T. 1998. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat. Med. 4:1318-1320.
Serpell, L. C., Berriman, J., Jakes, R., Goedert, M., and Crowther, R. A. 2000. Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. Proc. Natl. Acad. Sci. USA 97:4897-4902.
Conway, K. A., Rochet, J. C., Bieganski, R. M., and Lansbury, P. T., Jr. 2001. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 294:1346-1349.
Li, J., Uversky, V. N., and Fink, A. L. 2001. Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. Biochemistry 40:11604-11613.
McLean, P. J., Kawamata, H., and Hyman, B. T. 2001. Alpha-synuclein-enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons. Neuroscience 104:901-912.
El-Agnaf, O. M., Jakes, R., Curran, M. D., and Wallace, A. 1998. Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha-synuclein, protein implicated in Parkinson's disease. FEBS Lett. 440:67-70.
Wood, S. J., Wypych, J., Steavenson, S., Louis, J. C., Citron, M., and Biere, A. L. 1999. Alpha-synuclein fibrillogenesis is nucleation-dependent: Implications for the pathogenesis of Parkinson's disease. J. Biol. Chem. 274:19509-19512.
Uversky, V. N., Lee, H. J., Li, J., Fink, A. L., and Lee, S. J. 2001. Stabilization of partially folded conformation during α-synuclein oligomerization in both purified and cytosolic preparations. J. Biol. Chem. 5:5.
Weinreb, P. H., Zhen, W., Poon, A. W., Conway, K. A., and Lansbury, P. T., Jr. 1996. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 35:13709-13715.
Kim, J. 1997. Evidence that the precursor protein of non-A beta component of Alzheimer's disease amyloid (NACP) has an extended structure primarily composed of random-coil. Mol. Cells 7:78-83.
Davidson, W. S., Jonas, A., Clayton, D. F., and George, J. M. 1998. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 273: 9443-9449.
McLean, P. J., Kawamata, H., Ribich, S., and Hyman, B. T. 2000. Membrane association and protein conformation of alpha-synuclein in intact neurons: Effect of Parkinson's disease-linked mutations. J. Biol. Chem. 275:8812-8816.
McLean, P. J., Ribich, S., and Hyman, B. T. 2000. Subcellular localization of alpha-synuclein in primary neuronal cultures: Effect of missense mutations. J. Neural. Transm. Suppl. 58:53-63.
Jakes, R., Spillantini, M. G., and Goedert, M. 1994. Identification of two distinct synucleins from human brain. FEBS Lett. 345:27-32.
Irizarry, M. C., Kim, T. W., McNamara, M., Tanzi, R. E., George, J. M., Clayton, D. F., and Hyman, B. T. 1996. Characterization of the precursor protein of the non-A beta component of senile plaques (NACP) in the human central nervous system. J. Neuropathol. Exp. Neurol. 55:889-895.
Lavedan, C. 1998. The synuclein family. Genome Res. 8:871-880.
Kahle, P. J., Neumann, M., Ozmen, L., Muller, V., Jacobsen, H., Schindzielorz, A., Okochi, M., Leimer, U., van Der Putten, H., Probst, A., et al. 2000. Subcellular localization of wild-type and Parkinson's disease-associated mutant alpha-synuclein in human and transgenic mouse brain. J. Neurosci. 20:6365-6373.
Jensen, P. H., Nielsen, M. S., Jakes, R., Dotti, C. G., and Goedert, M. 1998. Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation. J. Biol. Chem. 273:26292-26294.
Jo, E., Fuller, N., Rand, R. P., St George-Hyslop, P., and Fraser, P. E. 2002. Defective membrane interactions of familial Parkinson's disease mutant A30P alpha-synuclein. J. Mol. Biol. 315: 799-807.
Colley, W. C., Sung, T. C., Roll, R., Jenco, J., Hammond, S. M., Altshuller, Y., Bar-Sagi, D., Morris, A. J., and Frohman, M. A. 1997. Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganization. Curr. Biol. 7:191-201.
Jenco, J. M., Rawlingson, A., Daniels, B., and Morris, A. J. 1998. Regulation of phospholipase D2: Selective inhibition of mammalian phospholipase D isoenzymes by alpha-and beta-synucleins. Biochemistry 37:4901-4909.
Murphy, D. D. Rueter, S. M., Trojanowski, J. Q., and Lee, V. M. 2000. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J. Neurosci. 20:3214-3220.
Cabin, D. E., Shimazu, K., Murphy, D., Cole, N. B., Gottschalk, W., McIlwain, K. L., Orrison, B., Chen, A., Ellis, C. E., Paylor, R., et al. 2002. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J. Neurosci. 22:8797-8807.
Mesulam, M. M. 2000. A plasticity-based theory of the pathogenesis of Alzheimer's disease. Ann. N Y Acad. Sci. 924:42-52.
Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., de Silva, H. A., Kittel, A., and Saitoh, T. 1995. The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron 14:467-475.
Huber, G., Bailly, Y., Martin, J. R., Mariani, J., and Brugg, B. 1997. Synaptic beta-amyloid precursor proteins increase with learning capacity in rats. Neuroscience 80:313-320.
Ingelsson, M. and Hyman, B. T. 2002. Disordered proteins in dementia. Ann. Med. 34:259-271.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Klucken, J., McLean, P.J., Gomez-Tortosa, E. et al. Neuritic Alterations and Neural System Dysfunction in Alzheimer's Disease and Dementia with Lewy Bodies. Neurochem Res 28, 1683–1691 (2003). https://doi.org/10.1023/A:1026061021946
Issue Date:
DOI: https://doi.org/10.1023/A:1026061021946