Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer's disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.

Axon Neuroscience GmbH Bratislava Slovak Republic

Axon Neuroscience GmbH Bratislava Slovak Republic ; Institute of Mathematics and Statistics Masaryk University Brno Czech Republic

Institute of Neuroimmunology Slovak Academy of Sciences Bratislava Slovak Republic

Institute of Neuroimmunology Slovak Academy of Sciences Bratislava Slovak Republic ; Axon Neuroscience GmbH Bratislava Slovak Republic

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Andorfer C., Kress Y., Espinoza M., de Silva R., Tucker K. L., Barde Y. A., et al. . (2003). Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J. Neurochem. 86, 582–590. 10.1046/j.1471-4159.2003.01879.x PubMed DOI

Arriagada P. V., Growdon J. H., Hedley-Whyte E. T., Hyman B. T. (1992). Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42, 631–639. 10.1212/wnl.42.3.631 PubMed DOI

Augustinack J. C., Schneider A., Mandelkow E. M., Hyman B. T. (2002). Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol. 103, 26–35. 10.1007/s004010100423 PubMed DOI

Bajo M., Yoo B. C., Cairns N., Gratzer M., Lubec G. (2001). Neurofilament proteins NF-L, NF-M and NF-H in brain of patients with Down syndrome and Alzheimer’s disease. Amino Acids 21, 293–301. 10.1007/s007260170015 PubMed DOI

Bigio E. H., Vono M. B., Satumtira S., Adamson J., Sontag E., Hynan L. S., et al. . (2001). Cortical synapse loss in progressive supranuclear palsy. J. Neuropathol. Exp. Neurol. 60, 403–410. PubMed

Bitan G., Kirkitadze M. D., Lomakin A., Vollers S. S., Benedek G. B., Teplow D. B. (2003). Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways. Proc. Natl. Acad. Sci. U S A 100, 330–335. 10.1073/pnas.222681699 PubMed DOI PMC

Blennow K., Bogdanovic N., Alafuzoff I., Ekman R., 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. 10.1007/bf01273157 PubMed DOI

Blomberg F., Cohen R. S., Siekevitz P. (1977). The structure of postsynaptic densities isolated from dog cerebral cortex. II. Characterization and arrangement of some of the major proteins within the structure. J. Cell Biol. 74, 204–225. 10.1083/jcb.74.1.204 PubMed DOI PMC

Braak H., Braak E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259. 10.1007/bf00308809 PubMed DOI

Brun A., Liu X., Erikson C. (1995). Synapse loss and gliosis in the molecular layer of the cerebral cortex in Alzheimer’s disease and in frontal lobe degeneration. Neurodegeneration 4, 171–177. 10.1006/neur.1995.0021 PubMed DOI

Callahan L. M., Coleman P. D. (1995). Neurons bearing neurofibrillary tangles are responsible for selected synaptic deficits in Alzheimer’s disease. Neurobiol. Aging 16, 311–314. 10.1016/0197-4580(95)00035-d PubMed DOI

Callahan L. M., Selski D. J., Martzen M. R., Cheetham J. E., Coleman P. D. (1994). Preliminary evidence: decreased GAP-43 message in tangle-bearing neurons relative to adjacent tangle-free neurons in Alzheimer’s disease parahippocampal gyrus. Neurobiol. Aging 15, 381–386. 10.1016/0197-4580(94)90041-8 PubMed DOI

Callahan L. M., Vaules W. A., Coleman P. D. (2002). Progressive reduction of synaptophysin message in single neurons in Alzheimer disease. J. Neuropathol. Exp. Neurol. 61, 384–395. PubMed

Ciani L., Boyle K. A., Dickins E., Sahores M., Anane D., Lopes D. M., et al. . (2011). Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca2+/Calmodulin-dependent protein kinase II. Proc. Natl. Acad. Sci. U S A 108, 10732–10737. 10.1073/pnas.1018132108 PubMed DOI PMC

Cohen R. S., Blomberg F., Berzins K., Siekevitz P. (1977). The structure of postsynaptic densities isolated from dog cerebral cortex. I. Overall morphology and protein composition. J. Cell Biol. 74, 181–203. 10.1083/jcb.74.1.181 PubMed DOI PMC

Coleman P. D., Kazee A. M., Lapham L., Eskin T., Rogers K. (1992). Reduced GAP-43 message levels are associated with increased neurofibrillary tangle density in the frontal association cortex (area 9) in Alzheimer’s disease. Neurobiol. Aging 13, 631–639. 10.1016/0197-4580(92)90085-c PubMed DOI

Coleman P. D., Yao P. J. (2003). Synaptic slaughter in Alzheimer’s disease. Neurobiol. Aging 24, 1023–1027. 10.1016/j.neurobiolaging.2003.09.001 PubMed DOI

Counts S. E., Nadeem M., Lad S. P., Wuu J., Mufson E. J. (2006). Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment. J. Neuropathol. Exp. Neurol. 65, 592–601. 10.1097/00005072-200606000-00007 PubMed DOI

Cras P., Kawai M., Lowery D., Gonzalez-DeWhitt P., Greenberg B., Perry G. (1991). Senile plaque neurites in Alzheimer disease accumulate amyloid precursor protein. Proc. Natl. Acad. Sci. U S A 88, 7552–7556. 10.1073/pnas.88.17.7552 PubMed DOI PMC

Davies C. A., Mann D. M., Sumpter P. Q., Yates P. O. (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. 10.1016/0022-510x(87)90057-8 PubMed DOI

DeKosky S. T., Scheff S. W. (1990). Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann. Neurol. 27, 457–464. 10.1002/ana.410270502 PubMed DOI

Efron B., Tibshirani R. J. (1993). An Introduction to the Bootstrap. 1st Edn. New York: Chapman and Hall.

Falke E., Nissanov J., Mitchell T. W., Bennett D. A., Trojanowski J. Q., Arnold S. E. (2003). Subicular dendritic arborization in Alzheimer’s disease correlates with neurofibrillary tangle density. Am. J. Pathol. 163, 1615–1621. 10.1016/s0002-9440(10)63518-3 PubMed DOI PMC

Fein J. A., Sokolow S., Miller C. A., Vinters H. V., Yang F., Cole G. M., et al. . (2008). Co-localization of amyloid beta and tau pathology in Alzheimer’s disease synaptosomes. Am. J. Pathol. 172, 1683–1692. 10.2353/ajpath.2008.070829 PubMed DOI PMC

Filipcik P., Zilka N., Bugos O., Kucerak J., Koson P., Novak P., et al. . (2012). First transgenic rat model developing progressive cortical neurofibrillary tangles. Neurobiol. Aging 33, 1448–1456. 10.1016/j.neurobiolaging.2010.10.015 PubMed DOI

Fischer D., Mukrasch M. D., Biernat J., Bibow S., Blackledge M., Griesinger C., et al. . (2009). Conformational changes specific for pseudophosphorylation at serine 262 selectively impair binding of tau to microtubules. Biochemistry 48, 10047–10055. 10.1021/bi901090m PubMed DOI

Greenberg S. G., Davies P. (1990). A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc. Natl. Acad. Sci. U S A 87, 5827–5831. 10.1073/pnas.87.15.5827 PubMed DOI PMC

Hahn C. G., Banerjee A., Macdonald M. L., Cho D. S., Kamins J., Nie Z., et al. . (2009). The postsynaptic density of human postmortem brain tissues: an experimental study paradigm for neuropsychiatric illnesses. PLoS One 4:e5251. 10.1371/journal.pone.0005251 PubMed DOI PMC

Hammond J., Cai D., Verhey K. J. (2008). Tubulin modifications and their cellular functions. Curr. Opin. Cell Biol. 20, 71–76. 10.1016/j.ceb.2007.11.010 PubMed DOI PMC

Hanes J., Zilka N., Bartkova M., Caletkova M., Dobrota D., Novak M. (2009). Rat tau proteome consists of six tau isoforms: implication for animal models of human tauopathies. J. Neurochem. 108, 1167–1176. 10.1111/j.1471-4159.2009.05869.x PubMed DOI

Heffernan J. M., Eastwood S. L., Nagy Z., Sanders M. W., McDonald B., Harrison P. J. (1998). Temporal cortex synaptophysin mRNA is reduced in Alzheimer’s disease and is negatively correlated with the severity of dementia. Exp. Neurol. 150, 235–239. 10.1006/exnr.1997.6772 PubMed DOI

Honer W. G. (2003). Pathology of presynaptic proteins in Alzheimer’s disease: more than simple loss of terminals. Neurobiol. Aging 24, 1047–1062. 10.1016/j.neurobiolaging.2003.04.005 PubMed DOI

Honer W. G., Dickson D. W., Gleeson J., Davies P. (1992). Regional synaptic pathology in Alzheimer’s disease. Neurobiol. Aging 13, 375–382. 10.1016/0197-4580(92)90111-a PubMed DOI

Ingelsson M., Fukumoto H., Newell K. L., Growdon J. H., Hedley-Whyte E. T., Frosch M. P., et al. . (2004). Early Abeta accumulation and progressive synaptic loss, gliosis and tangle formation in AD brain. Neurology 62, 925–931. 10.1212/01.wnl.0000115115.98960.37 PubMed DOI

Ittner L. M., Ke Y. D., Delerue F., Bi M., Gladbach A., van Eersel J., et al. . (2010). Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397. 10.1016/j.cell.2010.06.036 PubMed DOI

Ivanov A., Esclapez M., Ferhat L. (2009). Role of drebrin A in dendritic spine plasticity and synaptic function. Implications in neurological disorders. Commun. Integr. Biol. 2, 268–270. 10.4161/cib.2.3.8166 PubMed DOI PMC

Jan A., Gokce O., Luthi-Carter R., Lashuel H. A. (2008). The ratio of monomeric to aggregated forms of Abeta40 and Abeta42 is an important determinant of amyloid- beta aggregation, fibrillogenesis and toxicity. J. Biol. Chem. 283, 28176–28189. 10.1074/jbc.m803159200 PubMed DOI PMC

Kambe T., Motoi Y., Inoue R., Kojima N., Tada N., Kimura T., et al. . (2011). Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice. Neurobiol. Dis. 42, 404–414. 10.1016/j.nbd.2011.02.002 PubMed DOI

Kanai Y., Hirokawa N. (1995). Sorting mechanisms of tau and MAP2 in neurons: suppressed axonal transit of MAP2 and locally regulated microtubule binding. Neuron 14, 421–432. 10.1016/0896-6273(95)90298-8 PubMed DOI

Khatoon S., Grundke-Iqbal I., Iqbal K. (1994). Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains. FEBS Lett. 351, 80–84. 10.1016/0014-5793(94)00829-9 PubMed DOI

Kittur S., Hoh J., Endo H., Tourtellotte W., Weeks B. S., Markesbery W., et al. . (1994). Cytoskeletal neurofilament gene expression in brain tissue from Alzheimer’s disease patients. I. Decrease in NF-L and NF-M message. J. Geriatr. Psychiatry Neurol. 7, 153–158. 10.1177/089198879400700305 PubMed DOI

Kontsekova E., Zilka N., Kovacech B., Skrabana R., Novak M. (2014). Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res. Ther. 6:45. 10.1186/alzrt277 PubMed DOI PMC

Koson P., Zilka N., Kovac A., Kovacech B., Korenova M., Filipcik P., et al. . (2008). Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. Eur. J. Neurosci. 28, 239–246. 10.1111/j.1460-9568.2008.06329.x PubMed DOI

Lee G., Rook S. L. (1992). Expression of tau protein in non-neuronal cells: microtubule binding and stabilization. J. Cell Sci. 102, 227–237. PubMed

Liu S. H., Cheng H. H., Huang S. Y., Yiu P. C., Chang Y. C. (2006). Studying the protein organization of the postsynaptic density by a novel solid phase- and chemical cross-linking-based technology. Mol. Cell. Proteomics 5, 1019–1032. 10.1074/mcp.m500299-mcp200 PubMed DOI

Marcos S., Moreau J., Backer S., Job D., Andrieux A., Bloch-Gallego E. (2009). Tubulin tyrosination is required for the proper organization and pathfinding of the growth cone. PLoS One 4:e5405. 10.1371/journal.pone.0005405 PubMed DOI PMC

Masliah E., Ellisman M., Carragher B., Mallory M., Young S., Hansen L., et al. . (1992). Three-dimensional analysis of the relationship between synaptic pathology and neuropil threads in Alzheimer disease. J. Neuropathol. Exp. Neurol. 51, 404–414. 10.1097/00005072-199207000-00003 PubMed DOI

Masliah E., Mallory M., Alford M., DeTeresa R., Hansen L. A., McKeel D. W., Jr., et al. . (2001). Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56, 127–129. 10.1212/wnl.56.1.127 PubMed DOI

Matsuzaki K. (2011). Formation of toxic amyloid fibrils by amyloid β-protein on ganglioside clusters. Int. J. Alzheimers Dis. 2011:956104. 10.4061/2011/956104 PubMed DOI PMC

Mocanu M. M., Nissen A., Eckermann K., Khlistunova I., Biernat J., Drexler D., et al. . (2008). The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss and coassembly with endogenous Tau in inducible mouse models of tauopathy. J. Neurosci. 28, 737–748. 10.1523/jneurosci.2824-07.2008 PubMed DOI PMC

Mondragón-Rodríguez S., Trillaud-Doppia E., Dudilot A., Bourgeois C., Lauzon M., Leclerc N., et al. . (2012). Interaction of endogenous tau protein with synaptic proteins is regulated by N-Methyl-D-aspartate receptor-dependent tau phosphorylation. J. Biol. Chem. 287, 32040–32053. 10.1074/jbc.m112.401240 PubMed DOI PMC

Moreno H., Yu E., Pigino G., Hernandez A. I., Kim N., Moreira J. E., et al. . (2009). Synaptic transmission block by presynaptic injection of oligomeric amyloid beta. Proc. Natl. Acad. Sci. U S A 106, 5901–5906. 10.1073/pnas.0900944106 PubMed DOI PMC

Papasozomenos S. C., Su Y. (1991). Altered phosphorylation of tau protein in heat-shocked rats and patients with Alzheimer disease. Proc. Natl. Acad. Sci. U S A 88, 4543–4547. 10.1073/pnas.88.10.4543 PubMed DOI PMC

Paturle L., Wehland J., Margolis R. L., Job D. (1989). Complete separation of tyrosinated, detyrosinated and nontyrosinatable brain tubulin subpopulations using affinity chromatography. Biochemistry 28, 2698–2704. 10.1021/bi00432a050 PubMed DOI

Pauwels K., Williams T. L., Morris K. L., Jonckheere W., Vandersteen A., Kelly G., et al. . (2012). Structural basis for increased toxicity of pathological aβ42:aβ40 ratios in Alzheimer disease. J. Biol. Chem. 287, 5650–5660. 10.1074/jbc.m111.264473 PubMed DOI PMC

Perez M., Santa-Maria I., Gomez de Barreda E., Zhu X., Cuadros R., Cabrero J. R., et al. . (2009). Tau–an inhibitor of deacetylase HDAC6 function. J. Neurochem. 109, 1756–1766. 10.1111/j.1471-4159.2009.06102.x PubMed DOI

Ramsden M., Kotilinek L., Forster C., Paulson J., McGowan E., SantaCruz K., et al. . (2005). Age-dependent neurofibrillary tangle formation, neuron loss and memory impairment in a mouse model of human tauopathy (P301L). J. Neurosci. 25, 10637–10647. 10.1523/jneurosci.3279-05.2005 PubMed DOI PMC

R Development Core Team (2014). R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing; Available online at: http://www.r-project.org

Rebola N., Pinheiro P. C., Oliveira C. R., Malva J. O., Cunha R. A. (2003). Subcellular localization of adenosine A(1) receptors in nerve terminals and synapses of the rat hippocampus. Brain Res. 987, 49–58. 10.1016/s0006-8993(03)03247-5 PubMed DOI

Reddy P. H., Mani G., Park B. S., Jacques J., Murdoch G., Whetsell W., Jr., et al. . (2005). Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction. J. Alzheimers Dis. 7, 103–117. PubMed

Rinne J. O., Rummukainen J., Paljärvi L., Säkö E., Mölsä P., Rinne U. K. (1989). Neuronal loss in the substantia nigra in patients with Alzheimer’s disease and Parkinson’s disease in relation to extrapyramidal symptoms and dementia. Prog. Clin. Biol. Res. 317, 325–332. PubMed

Rodrigues D. I., Gutierres J., Pliássova A., Oliveira C. R., Cunha R. A., Agostinho P. (2014). Synaptic and sub-synaptic localization of amyloid-β protein precursor in the rat hippocampus. J. Alzheimers Dis. 40, 981–992. 10.3233/JAD-132030 PubMed DOI

Sahara N., Murayama M., Higuchi M., Suhara T., Takashima A. (2014). Biochemical distribution of tau protein in synaptosomal fraction of transgenic mice expressing human P301L tau. Front. Neurol. 5:26. 10.3389/fneur.2014.00026 PubMed DOI PMC

Samuel W., Masliah E., Hill L. R., Butters N., Terry R. (1994). Hippocampal connectivity and Alzheimer’s dementia: effects of synapse loss and tangle frequency in a two-component model. Neurology 44, 2081–2088. 10.1212/wnl.44.11.2081 PubMed DOI

Scheff S. W., Price D. A., Schmitt F. A., DeKosky S. T., Mufson E. J. (2007). Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68, 1501–1508. 10.1212/01.wnl.0000260698.46517.8f PubMed DOI

Serrano-Pozo A., Frosch M. P., Masliah E., Hyman B. T. (2011). Neuropathological alterations in Alzheimer disease. Cold Spring Harb. Perspect. Med. 1:a006189. 10.1101/cshperspect.a006189 PubMed DOI PMC

Sze C. I., Bi H., Kleinschmidt-DeMasters B. K., Filley C. M., Martin L. J. (2000). Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains. J. Neurol. Sci. 175, 81–90. 10.1016/s0022-510x(00)00285-9 PubMed DOI

Tai H. C., Serrano-Pozo A., Hashimoto T., Frosch M. P., Spires-Jones T. L., Hyman B. T. (2012). The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am. J. Pathol. 181, 1426–1435. 10.1016/j.ajpath.2012.06.033 PubMed DOI PMC

Takemura R., Okabe S., Umeyama T., Kanai Y., Cowan N. J., Hirokawa N. (1992). Increased microtubule stability and alpha tubulin acetylation in cells transfected with microtubule-associated proteins MAP1B, MAP2 or tau. J. Cell Sci. 103, 953–964. PubMed

Tannenberg R. K., Scott H. L., Tannenberg A. E., Dodd P. R. (2006). Selective loss of synaptic proteins in Alzheimer’s disease: evidence for an increased severity with APOE varepsilon4. Neurochem. Int. 49, 631–639. 10.1016/j.neuint.2006.05.004 PubMed DOI

Tao F., Tao Y. X., Mao P., Johns R. A. (2003). Role of postsynaptic density protein-95 in the maintenance of peripheral nerve injury-induced neuropathic pain in rats. Neuroscience 117, 731–739. 10.1016/s0306-4522(02)00801-1 PubMed DOI

Terry R. D., Masliah E., Salmon D. P., Butters N., DeTeresa R., Hill R., et al. . (1991). Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580. 10.1002/ana.410300410 PubMed DOI

Vechterova L., Kontsekova E., Zilka N., Ferencik M., Ravid R., Novak M. (2003). DC11: a novel monoclonal antibody revealing Alzheimer’s disease-specific tau epitope. Neuroreport 14, 87–91. 10.1097/00001756-200301200-00017 PubMed DOI

Verhey K. J., Gaertig J. (2007). The tubulin code. Cell Cycle 6, 2152–2160. 10.4161/cc.6.17.4633 PubMed DOI

Wakabayashi K., Honer W. G., 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. 10.1016/0006-8993(94)91709-4 PubMed DOI

Webster D. R., Gundersen G. G., Bulinski J. C., Borisy G. G. (1987). Differential turnover of tyrosinated and detyrosinated microtubules. Proc. Natl. Acad. Sci. U S A 84, 9040–9044. 10.1073/pnas.84.24.9040 PubMed DOI PMC

West M. J., Coleman P. D., Flood D. G., Troncoso J. C. (1994). Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet 344, 769–772. 10.1016/s0140-6736(94)92338-8 PubMed DOI

Willard M., Simon C. (1983). Modulation of neurofilament axonal transport during the development of rabbit retinal ganglion cells. Cell 35, 551–559. 10.1016/0092-8674(83)90189-7 PubMed DOI

Wischik C. M., Novak M., Edwards P. C., Klug A., Tichelaar W., Crowther R. A. (1988). Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc. Natl. Acad. Sci. U S A 85, 4884–4888. 10.1073/pnas.85.13.4884 PubMed DOI PMC

Wu J., Anwyl R., Rowan M. J. (1995). beta-Amyloid-(1–40) increases long-term potentiation in rat hippocampus in vitro. Eur. J. Pharmacol. 284, R1–R3. 10.1016/0014-2999(95)00539-w PubMed DOI

Zhang Z., Song M., Liu X., Kang S. S., Kwon I. S., Duong D. M., et al. . (2014). Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat. Med. 20, 1254–1262. 10.1038/nm.3700 PubMed DOI PMC

Zhou L., Martinez S. J., Haber M., Jones E. V., Bouvier D., Doucet G., et al. . (2007). EphA4 signaling regulates phospholipase Cgamma1 activation, cofilin membrane association and dendritic spine morphology. J. Neurosci. 27, 5127–5138. 10.1523/jneurosci.1170-07.2007 PubMed DOI PMC

Zilka N., Filipcik P., Koson P., Fialova L., Skrabana R., Zilkova M., et al. . (2006). Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 580, 3582–3588. 10.1016/j.febslet.2006.05.029 PubMed DOI

Enriched environment ameliorates propagation of tau pathology and improves cognition in rat model of tauopathy