**6. References**

Andreadis, A. (2005). Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim Biophys Acta 1739(2-3): 91-103.

Tau and Amyloid-β Conformational Change to β-Sheet

Int 36(3): 175-184.

31765.

345.

10716-10723.

122-132.

255(5045): 726-728.

Structures as Effectors in the Development of Alzheimer's Disease 381

Coulson, E. J., Paliga, K., Beyreuther, K. & Masters, C. L. (2000). What the evolution of the

Chang, E., Kim, S., Schafer, K. N. & Kuret, J. (2011). Pseudophosphorylation of tau protein

Chaudhary, N., Singh, S. & Nagaraj, R. (2009). Morphology of self-assembled structures

Chow, V. W., Mattson, M. P., Wong, P. C. & Gleichmann, M. (2010). An overview of APP processing enzymes and products. Neuromolecular medicine 12(1): 1-12. De Strooper, B. (2010). Proteases and proteolysis in Alzheimer disease: a multifactorial view

Duyckaerts, C., Delatour, B. & Potier, M. C. (2009). Classification and basic pathology of

Eckermann, K., Mocanu, M. M., Khlistunova, I., Biernat, J., Nissen, A., Hofmann, A.,

Estus, S., Golde, T. E., Kunishita, T., Blades, D., Lowery, D., Eisen, M., Usiak, M., Qu, X.

Fandrich, M., Schmidt, M. & Grigorieff, N. (2011). Recent progress in understanding

Fischer, D., Mukrasch, M. D., Biernat, J., Bibow, S., Blackledge, M., Griesinger, C.,

Fraser, P. E., Nguyen, J. T., Inouye, H., Surewicz, W. K., Selkoe, D. J., Podlisny, M. B. &

Friedhoff, P., von Bergen, M., Mandelkow, E. M. & Mandelkow, E. (2000). Structure of tau

García-Sierra, F., Ghoshal, N., Quinn, B., Berry, R. W. & Binder, L. I. (2003). Conformational

Schonig, K., Bujard, H., Haemisch, A., Mandelkow, E., Zhou, L., Rune, G. & Mandelkow, E. M. (2007). The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem 282(43): 31755-

M., Tabira, T., Greenberg, B. D. & et al. (1992). Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science

Alzheimer's beta-amyloid structures. Trends in biochemical sciences 36(6): 338-

Mandelkow, E. & Zweckstetter, M. (2009). Conformational changes specific for pseudophosphorylation at serine 262 selectively impair binding of tau to

Kirschner, D. A. (1992). Fibril formation by primate, rodent, and Dutchhemorrhagic analogues of Alzheimer amyloid beta-protein. Biochemistry 31(44):

protein and assembly into paired helical filaments. Biochim Biophys Acta 1502(1):

changes and truncation of tau protein during tangle evolution in Alzheimer's

solvent in which the peptides are dissolved. J Pept Sci 15(10): 675-684. Chen, B., Thurber, K. R., Shewmaker, F., Wickner, R. B. & Tycko, R. (2009). Measurement of

Proc Natl Acad Sci U S A 106(34): 14339-14344.

on the disease process. Physiol Rev 90(2): 465-494.

Alzheimer disease. Acta Neuropathol 118(1): 5-36.

microtubules. Biochemistry 48(42): 10047-10055.

disease. J Alzheimers Dis 5(2): 65-77.

amyloid protein precursor supergene family tells us about its function. Neurochem

directly modulates its aggregation kinetics. Biochim Biophys Acta 1814(2): 388-395.

formed by short peptides from the amyloidogenic protein tau depends on the

amyloid fibril mass-per-length by tilted-beam transmission electron microscopy.


Andreadis, A. (2011). Tau splicing and the intricacies of dementia. J Cell Physiol. May 20.

Andreadis, A., Wagner, B. K., Broderick, J. A. & Kosik, K. S. (1996). A tau promoter region

Antzutkin, O. N., Leapman, R. D., Balbach, J. J. & Tycko, R. (2002). Supramolecular

Ávila, J., Lim, F., Moreno, F., Belmonte, C. & Cuello, A. C. (2002). Tau function and

Ávila, J., Lucas, J. J., Pérez, M. & Hernández, F. (2004). Role of tau protein in both physiological and pathological conditions. Physiol Rev 84(2): 361-384. Barghorn, S. & Mandelkow, E. (2002). Toward a unified scheme for the aggregation of tau into Alzheimer paired helical filaments. Biochemistry 41(50): 14885-14896. Bemporad, F., Calloni, G., Campioni, S., Plakoutsi, G., Taddei, N. & Chiti, F. (2006).

Berriman, J., Serpell, L. C., Oberg, K. A., Fink, A. L., Goedert, M. & Crowther, R. A. (2003).

Binder, L. I., Guillozet-Bongaarts, A. L., García-Sierra, F. & Berry, R. W. (2005). Tau, tangles,

Bowerman, C. J., Liyanage, W., Federation, A. J. & Nilsson, B. L. (2011). Tuning beta-sheet

Buee, L., Bussiere, T., Buee-Scherrer, V., Delacourte, A. & Hof, P. R. (2000). Tau protein

Bulbarelli, A., Lonati, E., Cazzaniga, E., Gregori, M. & Masserini, M. (2009). Pin1 affects Tau phosphorylation in response to Abeta oligomers. Mol Cell Neurosci 42(1): 75-80. Campos-Peña, V., Tapia-Ramírez, J., Sanchez-Torres, C. & Meraz-Ríos, M. A. (2009).

Congdon, E. E., Kim, S., Bonchak, J., Songrug, T., Matzavinos, A. & Kuret, J. (2008).

expressed at the plasma membrane. J Alzheimers Dis 18(4): 919-933. Carter, D. B. & Chou, K. C. (1998). A model for structure-dependent binding of Congo red to

Alzheimer beta-amyloid fibrils. Neurobiol Aging 19(1): 37-40.

and Alzheimer's disease. Biochim Biophys Acta 1739(2-3): 216-223.

hydrophobicity and aromaticity. Biomacromolecules 12(7): 2735-2745. Braak, H. & Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta

structural constraints on Alzheimer's beta-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. Biochemistry 41(51): 15436-15450.

dysfunction in neurons: its role in neurodegenerative disorders. Mol Neurobiol

Sequence and structural determinants of amyloid fibril formation. Accounts of

Tau filaments from human brain and from in vitro assembly of recombinant protein show cross-beta structure. Proc Natl Acad Sci U S A 100(15): 9034-9038. Berthomieu, C. & Hienerwadel, R. (2009). Fourier transform infrared (FTIR) spectroscopy.

peptide self-assembly and hydrogelation behavior by modification of sequence

isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res

Pathological-like assembly of tau induced by a paired helical filament core

Nucleation-dependent tau filament formation: the importance of dimerization and an estimation of elementary rate constants. J Biol Chem 283(20): 13806-13816.

without neuronal specificity. J Neurochem 66(6): 2257-2263.

Ávila, J. (2010). Intracellular and extracellular tau. Front Neurosci 4: 49.

doi: 10.1002/jcp.22842. [Epub ahead of print]

25(3): 213-231.

chemical research 39(9): 620-627.

Neuropathol 82(4): 239-259.

Brain Res Rev 33(1): 95-130.

Photosynthesis research 101(2-3): 157-170.


Tau and Amyloid-β Conformational Change to β-Sheet

acid. J Biol Chem 271(31): 18342-18349.

3): 150-157.

Structures as Effectors in the Development of Alzheimer's Disease 383

Hung, A. Y., Koo, E. H., Haass, C. & Selkoe, D. J. (1992). Increased expression of beta-

Hwang, S. C., Jhon, D. Y., Bae, Y. S., Kim, J. H. & Rhee, S. G. (1996). Activation of

Hyman, B. T., Augustinack, J. C. & Ingelsson, M. (2005). Transcriptional and conformational

Jeganathan, S., Hascher, A., Chinnathambi, S., Biernat, J., Mandelkow, E. M. & Mandelkow,

Jeganathan, S., von Bergen, M., Mandelkow, E. M. & Mandelkow, E. (2008b). The natively

Jenkins, J. & Pickersgill, R. (2001). The architecture of parallel beta-helices and related folds.

Jenkins, S. M. & Johnson, G. V. (1998). Tau complexes with phospholipase C-gamma in situ.

Jicha, G. A., Bowser, R., Kazam, I. G. & Davies, P. (1997). Alz-50 and MC-1, a new

Johnson, G. V. & Stoothoff, W. H. (2004). Tau phosphorylation in neuronal cell function and

Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S. & Malinow, R. (2003). APP processing and synaptic function. Neuron 37(6): 925-937. Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H.,

Klein, W. L., Krafft, G. A. & Finch, C. E. (2001). Targeting small Abeta oligomers: the

Konig, G., Monning, U., Czech, C., Prior, R., Banati, R., Schreiter-Gasser, U., Bauer, J.,

Koren, J., 3rd, Jinwal, U. K., Davey, Z., Kiray, J., Arulselvam, K. & Dickey, C. A. (2011).

secretory cleavage. Proc Natl Acad Sci U S A 89(20): 9439-9443.

(MC-1) conformation. J Biol Chem 283(46): 32066-32076.

Progress in biophysics and molecular biology 77(2): 111-175.

epitopes on recombinant tau. J Neurosci Res 48(2): 128-132.

filaments. Biochemistry 47(40): 10526-10539.

dysfunction. J Cell Sci 117(Pt 24): 5721-5729.

tauopathies. Mol Neurobiol 44(1): 65-70.

Neuroreport 9(1): 67-71.

733-736.

224.

10809.

amyloid precursor protein during neuronal differentiation is not accompanied by

phospholipase C-gamma by the concerted action of tau proteins and arachidonic

changes of the tau molecule in Alzheimer's disease. Biochim Biophys Acta 1739(2-

E. (2008a). Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological

unfolded character of tau and its aggregation to Alzheimer-like paired helical

monoclonal antibody raised to paired helical filaments, recognize conformational

Multhaup, G., Beyreuther, K. & Muller-Hill, B. (1987). The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325(6106):

solution to an Alzheimer's disease conundrum? Trends in neurosciences 24(4): 219-

Masters, C. L. & Beyreuther, K. (1992). Identification and differential expression of a novel alternative splice isoform of the beta A4 amyloid precursor protein (APP) mRNA in leukocytes and brain microglial cells. J Biol Chem 267(15): 10804-

Bending tau into shape: the emerging role of peptidyl-prolyl isomerases in


García-Sierra, F., Mondragon-Rodriguez, S. & Basurto-Islas, G. (2008). Truncation of tau

García-Sierra, F., Wischik, C. M., Harrington, C. R., Luna-Muñoz, J. & Mena, R. (2001).

Ghoshal, N., García-Sierra, F., Wuu, J., Leurgans, S., Bennett, D. A., Berry, R. W. & Binder, L.

Glenner, G. G., Eanes, E. D. & Page, D. L. (1972). The relation of the properties of Congo red-

Goedert, M. & Spillantini, M. G. (2011). Pathogenesis of the Tauopathies. J Mol Neurosci. Jul

Golde, T. E., Estus, S., Usiak, M., Younkin, L. H. & Younkin, S. G. (1990). Expression of beta

Goux, W. J. (2002). The conformations of filamentous and soluble tau associated with Alzheimer paired helical filaments. Biochemistry 41(46): 13798-13806. Greenwald, J. & Riek, R. (2010). Biology of amyloid: structure, function, and regulation.

Halverson, K., Fraser, P. E., Kirschner, D. A. & Lansbury, P. T., Jr. (1990). Molecular

Hampel, H., Blennow, K., Shaw, L. M., Hoessler, Y. C., Zetterberg, H. & Trojanowski, J. Q.

Harrison, R. S., Sharpe, P. C., Singh, Y. & Fairlie, D. P. (2007). Amyloid peptides and

Hirokawa, N., Shiomura, Y. & Okabe, S. (1988). Tau proteins: the molecular structure and

Horowitz, P. M., LaPointe, N., Guillozet-Bongaarts, A. L., Berry, R. W. & Binder, L. I. (2006).

mode of binding on microtubules. J Cell Biol 107(4): 1449-1459.

of synthetic beta-protein fragments. Biochemistry 29(11): 2639-2644.

14(4): 401-409.

475-493.

38189.

77.

23. [Epub ahead of print]

Structure 18(10): 1244-1260.

disease. Exp Gerontol 45(1): 30-40.

Biochemistry 45(42): 12859-12866.

disease. J Chem Neuroanat 22(1-2): 65-77.

protein and its pathological significance in Alzheimer's disease. J Alzheimers Dis

Accumulation of C-terminally truncated tau protein associated with vulnerability of the perforant pathway in early stages of neurofibrillary pathology in Alzheimer's

I. (2002). Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimer's disease. Exp Neurol 177(2):

stained amyloid fibrils to the -conformation. J Histochem Cytochem 20(10): 821-826.

amyloid protein precursor mRNAs: recognition of a novel alternatively spliced form and quantitation in Alzheimer's disease using PCR. Neuron 4(2): 253-267. Gómez-Ramos, A., Diaz-Hernández, M., Cuadros, R., Hernández, F. & Ávila, J. (2006). Extracellular tau is toxic to neuronal cells. FEBS Lett 580(20): 4842-4850. Goode, B. L., Chau, M., Denis, P. E. & Feinstein, S. C. (2000). Structural and functional

differences between 3-repeat and 4-repeat tau isoforms. Implications for normal tau function and the onset of neurodegenetative disease. J Biol Chem 275(49): 38182-

determinants of amyloid deposition in Alzheimer's disease: conformational studies

(2010). Total and phosphorylated tau protein as biological markers of Alzheimer's

proteins in review. Reviews of physiology, biochemistry and pharmacology 159: 1-

N-terminal fragments of tau inhibit full-length tau polymerization in vitro.


Tau and Amyloid-β Conformational Change to β-Sheet

PLoS One 6(5): e19129.

13: e30.

3252-3257.

34(1): 62-75.

171(4): 615-625.

773-778.

Neurosci Lett.

Neurochem 112(6): 1353-1367.

Structures as Effectors in the Development of Alzheimer's Disease 385

Martin, L., Latypova, X. & Terro, F. (2011). Post-translational modifications of tau protein:

Matsuzaki, K., Kato, K. & Yanagisawa, K. (2010). Abeta polymerization through interaction with membrane gangliosides. Biochim Biophys Acta 1801(8): 868-877. Matthes, D., Gapsys, V., Daebel, V. & de Groot, B. L. (2011). Mapping the conformational

Meraz-Ríos, M. A., Lira-De León, K. I., Campos-Peña, V., De Anda-Hernández, M. A. &

Miklossy, J. (2011). Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med

Mizuno, N., Baxa, U. & Steven, A. C. (2011). Structural dependence of HET-s amyloid fibril

Mondragon-Rodriguez, S., Mena, R., Binder, L. I., Smith, M. A., Perry, G. & García-Sierra, F.

Muresan, Z. & Muresan, V. (2005). Coordinated transport of phosphorylated amyloid-beta

Murray, M. M., Bernstein, S. L., Nyugen, V., Condron, M. M., Teplow, D. B. & Bowers, M. T.

Mylonas, E., Hascher, A., Bernado, P., Blackledge, M., Mandelkow, E. & Svergun, D. I.

Nelson, R., Sawaya, M. R., Balbirnie, M., Madsen, A. O., Riekel, C., Grothe, R. & Eisenberg,

Nerelius, C., Fitzen, M. & Johansson, J. (2010). Amino acid sequence determinants and

Neve, R. L., Boyce, F. M., McPhie, D. L., Greenan, J. & Oster-Granite, M. L. (1996).

Nogalska, A., D'Agostino, C., Engel, W. K. & Askanas, V. (2011). Novel demonstration of

Nonaka, T., Watanabe, S. T., Iwatsubo, T. & Hasegawa, M. (2010). Seeded aggregation and

Perutz, M. F., Finch, J. T., Berriman, J. & Lesk, A. (2002). Amyloid fibers are water-filled

the American Chemical Society 131(18): 6316-6317.

scattering. Biochemistry 47(39): 10345-10353.

research communications 396(1): 2-6.

diseases. J Biol Chem 285(45): 34885-34898.

nanotubes. Proc Natl Acad Sci U S A 99(8): 5591-5595.

dynamics and pathways of spontaneous steric zipper Peptide oligomerization.

Mena-López, R. (2010). Tau oligomers and aggregation in Alzheimer's disease. J

infectivity assessed by cryoelectron microscopy. Proc Natl Acad Sci U S A 108(8):

(2008). Conformational changes and cleavage of tau in Pick bodies parallel the early processing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol

precursor protein and c-Jun NH2-terminal kinase-interacting protein-1. J Cell Biol

(2009). Amyloid beta protein: Abeta40 inhibits Abeta42 oligomerization. Journal of

(2008). Domain conformation of tau protein studied by solution small-angle X-ray

D. (2005). Structure of the cross-beta spine of amyloid-like fibrils. Nature 435(7043):

molecular chaperones in amyloid fibril formation. Biochemical and biophysical

Transgenic mice expressing APP-C100 in the brain. Neurobiol Aging 17(2): 191-203.

conformationally modified tau in sporadic inclusion-body myositis muscle fibers.

toxicity of {alpha}-synuclein and tau: cellular models of neurodegenerative

implications for Alzheimer's disease. Neurochem Int 58(4): 458-471.


Koren, J., 3rd, Jinwal, U. K., Lee, D. C., Jones, J. R., Shults, C. L., Johnson, A. G., Anderson, L.

LaPointe, N. E., Morfini, G., Pigino, G., Gaisina, I. N., Kozikowski, A. P., Binder, L. I. &

transport: implications for filament toxicity. J Neurosci Res 87(2): 440-451. Lee, G. (2005). Tau and src family tyrosine kinases. Biochim Biophys Acta 1739(2-3): 323-330. Lee, G., Newman, S. T., Gard, D. L., Band, H. & Panchamoorthy, G. (1998). Tau interacts with src-family non-receptor tyrosine kinases. J Cell Sci 111 ( Pt 21): 3167-3177. Leyssen, M., Ayaz, D., Hebert, S. S., Reeve, S., De Strooper, B. & Hassan, B. A. (2005).

Lin, Y. T., Cheng, J. T., Liang, L. C., Ko, C. Y., Lo, Y. K. & Lu, P. J. (2007). The binding and

Lira-De León, K. I., De Anda-Hernández, M.A., Campos-Peña, V. and Meraz-Ríos, MA.

Lu, M. & Kosik, K. S. (2001). Competition for microtubule-binding with dual expression of

Luna-Muñoz, J., Chávez-Macias, L., García-Sierra, F. & Mena, R. (2007). Earliest stages of tau

Luna-Muñoz, J., García-Sierra, F., Falcon, V., Menendez, I., Chávez-Macias, L. & Mena, R.

Luna-Muñoz, J., Peralta-Ramírez, J., Chávez-Macias, L., Harrington, C. R., Wischik, C. M. &

Alzheimer's disease in tissue imprints. Acta Neuropathol 116(5): 507-515. Luo, M. H., Tse, S. W., Memmott, J. & Andreadis, A. (2004). Novel isoforms of tau that lack

Makin, O. S., Atkins, E., Sikorski, P., Johansson, J. & Serpell, L. C. (2005). Molecular basis for amyloid fibril formation and stability. Proc Natl Acad Sci U S A 102(2): 315-320. Mandelkow, E., von Bergen, M., Biernat, J. & Mandelkow, E. M. (2007). Structural principles

Marshall, K. E., Morris, K. L., Charlton, D., O'Reilly, N., Lewis, L., Walden, H. & Serpell, L.

in amyloid fibril formation and stability. Biochemistry 50(12): 2061-2071.

the microtubule-binding domain. J Neurochem 90(2): 340-351.

tau missense and splice isoforms. Mol Biol Cell 12(1): 171-184.

Alzheimer's disease. J Alzheimers Dis 8(1): 29-41.

Cell Mol Med 13(4): 619-630.

813.

87994-9, 93-100

365-375.

83-90.

the Drosophila brain. EMBO J 24(16): 2944-2955.

J. & Dickey, C. A. (2009). Chaperone signalling complexes in Alzheimer's disease. J

Brady, S. T. (2009). The amino terminus of tau inhibits kinesin-dependent axonal

Amyloid precursor protein promotes post-developmental neurite arborization in

phosphorylation of Thr231 is critical for Tau's hyperphosphorylation and functional regulation by glycogen synthase kinase 3beta. J Neurochem 103(2): 802-

(2009). Plasma membrane-associated PHF-core could be the trigger for Tau aggregation in Alzheimer's Disease.in *Current Hypotheses and Research Milestones in Alzheimer's Disease*. Maccioni, R. & Perry, G. Springer New York. ISBN: 978-0-387-

conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer's disease. J Alzheimers Dis 12(4):

(2005). Regional conformational change involving phosphorylation of tau protein at the Thr231, precedes the structural change detected by Alz-50 antibody in

Mena, R. (2008). Thiazin red as a neuropathological tool for the rapid diagnosis of

of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol 17(1):

C. (2011). Hydrophobic, aromatic, and electrostatic interactions play a central role


Tau and Amyloid-β Conformational Change to β-Sheet

Neuropharmacology 59(4-5): 303-309.

molecular medicine 81(11): 678-699.

physical chemistry 62: 279-299.

Sci U S A 97(10): 5129-5134.

phosphorylation. J Cell Biochem.

biology 16(9): 973-978.

Experimental Biology 22(5): 1552-1559.

a004390.

727.

microtubules. Mol Biol Cell 6(12): 1887-1902.

Structures as Effectors in the Development of Alzheimer's Disease 387

Small, D. H., Mok, S. S. & Bornstein, J. C. (2001). Alzheimer's disease and Abeta toxicity:

Solomon, B. & Frenkel, D. (2010). Immunotherapy for Alzheimer's disease.

Stefani, M. & Dobson, C. M. (2003). Protein aggregation and aggregate toxicity: new insights

Takuma, H., Arawaka, S. & Mori, H. (2003). Isoforms changes of tau protein during development in various species. Brain Res Dev Brain Res 142(2): 121-127. Toyama, B. H. & Weissman, J. S. (2011). Amyloid structure: conformational diversity and

Trinczek, B., Biernat, J., Baumann, K., Mandelkow, E. M. & Mandelkow, E. (1995). Domains

Tycko, R. (2011). Solid-state NMR studies of amyloid fibril structure. Annual review of

Vabulas, R. M., Raychaudhuri, S., Hayer-Hartl, M. & Hartl, F. U. (2010). Protein folding in

von Bergen, M., Friedhoff, P., Biernat, J., Heberle, J., Mandelkow, E. M. & Mandelkow, E.

Wang, J. Z. & Liu, F. (2008). Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol 85(2): 148-175. Wang, Y., Gao, L., Conrad, C. G. & Andreadis, A. (2011). Saitohin, which is nested within

Weaver, C. L., Espinoza, M., Kress, Y. & Davies, P. (2000). Conformational change as one of

Wegmann, S., Jung, Y. J., Chinnathambi, S., Mandelkow, E. M., Mandelkow, E. & Muller, D.

Williamson, R., Usardi, A., Hanger, D. P. & Anderton, B. H. (2008). Membrane-bound beta-

Wischik, C. M., Crowther, R. A., Stewart, M. & Roth, M. (1985). Subunit structure of paired helical filaments in Alzheimer's disease. J Cell Biol 100(6): 1905-1912.

polymorphic structure and stability. J Biol Chem 285(35): 27302-27313. Wiltzius, J. J., Landau, M., Nelson, R., Sawaya, M. R., Apostol, M. I., Goldschmidt, L.,

into protein folding, misfolding diseases and biological evolution. Journal of

of tau protein, differential phosphorylation, and dynamic instability of

the cytoplasm and the heat shock response. Cold Spring Harb Perspect Biol 2(12):

(2000). Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad

the tau gene, interacts with tau and Abl and its human-specific allele influences Abl

the earliest alterations of tau in Alzheimer's disease. Neurobiol Aging 21(5): 719-

J. (2010). Human Tau isoforms assemble into ribbon-like fibrils that display

Soriaga, A. B., Cascio, D., Rajashankar, K. & Eisenberg, D. (2009). Molecular mechanisms for protein-encoded inheritance. Nature structural & molecular

amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism. The FASEB journal : official publication of the Federation of American Societies for

from top to bottom. Nat Rev Neurosci 2(8): 595-598.

consequences. Annual review of biochemistry 80: 557-585.


Plant, L. D., Boyle, J. P., Smith, I. F., Peers, C. & Pearson, H. A. (2003). The production of

Puzzo, D., Privitera, L., Leznik, E., Fa, M., Staniszewski, A., Palmeri, A. & Arancio, O. (2008).

Ranjbar, B. & Gill, P. (2009). Circular dichroism techniques: biomolecular and nanostructural

Sadqi, M., Hernández, F., Pan, U., Pérez, M., Schaeberle, M. D., Ávila, J. & Muñoz, V. (2002).

Scales, T. M., Derkinderen, P., Leung, K. Y., Byers, H. L., Ward, M. A., Price, C., Bird, I. N.,

Schubert, D., Behl, C., Lesley, R., Brack, A., Dargusch, R., Sagara, Y. & Kimura, H. (1995).

Selkoe, D. J. (1994). Alzheimer's disease: a central role for amyloid. J Neuropathol Exp

Serpell, L. C., Blake, C. C. & Fraser, P. E. (2000). Molecular structure of a fibrillar Alzheimer's

Sevcik, J., Skrabana, R., Dvorsky, R., Csokova, N., Iqbal, K. & Novak, M. (2007). X-ray

disordered protein tau in Alzheimer's disease. FEBS Lett 581(30): 5872-5878. Shirahama, T. & Cohen, A. S. (1965). Structure of amyloid fibrils after negative staining and

Shkumatov, A. V., Chinnathambi, S., Mandelkow, E. & Svergun, D. I. (2011). Structural

Sillen, A., Barbier, P., Landrieu, I., Lefebvre, S., Wieruszeski, J. M., Leroy, A., Peyrot, V. &

Skrabana, R., Dvorsky, R., Sevcik, J. & Novak, M. (2010). Monoclonal antibody MN423 as a

Skrabana, R., Kontsek, P., Mederlyova, A., Iqbal, K. & Novak, M. (2004). Folding of

Small, D. H., Clarris, H. L., Williamson, T. G., Reed, G., Key, B., Mok, S. S., Beyreuther, K.,

high-resolution electron microscopy. Nature 206(985): 737-738.

protein tau and the microtubules. Biochemistry 46(11): 3055-3064.

analyses- a review. Chemical biology & drug design 74(2): 101-120.

Neurosci 23(13): 5531-5535.

Biochemistry 41(22): 7150-7155.

Neurodegener 6: 12.

U S A 92(6): 1989-1993.

Neurol 53(5): 438-447.

Proteins 79(7): 2122-2131.

Biol.

285.

568(1-3): 178-182.

hippocampus. J Neurosci 28(53): 14537-14545.

A beta fragment. Biochemistry 39(43): 13269-13275.

amyloid beta peptide is a critical requirement for the viability of central neurons. J

Picomolar amyloid-beta positively modulates synaptic plasticity and memory in

Alpha-helix structure in Alzheimer's disease aggregates of tau-protein.

Perera, T., Kellie, S., Williamson, R., Anderton, B. H. & Reynolds, C. H. (2011). Tyrosine phosphorylation of tau by the SRC family kinases lck and fyn. Mol

Amyloid peptides are toxic via a common oxidative mechanism. Proc Natl Acad Sci

structure of the PHF core C-terminus: insight into the folding of the intrinsically

memory of natively unfolded tau protein detected by small-angle X-ray scattering.

Lippens, G. (2007). NMR investigation of the interaction between the neuronal

stable mold facilitates structure determination of disordered tau protein. J Struct

Alzheimer's core PHF subunit revealed by monoclonal antibody 423. FEBS Lett

Masters, C. L. & Nurcombe, V. (1999). Neurite-outgrowth regulating functions of the amyloid protein precursor of Alzheimer's disease. J Alzheimers Dis 1(4-5): 275-


**16** 

**Alzheimer's Disease: Approaches** 

Greg T. Sutherland and Jillian J. Kril *Disciplines of Pathology and Medicine,* 

> *Sydney Medical School, University of Sydney,*

> > *Australia*

**to Pathogenesis in the Genomic Age** 

The prevalence of Alzheimer's disease (AD), the most common form of dementia, is rising rapidly worldwide. A seemingly imminent epidemic is predicted to have wide reaching societal and economic consequences, becoming the leading health issue for many countries by the middle of this century. This epidemic is driven by an ageing world population in combination with a lack of disease modifying treatments or preventive strategies. The popular amyloid cascade hypothesis suggests that AD is precipitated by the dysregulated metabolism of the amyloid precursor protein resulting in the accumulation of the betaamyloid peptide (A) in the brain. This hypothesis is the basis for most experimental treatments currently in clinical trials. However, not all evidence supports a precipitating role

The completion of the human genome project in 2001 has ushered in a dramatic increase in the technologies available to biologists and these have been applied to understanding the pathogenesis of complex disorders, like AD. Genome-wide association and expression (transcriptomic) studies are now commonplace creating a more immediate and dynamic,

Transcriptomic studies in particular have the potential to greatly influence our understanding of complex diseases like AD, but to date they have provided quite discordant results. There are a number of potential reasons for this including our incomplete understanding of the complex nature of the human brain at the molecular level. It is now known that the evolutionary advances in our cognitive capacity have largely originated at the level of transcription with substantial increases in both coding and non-coding RNA variants. Until recently transcriptomic platforms only assayed a proportion of the coding RNA species, but with the introduction of next generation sequencing the whole

In this chapter we undertake a review of the clinical and pathological characteristics of AD before considering the impact of new technologies on AD research and their future role in

of abnormal A accumulation in the common forms of AD.

but invariably more complex, research environment.

finding a cure for this important disease.

transcriptome, both coding and non-coding, can now be investigated.

**1. Introduction** 

