Abstract
The search for a specific biochemical cause of Alzheimer’s disease began in the 1960s and 1970s, and was inspired by the burgeoning success of levodopa treatment for Parkinson’s disease. In the case of Alzheimer’s disease, brain regions associated with higher brain functions, primarily the hippocampus and neocortex, are affected. Investigations of those regions in the presence of senile dementia led to the discovery that (1) there are deficits in presynaptic terminals in the enzyme that catalyzes the synthesis of the neurotransmitter acetylcholine (ACh), namely, choline acetyltransferase (ChAT); (2) acetylcholine has a role in learning and memory, and (3) blocking its release leads to memory impairment.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Bibliography
Bartus, R. T., Dean, R. L., III, Beer, B., & Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science, 217, 408–414.
Blessed, G., Tomlinson, B. E., & Roth, M. (1968). The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. The British Journal of Psychiatry, 114, 797–811.
Davies, P., & Maloney, A. J. (1976). Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet, 2, 1403.
Goate, A., Chartier-Harlin, M. C., Mullan, M., Brown, J., Crawford, F., Fidani, L., et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature, 349, 704–706.
Hardy, J. A., & Higgins, G. A. (1992). Alzheimer’s disease: The amyloid cascade hypothesis. Science, 256, 184–185.
Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science, 297, 353–356.
Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., et al. (1995). Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science, 269, 973–977.
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature, 375, 754–760.
St. George-Hyslop, P. H., Tanzi, R. E., Polinsky, R. J., Haines, J. L., Nee, L., Watkins, P. C., et al. (1987b). The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science, 235, 885–890.
Tanzi, R. E., & Bertram, L. (2005). Twenty years of the Alzheimer’s disease amyloid hypothesis: A genetic perspective. Cell, 120, 545–555.
APP Processing
Chami, L., Buggia-Prévot, V., Duplan, E., Delprete, D., Chami, M., Peyron, J. F., et al. (2012). Nuclear factor-κB regulates β APP and β - and γ-secretases differentially at physiological and supraphysiological Aβ concentrations. The Journal of Biological Chemistry, 287, 24573–24584.
Christensen, M. A., Zhou, W., Qing, H., Lehman, A., Philipsen, S., & Song, W. (2004). Transcriptional regulation of BACE1, the β-amyloid protein β-secretase by Sp1. Molecular and Cellular Biology, 24, 865–874.
De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., et al. (1998). Deficiency of prersenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature, 391, 387–390.
Hébert, S. S., Horré, H., Nicolaï, L., Papadopoulou, A. S., Mandemakers, W., Silahtaroglu, A. N., et al. (2008). Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/β -secretase expression. Proceedings of the National Academy of Sciences of the United States of America, 105, 6415–6420.
Kuhn, P. H., Wang, H., Dislich, B., Colombo, A., Zeitschel, U., Ellwart, J. W., et al. (2010). ADAM10 is the physiologically relevant, constitutive α- secretase of the amyloid precursor protein in primary neurons. The EMBO Journal, 29, 3020–3032.
Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, R., Jasionowski, M., et al. (1999). Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proceedings of the National Academy of Sciences of the United States of America, 96, 3922–3927.
O’Connor, T., Doherty-Sadleir, K. R., Maus, E., Velliquette, R. A., Zhao, J., Cole, S. L., et al. (2008). Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron, 60, 988–1009.
Roberts, B. R., Ryan, T. M., Bush, A. I., Masters, C. L., & Duce, J. A. (2012). The role of metallobiology and amyloid-β peptides in Alzheimer’s disease. Journal of Neurochemistry, 120(Suppl. 1), 149–166.
Sastre, M., Dewachter, I., Rossner, S., Bogdanovic, N., Rosen, E., Borghgraef, P., et al. (2006). Nonsteroidal anti-inflammatory drugs repress β - secretase gene promoter activity by the activation of PPARγ. Proceedings of the National Academy of Sciences of the United States of America, 103, 443–448.
Vassar, R., Bennett, B. D., Babu-Khan, S., Khan, S., Mendiaz, E. A., Denis, P., et al. (1999). β -Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmmembrane aspartic protease BACE. Science, 286, 735–741.
Vassar, R., Kuhn, P. H., Haass, C., Kennedy, M. E., Rajendran, L., Wong, P. C., et al. (2014). Function, therapeutic potential and cell biology of BACE proteases: Current status and future prospects. Journal of Neurochemistry, 130, 4–28. doi:10.1111/jnc.12715.
Wang, W. X., Rajeev, B. W., Stromberg, A. J., Ren, N., Tang, G., Huang, Q., et al. (2008). The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of β -site amyloid precursor protein-cleaving enzyme 1. Journal of Neuroscience, 28, 1213–1223.
Apolipoprotein E, Its Receptors and Cholesterol
Björkhem, I., & Meaney, S. (2004). Brain cholesterol: Long secret life behind a barrier. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 806–815.
Brown, M. S., & Goldstein, J. L. (1986). A receptor-mediated pathway for cholesterol homeostasis. Science, 232, 34–47 (Nobel lecture).
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., et al. (1993). Gene dosage of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261, 921–923.
Grimm, M. O., Grimm, H. S., Pätzold, A. J., Zinser, E. G., Halonen, R., Duering, M., et al. (2005). Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin. Nature Cell Biology, 7, 1118–1123.
Holtzman, D. M., Herz, J., & Bu, G. (2012). Apolipoprotein E and Apolipoprotein E receptors: Normal biology and roles in Alzheimer’s disease. Cold Spring Harbor Perspectives in Medicine, 2, a006312.
Liu, Q., Zerbinatti, C. V., Zhang, J., Hoe, H. S., Wang, B., Cole, S. L., et al. (2007). Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron, 56, 66–78.
Liu, C. C., Kanekiyo, T., Xu, H., & Bu, G. (2013). Apolipoprotein E and Alzheimer’s disease: Risk, mechanisms and therapy. Nature Reviews. Neurology, 9, 106–118.
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2006). Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 103, 5644–5651.
Aβ Oligomers
Barghorn, S., Nimmrich, V., Striebinger, A., Krantz, C., Keller, P., Janson, B., et al. (2005). Globular amyloid β -peptide1–42 oligomer—A homogeneous and stable neuropathological protein in Alzheimer’s disease. Journal of Neurochemistry, 95, 834–847.
Kayed, R., Pensalfini, A., Margol, L., Sokolov, Y., Sarsoza, F., Head, E., et al. (2009). Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer. The Journal of Biological Chemistry, 284, 4230–4237.
Larson, M. E., & Lesné, S. E. (2012). Soluble Aβ oligomer production and toxicity. Journal of Neurochemistry, 120, 125–139.
Walsh, D. M., & Selkoe, D. J. (2007). Aβ oligomers—A decade of discovery. Journal of Neurochemistry, 101, 1172–1184.
Synaptic Activity and Aβ-Mediated Neuroprotection
Cirrito, J. R., Yamada, K. A., Finn, M. B., Sloviter, R. S., Bales, K. R., May, P. C., et al. (2005). Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron, 48, 913–922.
Hsia, A. Y., Masliah, E., McConlogue, L., Yu, G. Q., Tatsuno, G., Hu, K., et al. (1999). Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proceedings of the National Academy of Sciences of the United States of America, 96, 3228–3233.
Hsieh, H., Boehm, J., Sato, C., Iwatsubo, T., Tomita, T., Sisoda, S., et al. (2006). AMPA-R removal underlies Aβ -induced synaptic depression and dendritic spine loss. Neuron, 52, 831–843.
Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., et al. (2003). APP processing and synaptic plasticity. Neuron, 37, 925–937.
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., et al. (2006b). A specific amyloid-β protein assembly in the brain impairs memory. Nature, 440, 352–357.
Puzzo, D., Privitera, L., Fa, M., Staniszewski, A., Hashimoto, G., Aziz, F., et al. (2011). Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory. Annals of Neurology, 69, 819–830.
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 in cognitive impairment. Annals of Neurology, 30, 572–580.
Tyan, S. H., Shih, A. Y. J., Walsh, J. J., Murayama, H., Sarsoza, F., Ku, L., et al. (2012). Amyloid precursor protein (APP) regulates synaptic structure and function. Molecular and Cellular Neurosciences, 51, 43–52.
Amyloid-β and Synaptic Function
Abramov, E., Dolev, I., Fogel, H., Ciccotosto, G. D., Ruff, E., & Slutsky, I. (2009). Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses. Nature Neuroscience, 12, 1567–1576.
Bliss, T. V. P., & Collingridge, G. L. (1993). A synaptic model of memory: Long-term potentiation in the hippocampus. Nature, 361, 31–39.
Bliss, T. V. P., & Lømo, T. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. The Journal of Physiology, 232, 331–356.
Lacor, P. N., Buniel, M. C., Furlow, P. W., Clemente, A. S., Velasco, P. T., Wood, M., et al. (2007). Aβ oligomers induced aberrations in synapse composition, shape and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. Journal of Neuroscience, 27, 796–807.
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., et al. (1998b). Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proceedings of the National Academy of Sciences of the United States of America, 95, 6448–6453.
Liu, Q. S., Kawai, H., & Berg, D. K. (2001). β-Amyloid peptide blocks the response of α7-containing nicotinic receptors on hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America, 98, 4734–4739.
Renner, M., Lacor, P. N., Velasco, P. T., Xu, J., Contractor, A., Klein, W. L., et al. (2010). Deleterious effects of amyloid β oligomers acting as an extracellular scaffold for mGluR5. Neuron, 66, 739–754.
Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., et al. (2008b). Amyloid-β protein dimers isolated directly from Alzheimer brains impair synaptic plasticity and memory. Nature Medicine, 14, 837–842.
Snyder, E. M., Nong, Y., Almeida, C. G., Paul, S., Moran, T., Choi, E. Y., et al. (2005). Regulation of NMDA receptor trafficking by amyloid-β. Nature Neuroscience, 8, 1051–1058.
Wang, H. Y., Lee, D. H. S., D’Andrea, M. R., Peterson, P. A., Shank, R. P., & Reitz, A. B. (2000). β-Amyloid1–42 binds to α7 nicotinic acetylcholine receptor with high affinity. The Journal of Biological Chemistry, 275, 5626–5632.
Aβo Receptors and Aberrant Signaling
Cissé, M., Halabisky, B., Harris, J., Devidze, N., Dubal, D. B., Sun, B., et al. (2011). Reversing EphB2 depletion rescues cognitive function in Alzheimer model. Nature, 469, 47–52.
Freier, D. B., Nicoll, A. J., Klyubin, I., Panico, S., Mc Donald, J. M., Risse, E., et al. (2011). Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Nature Communications 2, art. 336.
Kim, T., Vidal, G. S., Djurisic, M., William, C. M., Birnbaum, M. E., Garcia, K. C., et al. (2013). Human LilrB2 is a β -amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model. Science, 341, 1399–1404.
Larson, M., Sherman, M. A., Amar, F., Nuvolone, M., Schneider, J. A., Bennett, D. A., et al. (2012). The complex PrP -Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer’s disease. Journal of Neuroscience, 32, 16857–16871.
Roberson, E. D. (2011a). Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on Tau levels in multiple mouse models of Alzheimer’s disease. Journal of Neuroscience, 31, 700–711.
Rushworth, J. V., Griffiths, H. H., Watt, N. T., & Hooper, N. M. (2013). Prion protein-mediated toxicity of amyloid-β oligomers requires lipid rafts and the transmembrane LRP1. The Journal of Biological Chemistry, 288, 8935–8951.
Um, J. W., Kaufman, A. C., Kostylev, M., Heiss, J. K., Stagi, M., Takahashi, H., et al. (2013). Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron, 79, 887–902.
Calcium Signaling, Excitotoxicity, and Extrasynaptic NMDA Receptors
Berridge, M. J. (1998). Neuronal calcium signaling. Neuron, 21, 13–26.
Choi, D. W. (1990). Glutamate neurotoxicity and diseases of the nervous system. Neuron, 1, 623–634.
Clapham, D. E. (2007). Calcium signaling. Cell, 131, 1047–1058.
Hardingham, G. E., Fukunaga, Y., & Bading, H. (2002). Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neuroscience, 5, 405–414.
Olney, J. W. (1969). Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science, 164, 719–721.
Talantova, M., Sanz-Blasco, S., Zhang, X., Xia, P., Akhtar, M. W., Okamoto, S., et al. (2013). Aβ induces astrocyte glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proceedings of the National Academy of Sciences of the United States of America, 110, E2518–E2527.
Aβ at the Rafts
Ariga, T., McDonald, M. P., & Yu, R. K. (2008). Role of ganglioside metabolism in the pathogenesis of Alzheimer’s disease—A review. Journal of Lipid Research, 49, 1157–1175.
Di Paolo, G., & Kim, T. W. (2011). Linking lipids to Alzheimer’s disease: Cholesterol and beyond. Nature Reviews. Neuroscience, 12, 284–296.
Kalvodova, L., Kahya, N., Schwille, P., Ehehalt, R., Verkade, P., Drechsel, D., et al. (2005). Lipids as modulators of proteolytic activity of BACE. The Journal of Biological Chemistry, 280, 36815–36823.
Matsuoka, Y., Saito, M., LaFrancois, J., Saito, M., Gaynor, K., Olm, V., et al. (2003). Novel therapeutic approach for the treatment of Alzheimer’s disease by peripheral administration of agents with an affinity for β -amyloid. Journal of Neuroscience, 23, 29–33.
Vetrivel, K. S., & Thinakaran, G. (2010). Membrane rafts in Alzheimer’s disease beta-amyloid production. Biochimica et Biophysica Acta, 1801, 860–867.
Blood-Brain Barrier and Neurovascular Unit
Abbott, N. J., Rönnbäck, L., & Hansson, E. (2006). Astrocyte-endothelial interactions at the blood-brain barrier. Nature Reviews. Neuroscience, 7, 41–53.
Brightman, M. W., & Reese, T. S. (1969). Junctions between intimately opposed cell membranes in the vertebrate brain. The Journal of Cell Biology, 40, 648–677.
Reese, T. S., & Karnovsky, M. J. (1967). Fine structural localization of a blood-brain barrier to exogenous peroxidase. The Journal of Cell Biology, 34, 207–217.
Suzuki, N., Cheung, T. T., Cai, X. D., Odaka, A., Otvos, L., Jr., Eckman, C., et al. (1994). An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (β APP717) mutants. Science, 264, 1336–1340.
Zlokovic, B. V. (2008). The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron, 57, 178–201.
Zlokovic, B. V. (2011). Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nature Reviews. Neuroscience, 12, 723–738.
Aβ and Vascular Injury
Buée, L., Hof, P. R., Bouras, C., Delacourte, A., Perl, D. P., Morrison, J. H., et al. (1994). Pathological alterations in the cerebral microvasculature in Alzheimer’s disease and related dementing disorders. Acta Neuropathologica, 87, 469–480.
Iadecola, C. (2010). The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathologica, 120, 287–296.
Inflammation in AD
Heneka, M. T., Kummer, M. P., Stutz, A., Delekate, A., Schwartz, S., Vieira-Saecker, A., et al. (2013). NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature, 493, 674–678.
McGeer, P. L., & McGeer, E. G. (2001). Inflammation, autotoxicity and Alzheimer’s disease. Neurobiology of Aging, 22, 799–809.
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308, 1314–1318.
Oberheim, N. A., Takano, T., Han, X., He, W., Lin, J. H. C., Wang, F., et al. (2009). Uniquely hominid features of adult human astrocytes. Journal of Neuroscience, 29, 3276–3287.
Rogers, J., Cooper, N. R., Webster, S., Schultz, J., McGeer, P. L., Styren, S. D., et al. (1992). Complement activation by β -amyloid in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 89, 10016–10020.
Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., et al. (2008). The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunology, 9, 857–865.
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., et al. (2012). Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron, 74, 691–705.
Stephan, A. H., Madison, D. V., Mateos, J. M., Fraser, D. A., Lovelett, E. A., Coutellier, L., et al. (2013). A dramatic increase of C1q protein in the CNS during normal aging. Journal of Neuroscience, 33, 13460–13474.
Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., et al. (2007). The classical complement cascade mediates CNS synapse elimination. Cell, 131, 1164–1168.
Volterra, A., & Meldolesi, J. (2005). Astrocytes, from brain glue to communication elements: The revolution continues. Nature Reviews. Neuroscience, 6, 626–640.
APP Oligomers and Tau
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 Neuropathologica, 103, 26–35.
de Calignon, A., Fox, L. M., Pitstick, R., Carlson, G. A., Bacskai, B. J., Spires-Jones, T. L., et al. (2010). Caspase activation precedes and leads to tangles. Nature, 464, 1201–1204.
Götz, J., Chen, F., van Dorpe, J., & Nitsch, R. M. (2001). Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science, 293, 1491–1495.
Hoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K., et al. (2010). Tau mislocation to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron, 68, 1067–1081.
Ittner, L. M., Ke, Y. D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., et al. (2010). Dendritic function of tau mediates amyloid-β toxicity in Alzheimer’s disease mouse models. Cell, 142, 387–397.
Jin, M., Shephardson, N., Yang, T., Chen, G., Walsh, D., & Selkoe, D. J. (2011). Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proceedings of the National Academy of Sciences of the United States of America, 108, 5819–5824.
Lewis, J., Dickson, D. W., Lin, W. L., Chisholm, L., Corral, L., Jones, G., et al. (2001). Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science, 293, 1487–1491.
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., et al. (2003). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Aβ and synaptic dysfunction. Neuron, 39, 409–421.
Roberson, E. D. (2011b). Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on Tau levels in multiple mouse models of Alzheimer’s disease. Journal of Neuroscience, 31, 700–711.
Shipton, O. A., Leitz, J. R., Dworzak, J., Acton, C. E. J., Tunbridge, E. M., Denk, F., et al. (2011). Tau protein is required for amyloid β -induced impairment of hippocampal long-term potentiation. Journal of Neuroscience, 31, 1688–1692.
Vossel, K. A., Zhang, K., Brodbeck, J., Daub, A. C., Sharma, P., Finkbeiner, S., et al. (2010). Tau reduction prevents Aβ -induced defects in axonal transport. Science, 330, 198.
Wang, Y., Martinez-Vicente, M., Krüger, U., Kaushik, S., Wong, E., Mandelkow, E. M., et al. (2009). Tau fragmentation, aggregation and clearance: The dual role of lysosomal processing. Human Molecular Genetics, 18, 4153–4170.
Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E. M. (2010). Aβ oligomers cause localized Ca2+ elevation, missorting of endogenous tau into dendrites, tau phosphorylation, and destruction of microtubules and spines. Journal of Neuroscience, 30, 11938–11950.
Zempel, H., Luedtke, J., Kumar, Y., Biernat, J., Dawson, H., Mandelkow, E., et al. (2013). Amyloid-β oligomers induce damage via tau-dependent microtubule severing by TTLL6 and spastin. The EMBO Journal, 32, 2920–2937.
Prion-Like Spread
Bero, A. W., Yan, P., Roh, J. H., Cirrito, J. R., Stewart, F. R., Raichle, M. E., et al. (2011). Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nature Neuroscience, 14, 750–756.
Domert, J., Rao, S. B., Agholme, L., Brorsson, A. C., Marcusson, J., Hallbeck, M., et al. (2014). Spreading of amyloid-β peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance. Neurobiology of Disease, 65, 82–92.
Eisele, Y. S., Obermüller, U., Heilbronner, G., Baumann, F., Kaeser, S. A., Wolburg, H., et al. (2010). Peripherally applied Aβ -containing inoculates induce cerebral β -amyloidosis. Science, 330, 980–982.
Meyer-Luehmann, M., Coomaraswamy, J., Bolmont, T., Kaeser, S., Schaefer, C., Kilger, E., et al. (2006). Exogenous induction of cerebral β - amyloidogenesis is governed by agent and host. Science, 313, 1781–1784.
Nath, S., Agholme, L., Kurudenkandy, F. R., Granseth, B., Marcusson, J., & Hallbeck, M. (2012). Spreading of neurodegenerative pathology via neuron-to-neuron transmission of β -amyloid. Journal of Neuroscience, 32, 8767–8777.
Stöhr, J., Watts, J. C., Mensinger, Z. L., Oehler, A., Grillo, S. K., DeArmond, S. J., et al. (2012). Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions. Proceedings of the National Academy of Sciences of the United States of America, 109, 11025–11030.
Regulated Intramembrane Proteolysis
Brown, M. S., Ye, J., Rawson, R. B., & Goldstein, J. L. (2000). Regulated intramembrane proteolysis: A control mechanism conserved from bacteria to humans. Cell, 100, 391–398.
Cao, X., & Südhof, T. C. (2001). A transcriptionally [correction of transcriptively] active complex of APP with Fe56 and the histone acetyltransferase Tip60. Science, 293, 115–120.
De Strooper, B., Vassar, R., & Golde, T. (2010). The secretases: Enzymes with therapeutic potential in Alzheimer disease. Nature Reviews. Neurology, 6, 99–107.
Kopan, R., & Ilagen, M. X. (2009). The canonical Notch signaling pathway: Unfolding the activation mechanism. Cell, 137, 216–233.
Lichtenthaler, S. F., Haase, C., & Steiner, G. H. (2011). Regulated intramembrane proteolysis—Lessons from amyloid precursor protein processing. Journal of Neurochemistry, 117, 779–796.
Lipoproteins
Mahley, R. W. (1988). Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science, 240, 622–630.
Olson, R. E. (1998). Discovery of the lipoproteins, their role in fat transport and their significance as risk factors. The Journal of Nutrition, 128, 439S–443S.
Author information
Authors and Affiliations
Appendices
Appendix 1. Regulated Intramembrane Proteolysis (RIP)
The cleavage of transmembrane protein such as APP occurs both outside and within their membrane-spanning portions. This process, first uncovered in the mid to late 1990s, is known as regulated intramembrane proteolysis (RIP). The stubs and other fragments proteolytically generated from the Type I or Type II single-pass proteins can either be discarded or used as signaling molecules. In the latter instance, the signaling pathway to the nucleus is remarkable short and direct, bypassing the typical protein kinase, phosphatase and other signal transducers.
A number of signaling proteins are produced in this manner. These include Notch, a key developmental and repair regulator of neurons, sterol regulatory element-binding protein (SREPB), a major regulator of cholesterol biosynthesis, and tumor necrosis factor α (TNFα) a key mediator of inflammation . In all of these cases, extracellular cleavage occurs first that generates an ectodomain stub and reduces the length of the portion remaining for the second intramembrane cleavage step. ADAM10 and TACE (tumor necrosis factor-α converting enzyme) are responsible in many instances for the first cut and γ-secretase with its presenilins for the second step. A number of BACE1 substrates have been identified, as well. These include LRP1, neuregulins (proteins involved in myelination and synapse formation, and a schizophrenia risk factor ), and voltage-gated sodium channels, among others. Lastly, the γ-secretase is remarkably promiscuous. By 2011 at least 90 substrates had been identified. In those instances where the fragments are simply discarded and have no signaling role, the picture is one where the γ-secretase functions as a member of the cellular protein quality control machinery.
Turning to the nuclear transit of APP and Notch signaling elements, the amyloid precursor protein intracellular domain (AICD) is generated through actions of gamma-secretase on the APP at one of a number of sites. Cuts are made at the γ-cleavage sites (at residues 38, 40, 42) C-terminal to the β-cleavage site, or alternatively to an ε-cleavage site (49) or a ζ-cleavage site (46) within the transmembrane portion of the APP. These operations and the resulting actions of the fragments resemble the situation generated by the presenilins on the Notch protein. In the case of Notch, the released C-terminal fragment, referred to as the Notch intracellular domain (NICD) translocates to the nuclear where it functions as a transcription factor. The actions taken in the case of the APP are slightly different. The AICD influences transcription by activating the Fe65 adaptor protein and this dimer interacts with other the histone acetyltransferase Tip60 to produce a transcriptionally active complex. Genes influenced include those promoting developmental and injury related alterations to the actin cytoskeleton structure.
Lastly, designing drugs that treat neurodegenerative disorders is a challenging endeavor. In the case of Alzheimer’s disease, the hurdles are at least threefold. First, the drugs must get past the blood–brain barrier. Secondly, drugs that directly target Aβ peptides must deal with the existence of multiple oligomeric forms. Thirdly, drugs aimed at the secretases must take into account the presence of substrates other than APP. BACE1 is arguably the most promising drug target because of its role as the rate-limiting enzyme, but here too the recent discovery of other substrates presents challenges.
Appendix 2. The Five Types of Lipoprotein Particles
There are five kinds of lipoproteins, each differing in size, density and composition. The physical and chemical properties of these cholesterol , triglyceride and phospholipid transport molecules are summarized in Table 8.2. These entries have been ordered from the largest and least dense chylomicrons to the smallest and most dense high-density lipoproteins (HDLs). The alterations in size and density reflect differences in composition. The chylomicrons mostly transport triglycerides, while the LDLs and HDLs primarily convey cholesterol and phospholipids and carry only small amounts of TGs.
Chylomicrons are produced in the small intestine by absorptive cells (enterocytes), and enter the bloodstream via the lymphatic system. They transport TG derived from foodstuffs to the liver, adipose tissue, cardiac and skeletal tissues. Very low density lipoproteins (VLDLs) are synthesized in the liver. They are the main vehicle for transport of triglycerides from the liver to adipocytes and muscle tissue for energy storage and production of energy through oxidation. The fatty acid component of the VLDLs is released to the muscle cells and adipocytes; this loss together with the loss of the ApoCs leaves a VLDL remnant, termed an intermediate density lipoprotein (IDL). Some VLDLs are taken up by the liver, while others are transformed in the blood and become LDLs. The LDLs transport cholesterol , phospholipids and small amounts of TGs from the liver and intestines to other organs and peripheral tissues in the body; HLDs remove and return them to the liver for eventual removal from the body.
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Beckerman, M. (2015). Alzheimer’s Disease. In: Fundamentals of Neurodegeneration and Protein Misfolding Disorders. Biological and Medical Physics, Biomedical Engineering. Springer, Cham. https://doi.org/10.1007/978-3-319-22117-5_8
Download citation
DOI: https://doi.org/10.1007/978-3-319-22117-5_8
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-22116-8
Online ISBN: 978-3-319-22117-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)