Abstract
The molecular causes and the genetic and environmental modifying factors of the sporadic form of Alzheimer’s disease (AD) remain elusive. Extrapolating from the known mutations that cause the rare familial forms and from the typical post-mortem pathological lesions in all AD patients—e.g., amyloid plaques and neurofibrillary tangles (NFTs)—the evident molecular candidates are amyloid precursor protein (APP), presenilin, and tau protein. To include ApoE4 as the only certain genetic modifier known leaves us to face the challenge of implementing these very different molecules into an evident pathological partnership. In more than one respect, the proposition of disturbed axonal transport appears attractive with more details becoming available on APP processing and microtubular transport and also of the pathology in the model systems—e.g., transgenic mice expressing APP or protein tau. Conversely, the resistance of APP-transgenic mice with full-blown amyloid pathology to also develop tau-related neurofibrillar pathology is a major challenge for this hypothesis. From the most relevant data discussed here, we conclude that the postulate of disturbed axonal transport as the primary event in AD is difficult to defend. On the other hand, failing axonal transport appears to be of major importance in the later stages in AD, by further compromising tau protein, APP metabolism, and synaptic functioning. Protein tau may thus be the central “executer” in the chain of events leading from amyloid neurotoxicity to tau hyperphosphorylation, microtubular destabilization, disturbed axonal transport, and synaptic failure to neurodegeneration. In order to identify normal physiological processes and novel pathological targets, definition is needed—in molecular detail—of the complex mechanisms involved.
Similar content being viewed by others
References
Alonso A. C., Grundke-Iqbal I., and Iqbal K. (1996) Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat. Med. 2, 783–787.
Alonso A. C., Zaidi T., Novak M., Grundke-Iqbal I., and Iqbal K. (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. PNAS 98, 6923–6928.
Baas P. W., Pienkowski T. P., and Kosik K. S. (1991) Processes induced by tau expression in Sf9 cells have an axon-like microtubule organization. J. Cell Biol. 115, 1333–1344.
Baumann K., Mandelkow E.-M., Biernat J., Piwnica-Worms H., and Mandelkow E. (1993) Abnormal Alzheimer-like phosphorylation of protein tau by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 336, 417–424.
Biernat J. and Mandelkow E.-M. (1999) The development of cell processes induced by protein tau requires phosphorylation of serine 262 and 356 in the repeat domain and is inhibited by phosphorylation in the proline-rich domains. Mol. Biol. Cell 10, 727–740.
Braak E. and Braak E. (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259.
Braak E., Braak H., and Mandelkow E.-M. (1994) A sequence of cytoskeletal changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol. 87, 554–567.
Buée L., Bussière T., Buée-Scherrer V., Delacourte A., and Hof P. R. (2000) Tau protein isoforms, phosphorylation and role in neurogenerative disorders. Brain Res. Rev. 33, 95–130.
Caceras A. and Kosik K. S. (1990) Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature 343, 461–463.
Caceras A., Potrebic S., and Kosik K. S. (1991) The effect of tau antisense oligonucleotides on neurite formation of cultured cerebellar macroneurons. J. Neurosci. 11, 1515–1523.
Delacourte A. and Buée L. (2000) Tau pathology: a marker of neurodegenerative disorders. Curr. Opin. Neurol. 13, 371–376.
Delacourte A., David J. P., Sergeant N., et al. (1999) The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology 52, 1158–1165.
Dewachter I., Van Dorpe J., Smeijers L., Gilis M., Kuiperi C., Laenen I., et al. (2000) Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilin 1. J. Neurosci. 20, 6452–6458.
Dewachter I., Reverse D., Caluwaerts N., Ris L., Kuipéri C., Van den Haute C., et al. (2002) Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J. Neurosci. 22, 3445–3453.
Drewes G., Lichtenberg-Kraag B., Doring F., Mandelkow E.-M., Biernat J., Goris J., et al. (1992) Mitogen activated protein (MAP) kinase transforms protein tau into an Alzheimer-like state. EMBO J. 11, 2131–2138.
Drewes G., Mandelkow E.-M., Baumann K., Goris J., Merlevede W., and Mandelkow E. (1993) Dephosphorylation of protein tau and Alzheimer paired helical filaments by calcineurin and phosphatase-2A. FEBS Lett. 336, 424–432.
Drubin D. G. and Kirschner M. W. (1986) Protein tau function in living cells. J. Cell Biol. 103, 2739–2746.
Ebneth A., Godeman R., Stamer K., Illenberger S., Trinczek B., Mandelkow E.-M., et al. (1998) Overexpression of protein tau inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmatic reticulum: implications for Alzheimer’s disease. J. Cell Biol. 143, 777–794.
Esler W. P. and Wolfe M. S. (2001) A portrait of Alzheimer secretases—new features and familiar faces. Science 293, 1449–1454.
Elyaman W., Terro F., Wong N. S., and Hugon J. (2002) In vivo activation and nuclear translocation of phosphorylated glycogen synthase kinase-3β in neuronal apoptosis: links to tau phosphorylation Eur. J. Neurosci. 15, 651–660.
Friedhoff P., von Bergen M., Mandelkow E.-M., and Mandelkow E. (2000) Structure of protein tau and assembly into paired helical filaments. BBA 1502, 122–132.
Geula C., Wu C. K., Saroff D., Lorenzo A., Yuan M., and Yankner B. A. (1998) Aging renders the brain vulnerable to amyloid-β protein neurotoxicity. Nat. Med. 4, 827–831.
Goedert M., Spillantini M. G., Potier M. C., Ulrich J., and Crowther R. A. (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of protein tau mRNAs in human brain. EMBO J. 8, 393–399.
Goedert M. and Jakes R. (1990) Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerisation. EMBO J. 9, 4225–4230.
Goedert M., Hasegawa M., Jakes R., Lawler S., Cuenda A., and Cohen P. (1997) Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett. 409, 57–62.
Goldstein L. S. B. (2001) Kinesin molecular motors: transport pathways, receptors, and human disease. PNAS 98, 6999–7003.
Götz J., Chen F., Van Dorpe J., and Nitsch R. M. (2001) Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491–1495.
Greenwood J. A., Scott C. W., Spreen R. C., Caputo C. B., and Johnson G. V. (1994) Casein kinase II preferentially phosphorylates tau isoforms containing an amino-terminal insert. Identification of threonine 39 as the primary phosphate acceptor. J. Biol. Chem. 269, 4373–4380.
Gunawardena S. and Goldstein L. S. B. (2001) Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32, 389–401.
Hanemaaijer R. and Ginzburg I. (1991) Involvement of mature tau isoforms in the stabilization of neurites in PC12 cells. J. Neurosci. 30, 163–171.
Harada A., Oguchi K., Okabe S., Kuno J., Terada S., Oshima T., et al. (1994) Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369, 488–491.
Hasegawa M., Smith M. J., and Goedert M. (1998) Tau proteins with FTDP-17 mutations have reduced ability to promote microtubule assembly. FEBS Lett. 437, 207–210.
Hong M., Zhukareva V., Vogelsberg-Ragaglia V., Wszolek Z., Reed L., Miller B. I., et al. (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914–1917.
Hutton M., Lendon C. L., Rizzu P., Baker M., Froelich S., Houlden H., et al. (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705.
Iqbal K., Grundke-Iqbal I., Zaidi T., Merz P. A., Wen G. Y., Shaikh S. S., et al. (1986) Defective brain microtubule assembly in Alzheimer’s disease. Lancet 2, 421–426.
Ishihara T., Higuchi M., Zhang B., Yoshiyama Y., Hong M., Trojanowski J. Q., et al. (2001a) Attenuated neurodegenerative disease phenotype in tau transgenic mouse lacking neurofilaments. J. Neurosci. 21, 6026–6035.
Ishihara T., Zhang B., Higuchi M., Yoshiyama Y., Trojanowski J. Q., and Lee V. M.-Y. (2001b) Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am. J. Pathol. 158, 555–562.
Jackson G. R., Wiedau-Pazos M., Sang T.-K., Wagle N., Brown C. A., Massachi S., et al. (2002) Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34, 509–519.
Johnson G. V. (1992) Differential phosphorylation of tau by cyclic AMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase II: metabolic and functional consequences. J. Neurochem. 59, 2056–2062.
Kamal A., Stokin G. B., Yang Z., Xia C.-H., and Goldstein S. B. (2000) Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-1. Neuron 28, 449–459.
Kamal A., Almenar-Queralt A., Leblanc J. F., Roberts E. A., and Goldstein L. S. B. (2001) Kinesin-mediated axonal transport of a membrane compartment containing β-secretase and presenilin-1 requires APP. Nature 414, 643–647.
Koo E. H., Lansbury P. T. Jr, and Kelly J. W. (1999) Amyloid diseases: abnormal protein aggregation in neurodegeneration. PNAS 96, 9989–9990.
Khatoon S., Grundke-Iqbal I., and Iqbal K. (1992) Brain levels of microtubule-associated protein tau are elevated in Alzheimer’s disease: a radioimmunoslot-blot assay for nanograms of the protein. J. Neurochem. 59, 750–753.
Ksiezak-Reding H., Binder L. I., and Yen S. H. (1988) Immunochemical and biochemical characterization of tau protein in normal and Alzheimer’s disease brains with Alz 50 and Tau-1. J. Biol. Chem. 263, 7948–7953.
Künzi V., Glatzel M., Nakano M. Y., Greber U. F., Van Leuven F., and Aguzzi A. (2002) Unhampered prion neuroinvasion despite impaired fast axonal transport in transgenic mice overexpressing four-repeat tau. J. Neurosci. 22, 7471–7477.
Lambert M. P., Barlow A. K., Chromy B. A., Edwards C., Freed R., Liosatos M., et al. (1998) Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. PNAS 95, 6448–6453.
Lee G., Neve R. L., and Kosik K. S. (1989) The microtubule binding domain of tau protein. Neuron 2, 1615–1624.
Lewis J., Dickson D. W., Lin W.-L., Chisholm L., Corral A., Jones G., Yen S.-H., et al. (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491.
Lucas J. J., Hernandez F., Gomez-Ramos P., Moran M. A., Hen R. and Avila J. (2001) Decreased nuclear β-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3β conditional transgenic mice. EMBO J. 20, 27–39.
Mandelkow E.-M., Biernat J., Drewes G., Gustke N., Trinczek B., and Mandelkow E. (1995) Tau domains, phosphorylation, and interaction with microtubules. Neurobiol. Aging 16, 355–363.
Matsuo E. S., Shin R.-W., Billingsley M. L., Van de Voorde A., O’Connor M., Trojanowski J. Q., et al. (1994) Biopsy-derived adult human tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron 13, 989–1002.
Mattson M. P. (1997) Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev. 77, 1081–1132.
Mattson M. P., Fu W., Waeg G., and Uchida K. (1997) 4-Hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau. Neuroreport 8, 2275–2281.
Michel G., Mercken M., Murayama M., Noguchi K., Ishiguro K., Imahori K., et al. (1998) Characterization of tau phosphorylation in glycogen synthase kinase-3β and cyclin dependent kinase-5 activator (p23) transfected cells. BBA 1380, 177–182.
Moechars D., Dewachter I., Lorent K., Reverse D., Baekelandt V., Naidu A., et al. (1999) Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J. Biol. Chem. 274, 6483–6492.
Morfini G., Szebenyi G., Elluru R., Ratner N., and Brady S. T. (2002) Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J. 21, 281–293.
Nakazato Y., Sasaki A., Hirato J., and Ishida Y. (1984) Immunohistochemical localization of neurofilament protein in neuronal degenerations. Acta Neuropathol. (Berl.) 64, 30–36.
Norlund M. A., Lee J. M., Zainelli G. M., and Muma N. A. (1999) Elevated transglutaminase-induced bonds in PHF tau in Alzheimer’s disease. Brain Res. 851, 154–163.
Nuydens R., Van den Kieboom G., Nolten C., Verhulst C., Van Osta P., Spittaels K., et al. (2002) Coexpression of GSK-3β corrects phenotypic aberrations of dorsal root ganglion cells, cultured from adult transgenic mice overexpressing human protein tau. Neurobiol. Dis. 9, 38–48.
Patrick G. N., Zukerberg L., Nikolic M., De La Monte S., Dikkes P., and Tsai L. H. (1999) Conversion of p35 to p25 deregulates cdk5 activity and promotes neurodegeneration. Nature 402, 615–622.
Pedersen W. A., Culmsee C., Ziegler D., Herman J. P., and Mattson M. P. (1999) Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer’s disease. J. Mol. Neurosci. 13, 159–165.
Pei J. J., Braak E., Braak H., Grundke-Iqbal I., Iqbal K., Winblad B., et al. (1999) Distribution of active glycogen synthase kinase-3β (GSK-3β) in brains staged for Alzheimer disease neurofibrillary changes. J. Neuropathol. Exp. Neurol. 58, 1010–1019.
Perry G., Kawai M., Tabaton M., Onorato M., Mulvihill P., Richey P., et al. (1991) Neuropil threads of Alzheimer’s disease show a marked alteration of the normal cytoskeleton. J. Neurosci. 11, 1748–1755.
Rapoport M. and Ferreira A. (2000) PD98059 prevents neurite degeneration induced by fibrillar β-amyloid in mature hippocampal neurons. J. Neurochem. 74, 125–133.
Rapoport M., Dawson H. N., Binder L. I., Vitek M. P., and Ferreira A. (2002) Tau is essential to β-amyloid-induced neurotoxicity. PNAS 99, 6364–6369.
Rouleau G. A., Clarke A. W., Rooke K., Pramatarova A., Krizus A., Suchowersky O., et al. (1996) SOD1 mutation is associated with accumulations of neurofilaments in amyotrophic lateral sclerosis. Ann. Neurol. 39, 128–131.
Ruben G. C., Ciardelli T. L., Grundke-Iqbal I., and Iqbal K. (1997) Alzheimer disease hyperphosphorylated tau aggregates hydrophobically. Synapse 27, 208–229.
Sawamura N., Gong J.-S., Garver W. S., Heidenreich R. A., Ninomiya H., Ohno K., et al. (2001) Site-specific phosphorylation of tau accompanied by activation of mitogen-activated protein kinase (MAPK) in brains of Niemann-Pick type C mice. J. Biol. Chem. 276, 10,314–10,319.
Scott C. W., Blowers D. P., Barth P. T., Lo M. M., Salama A. I., and Caputo C. B. (1991) Differences in the abilities of human tau isoforms to promote microtubule assembly. J. Neurosci. Res. 30, 154–162.
Shankar S. K., Yanagihara R, Garruto R. M., Grundke-Iqbal I, Kosik K. S., and Gajdusek D. C. (1989) Immunocytochemical characterization of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Ann. Neurol. 25, 146–151.
Sisodia S. S. and St. George-Hyslop P. H. (2002) γ-secretase, Notch, Aβ and Alzheimer’s disease: where do the presenilins fit in? Nature Rev. Neurosci. 3, 281–290.
Spillantini M. G., Murrell J. R., Goedert M., Farlow M. R., Klug A., and Ghetti B. (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. PNAS 95, 7737–7741.
Spittaels K., Van den Haute C., Van Dorpe J., Bruynseels K., et al. (1999) Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am. J. Pathol. 155, 2153–2165.
Spittaels K., Van den Haute C., Van Dorpe J., Geerts H., Mercken M., Bruynseels K., et al. (2000) Glycogen synthase kinase-3β phosphorylates tau and rescues axonopathy in the central nervous system of human four-repeat tau transgenic mice. J. Biol. Chem. 275, 41,340–41,349.
Spittaels K., Van den Haute C., Van Dorpe J., Terwel D., Vandezande K., Lasrado R., et al. (2002) Neonatal neuronal over-expression of glycogen synthase kinase-3β reduces brain-size in transgenic mice. 113, 797–808.
Stamer K., Vogel R., Thies E., Mandelkow E., and Mandelkow E.-M. (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J. Cell Biol. 156, 1051–1063.
Tesseur I., Van Dorpe J., Spittaels K., Van den Haute C., Moechars D., and Van Leuven F. (2000) Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am. J. Pathol. 156, 951–964.
Tesseur I., Van Dorpe J., Bruynseels K., Bronfman, F., Sciot R., Van Lommel A., et al. (2000) Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am. J. Pathol. 157, 1495–1510.
Trinczek B., Ebneth A., Mandelkow E.-M., and Mandelkow E. (1999) Tau regulates the attachment/detachment but not the speed of motors in microtubule-dependent transport of single vesicles and organelles. J. Cell Sci. 112, 2355–2367.
Van Dorpe J., Smeijers L., Dewachter I., Nuyens D., Spittaels K., Van den Haute C., et al. (2002) Promiment cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons. Am. J. Pathol. 157, 1283–1298.
Voikar V, Rauvala H, and Ikonen E. (2002) Cognitive deficit and development of motor impairment in a mouse model of Niemann-Pick type C disease. Behav. Brain Res. 132, 1–10.
Walsh D. M., Tseng B. P., Rydel R. E., Podlisney M. B., and Selkoe D. J. (2000) The oligomerization of amyloid β-protein begins intracellularly in cells derived from human brain. Biochemistry 39, 10,831–10,839.
Wang J. Z., Grundke-Iqbal I., and Iqbal K. (1996) Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat. Med. 2, 871–875.
Williamson R., Scales T., Clark B. R., Gibb G., Reynolds C. H., Kellie S., et al. (2002) Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-β peptide exposure: involvement of src family protein kinases. J. Neurosci. 22, 10–20.
Yoshida H. and Ihara Y. (1993) Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament tau. J. Neurochem. 61, 1183–1186.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Terwel, D., Dewachter, I. & Van Leuven, F. Axonal transport, tau protein, and neurodegeneration in Alzheimer’s disease. Neuromol Med 2, 151–165 (2002). https://doi.org/10.1385/NMM:2:2:151
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/NMM:2:2:151