Key Peptides and Proteins in Alzheimer’s Disease

Author(s): Botond Penke*, Ferenc Bogár, Gábor Paragi, János Gera, Lívia Fülöp

Journal Name: Current Protein & Peptide Science

Volume 20 , Issue 6 , 2019

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Graphical Abstract:


Alzheimer’s Disease (AD) is a form of progressive dementia involving cognitive impairment, loss of learning and memory. Different proteins (such as amyloid precursor protein (APP), β- amyloid (Aβ) and tau protein) play a key role in the initiation and progression of AD. We review the role of the most important proteins and peptides in AD pathogenesis. The structure, biosynthesis and physiological role of APP are shortly summarized. The details of trafficking and processing of APP to Aβ, the cytosolic intracellular Aβ domain (AICD) and small soluble proteins are shown, together with other amyloid-forming proteins such as tau and α-synuclein (α-syn). Hypothetic physiological functions of Aβ are summarized. The mechanism of conformational change, the formation and the role of neurotoxic amyloid oligomeric (oAβ) are shown. The fibril formation process and the co-existence of different steric structures (U-shaped and S-shaped) of Aβ monomers in mature fibrils are demonstrated. We summarize the known pathogenic and non-pathogenic mutations and show the toxic interactions of Aβ species after binding to cellular receptors. Tau phosphorylation, fibrillation, the molecular structure of tau filaments and their toxic effect on microtubules are shown. Development of Aβ and tau imaging in AD brain and CSF as well as blood biomarkers is shortly summarized. The most probable pathomechanisms of AD including the toxic effects of oAβ and tau; the three (biochemical, cellular and clinical) phases of AD are shown. Finally, the last section summarizes the present state of Aβ- and tau-directed therapies and future directions of AD research and drug development.

Keywords: Alzheimer's disease, APP, β-amyloid, Tau, ApoE, amyloid aggregation, AD-pathomechanisms, AD drugs.

Kovacs, G.G. Molecular pathological classification of neurodegenerative diseases: Turning towards precision medicine. Int. J. Mol. Sci., 2016, 17(2), 189.
Rahimi, J.; Kovacs, G.G. Prevalence of mixed pathologies in the aging brain. Alzheimers Res. Ther., 2014, 6(9), 82.
Kovacs, G.G.; Adle-Biassette, H.; Milenkovic, I.; Cipriani, S.; Van Scheppingen, J.; Aronica, E. Linking pathways in the developing and aging brain with neurodegeneration. Neuroscience, 2014, 269, 152-172.
Kovacs, G.G. Concepts and classification of neurodegenerative diseases.In Handbook of Clinical Neurology., Kovacs, G.G.; Alafuzoff,I.; Eds. Elsevier: Amsterdam,. 2018, Vol. 145, 301-307.
Braak, H.; Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol., 1991, 82(4), 239-259.
Thal, D.R.; Rub, U.; Orantes, M.; Braak, H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology, 2002, 58(12), 1791-1800.
Kim, W.S.; Kagedal, K.; Halliday, G.M. Alpha-synuclein biology in Lewy body diseases. Alzheimers Res. Ther., 2014, 6(5), 73.
Ping, L.; Duong, D.M.; Yin, L.; Gearing, M.; Lah, J.J.; Levey, A.I.; Seyfried, N.T. Global quantitative analysis of the human brain proteome in Alzheimer’s and Parkinson’s Disease. Sci. Data, 2018, 5, 180036.
Bereczki, E.; Branca, R.M.; Francis, P.T.; Pereira, J.B.; Baek, J.H.; Hortobagyi, T.; Winblad, B.; Ballard, C.; Lehtio, J.; Aarsland, D. Synaptic markers of cognitive decline in neurodegenerative diseases: A proteomic approach. Brain, 2018, 141(2), 582-595.
Zhang, Q.; Ma, C.; Gearing, M.; Wang, P.G.; Chin, L.S.; Li, L. Integrated proteomics and network analysis identifies protein hubs and network alterations in Alzheimer’s disease. Acta Neuropathol. Commun., 2018, 6, 19.
Caselli, R.J.; Reiman, E.M. Characterizing the preclinical stages of Alzheimer’s disease and the prospect of presymptomatic intervention. J. Alzheimers Dis., 2013, 33, S405-S416.
Boehm, J.; Fernandes, K.; Leclerc, N.; Robitaille, R. The neurobiology of aging and Alzheimer’s disease: walking down the same road? Eur. J. Neurosci., 2013, 37(12), 1885-1886.
Duyckaerts, C.; Delatour, B.; Potier, M.C. Classification and basic pathology of Alzheimer disease. Acta Neuropathol., 2009, 118(1), 5-36.
Castellani, R.J.; Rolston, R.K.; Smith, M.A. Alzheimer disease. Dis. Mon., 2010, 56(9), 484-546.
Drummond, E.; Nayak, S.; Pires, G.; Ueberheide, B.; Wisniewski, T. Isolation of amyloid plaques and neurofibrillary tangles from archived Alzheimer’s disease tissue using laser-capture microdissection for downstream proteomics. Methods Mol. Biol., 2018, 1723, 319-334.
Khachaturian, Z.S. Diagnosis of Alzheimers-disease. Arch. Neurol., 1985, 42(11), 1097-1104.
Mirra, S.S.; Heyman, A.; Mckeel, D.; Sumi, S.M.; Crain, B.J.; Brownlee, L.M.; Vogel, F.S.; Hughes, J.P.; Vanbelle, G.; Berg, L. The consortium to establish a registry for Alzheimers-disease (Cerad). 2. standardization of the neuropathologic assessment of Alzheimers-disease. Neurology, 1991, 41(4), 479-486.
Smith, M.A. Alzheimer disease. Int. Rev. Neurobiol., 1998, 42, 1-54.
Lacosta, A.M.; Insua, D.; Badi, H.; Pesini, P.; Sarasa, M. Neurofibrillary tangles of A beta(x-40) in Alzheimer’s disease brains. J. Alzheimers Dis., 2017, 58(3), 661-667.
Marks, S.M.; Lockhart, S.N.; Baker, S.L.; Jagust, W.J. Tau and beta-amyloid are associated with medial temporal lobe structure, function, and memory encoding in normal aging. J. Neurosci., 2017, 37(12), 3192-3201.
Bouras, C.; Hof, P.R.; Giannakopoulos, P.; Michel, J.P.; Morrison, J.H. Regional distribution of neurofibrillary tangles and senile plaques in the cerebral-cortex of elderly patients - a quantitative-evaluation of a one-year autopsy population from a geriatric hospital. Cereb. Cortex, 1994, 4(2), 138-150.
Bennett, D.A.; Cochran, E.J.; Saper, C.B.; Leverenz, J.B.; Gilley, D.W.; Wilson, R.S. Pathological changes in frontal cortex from biopsy to autopsy in Alzheimer’s disease. Neurobiol. Aging, 1993, 14(6), 589-596.
Masliah, E.; Terry, R.D.; Deteresa, R.M.; Hansen, L.A. Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer-disease. Neurosci. Lett., 1989, 103(2), 234-239.
Hardy, J.; Allsop, D. Amyloid deposition as the central event in the etiology of Alzheimers-disease. Trends Pharmacol. Sci., 1991, 12(10), 383-388.
Gray, E.G.; Paulabarbosa, M.; Roher, A. Alzheimers-disease - paired helical filaments and cytomembranes. Neuropathol. Appl. Neurobiol., 1987, 13(2), 91-110.
Nhan, H.S.; Chiang, K.; Koo, E.H. The multifaceted nature of amyloid precursor protein and its proteolytic fragments: Friends and foes. Acta Neuropathol., 2015, 129(1), 1-19.
van der Kant, R.; Goldstein, L.S. Cellular functions of the amyloid precursor protein from development to dementia. Dev. Cell, 2015, 32(4), 502-515.
Deyts, C.; Thinakaran, G.; Parent, A.T. APP receptor? To be or not to be. Trends Pharmacol. Sci., 2016, 37(5), 390-411.
Zheng, H.; Koo, E.H. Biology and pathophysiology of the amyloid precursor protein. Mol. Neurodegener., 2011, 6(1), 27.
Southam, K.A.; Stennard, F.; Pavez, C.; Small, D.H. Knockout of Amyloid beta Protein Precursor (APP) expression alters synaptogenesis, neurite branching and axonal morphology of hippocampal neurons. Neurochem. Res., 2018.
[ [Epub ahead of print].]
Stahl, R.; Schilling, S.; Soba, P.; Rupp, C.; Hartmann, T.; Wagner, K.; Merdes, G.; Eggert, S.; Kins, S. Shedding of APP limits its synaptogenic activity and cell adhesion properties. Front. Cell. Neurosci., 2014, 8, 410.
Puzzo, D.; Piacentini, R.; Fa, M.; Gulisano, W.; Li, P. D.D.; Staniszewski, A.; Zhang, H.; Tropea, M.R.; Cocco, S.; Palmeri, A.; Fraser, P.; D’Adamio, L.; Grassi, C.; Arancio, O. LTP and memory impairment caused by extracellular A beta and Tau oligomers is APP-dependent. eLife, 2017, 6, 26991.
Wang, Z.M.; Jackson, R.J.; Hong, W.; Taylor, W.M.; Corbett, G.T.; Moreno, A.; Liu, W.; Li, S.M.; Frosch, M.P.; Slutsky, I.; Young-Pearse, T.L.; Spires-Jones, T.L.; Walsh, D.M. Human brain-derived a beta oligomers bind to synapses and disrupt synaptic activity in a manner that requires APP. J. Neurosci., 2017, 37(49), 11947-11966.
Grimm, M.O.W.; Mett, J.; Grimm, H.S.; Hartmann, T. APP function and lipids: A bidirectional link. Front. Mol. Neurosci., 2017, 10, 63.
Penke, B.; Bogar, F.; Fulop, L. β-amyloid and the pathomechanisms of Alzheimer’s disease: A comprehensive view. Molecules, 2017, 22(10), 1692.
Elliott, C.; Rojo, A.I.; Ribe, E.; Broadstock, M.; Xia, W.; Morin, P.; Semenov, M.; Baillie, G.; Cuadrado, A.; Al-Shawi, R.; Ballard, C.G.; Simons, P.; Killick, R. A role for APP in Wnt signalling links synapse loss with beta-amyloid production. Transl. Psychiatry, 2018, 8(1), 179.
Belaidi, A.A.; Gunn, A.P.; Wong, B.X.; Ayton, S.; Appukuttan, A.T.; Roberts, B.R.; Duce, J.A.; Bush, A.I. Marked age-related changes in brain iron homeostasis in amyloid protein precursor knockout mice. Neurotherapeutics, 2018, 15(4), 1055-1062.
Norstrom, E. Metabolic Processing of the amyloid precursor protein -- new pieces of the Alzheimer’s puzzle. Discov. Med., 2017, 23(127), 269-276.
Manucat-Tan, N.B.; Saadipour, K.; Wang, Y.J.; Bobrovskaya, L.; Zhou, X.F. Cellular trafficking of amyloid precursor protein in amyloidogenesis physiological and pathological significance. Mol. Neurobiol., 2018.[Epub ahead of print]..
Muller, T.; Meyer, H.E.; Egensperger, R.; Marcus, K. The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-relevance for Alzheimer’s disease. Prog. Neurobiol., 2008, 85(4), 393-406.
Tam, J.H.K.; Seah, C.; Pasternak, S.H. The amyloid precursor protein is rapidly transported from the golgi apparatus to the lysosome and where it is processed into beta-amyloid. Mol. Brain, 2014, 7, 54.
Haass, C.; Schlossmacher, M.G.; Hung, A.Y.; Vigopelfrey, C.; Mellon, A.; Ostaszewski, B.L.; Lieberburg, I.; Koo, E.H.; Schenk, D.; Teplow, D.B.; Selkoe, D.J. Amyloid beta-peptide is produced by cultured-cells during normal metabolism. Nature, 1992, 359(6393), 322-325.
Wang, X.; Zhou, X.; Li, G.Y.; Zhang, Y.; Wu, Y.L.; Song, W.H. Modifications and trafficking of APP in the pathogenesis of Alzheimer’s disease. Front. Mol. Neurosci., 2017, 10, 294.
Lammich, S.; Kojro, E.; Postina, R.; Gilbert, S.; Pfeiffer, R.; Jasionowski, M.; Haass, C.; Fahrenholz, F. Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl. Acad. Sci. USA, 1999, 96(7), 3922-3927.
Kuhn, P.H.; Wang, H.; Dislich, B.; Colombo, A.; Zeitschel, U.; Ellwart, J.W.; Kremmer, E.; Rossner, S.; Lichtenthaler, S.F. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J., 2010, 29(17), 3020-3032.
Chasseigneaux, S.; Allinquant, B. Functions of Aβ, sAPPα and sAPPβ: Similarities and differences. J. Neurochem., 2012, 120, 99-108.
Haass, C.; Kaether, C.; Thinakaran, G.; Sisodia, S. Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med., 2012, 2(5), 006270.
Haapasalo, A.; Kovacs, D.M. The many substrates of presenilin/gamma-secretase. J. Alzheimers Dis., 2011, 25(1), 3-28.
De Strooper, B.; Gutierrez, L.C. Learning by failing: Ideas and concepts to tackle gamma-secretases in Alzheimer’s disease and beyond. Annu. Rev. Pharmacol. Toxicol., 2015, 55, 419-437.
Willem, M.; Tahirovic, S.; Busche, M.A.; Ovsepian, S.V.; Chafai, M.; Kootar, S.; Hornburg, D.; Evans, L.D.B.; Moore, S.; Daria, A.; Hampel, H.; Muller, V.; Giudici, C.; Nuscher, B.; Wenninger-Weinzierl, A.; Kremmer, E.; Heneka, M.T.; Thal, D.R.; Giedraitis, V.; Lannfelt, L.; Muller, U.; Livesey, F.J.; Meissner, F.; Herms, J.; Konnerth, A.; Marie, H.; Haass, C. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature, 2015, 526(7573), 443-447.
Simons, M.; DeStrooper, B.; Multhaup, G.; Tienari, P.J.; Dotti, C.G.; Beyreuther, K. Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons. J. Neurosci., 1996, 16(3), 899-908.
Zhang, Z.T.; Song, M.K.; Liu, X.; Kang, S.S.; Duong, D.M.; Seyfried, N.T.; Cao, X.B.; Cheng, L.M.; Sun, Y.E.; Yu, S.P.; Jia, J.P.; Levey, A.I.; Ye, K.Q. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease. Nat. Commun., 2015, 6, 8762.
Bien, J.; Jefferson, T.; Causevic, M.; Jumpertz, T.; Munter, L.; Multhaup, G.; Weggen, S.; Becker-Pauly, C.; Pietrzik, C.U. The metalloprotease meprin beta generates amino terminal-truncated amyloid beta peptide species. J. Biol. Chem., 2012, 287(40), 33304-33313.
Salminen, A.; Kauppinen, M.; Kaamiranta, K. Hypoxia/ischemia activate processing of amyloid precursor protein: Impact of vascular dysfunction in the pathogenesis of Alzheimer’s disease. J. Neurochem., 2017, 140(4), 536-549.
Chong, F.P.; Ng, K.Y.; Koh, R.Y.; Chye, S.M. Tau proteins and tauopathies in Alzheimer’s disease. Cell. Mol. Neurobiol., 2018, 38(5), 965-980.
Goedert, M.; Clavaguera, F.; Tolnay, M. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci., 2010, 33(7), 317-325.
Gotz, J.; Lim, Y.A.; Ke, Y.D.; Eckert, A.; Ittner, L.M. Dissecting toxicity of tau and beta-amyloid. Neurodegener. Dis., 2010, 7(1-3), 10-12.
Kovacs, G.G. Invited review: Neuropathology of tauopathies: Principles and practice. Neuropathol. Appl. Neurobiol., 2015, 41(1), 3-23.
Mandelkow, E.M.; Mandelkow, E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb. Perspect. Med., 2012, 2(7), 006247.
Mukrasch, M.D.; Bibow, S.; Korukottu, J.; Jeganathan, S.; Biernat, J.; Griesinger, C.; Mandelkow, E.; Zweckstetter, M. Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol., 2009, 7(2), 399-414.
Crowther, R.A. Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc. Natl. Acad. Sci. USA, 1991, 88(6), 2288-2292.
Fitzpatrick, A.W.P.; Falcon, B.; He, S.; Murzin, A.G.; Murshudov, G.; Garringer, H.J.; Crowther, R.A.; Ghetti, B.; Goedert, M.; Scheres, S.H.W. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature, 2017, 547(7662), 185-190.
Goedert, M.; Spillantini, M.G.; Jakes, R.; Rutherford, D.; Crowther, R.A. Multiple isoforms of human microtubule-associated protein-tau - sequences and localization in neurofibrillary tangles of Alzheimers-disease. Neuron, 1989, 3(4), 519-526.
Duan, A.R.; Jonasson, E.M.; Alberico, E.O.; Li, C.L.; Scripture, J.P.; Miller, R.A.; Alber, M.S.; Goodson, H.V. Interactions between tau and different conformations of tubulin: implications for tau function and mechanism. J. Mol. Biol., 2017, 429(9), 1424-1438.
Brady, S.T.; Sperry, A.O. Biochemical and functional diversity of microtubule motors in the nervous system. Curr. Opin. Neurobiol., 1995, 5(5), 551-558.
Moussaud, S.; Jones, D.R.; Moussaud-Lamodiere, E.L.; Delenclos, M.; Ross, O.A.; McLean, P.J. Alpha-synuclein and tau: Teammates in neurodegeneration? Mol. Neurodegener., 2014, 9, 43.
Zhang, Z.T.; Kang, S.S.; Liu, X.; Ahn, E.H.; Zhang, Z.H.; He, L.; Iuvone, P.M.; Duong, D.M.; Seyfried, N.T.; Benskey, M.J.; Manfredsson, F.P.; Jin, L.J.; Sun, Y.E.; Wang, J.Z.; Ye, K.Q. Asparagine endopeptidase cleaves alpha-synuclein and mediates pathologic activities in Parkinson’s disease. Nat. Struct. Mol. Biol., 2017, 24(8), 632-642.
Larson, M.E.; Sherman, M.A.; Greimel, S.; Kuskowski, M.; Schneider, J.A.; Bennett, D.A.; Lesne, S.E. Soluble alpha-synuclein is a novel modulator of Alzheimer’s disease pathophysiology. J. Neurosci., 2012, 32(30), 10253-10266.
Yokota, O.; Terada, S.; Ishizu, H.; Tsuchiya, K.; Kitamura, Y.; Ikeda, K.; Ueda, K.; Kuroda, S. NACP/alpha-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC). Acta Neuropathol., 2002, 104(4), 333-341.
Diao, J.J.; Burre, J.; Vivona, S.; Cipriano, D.J.; Sharma, M.; Kyoung, M.; Sudhof, T.C.; Brunger, A.T. Native alpha-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. eLife, 2013, 2, 00592.
Alim, M.A.; Hossain, M.S.; Arima, K.; Takeda, K.; Izumiyama, Y.; Nakamura, M.; Kaji, H.; Shinoda, T.; Hisanaga, S.; Ueda, K. Tubulin seeds alpha-synuclein fibril formation. J. Biol. Chem., 2002, 277(3), 2112-2117.
Bartels, T.; Choi, J.G.; Selkoe, D.J. Alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature, 2011, 477(7362), 107-110.
Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.Y.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. Alpha-synuclein in Lewy bodies. Nature, 1997, 388(6645), 839-840.
Sadigh-Eteghad, S.; Talebi, M.; Farhoudi, M. Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer’s disease A meta-analysis. Neurosciences, 2012, 17(3), 321-326.
Sepehrnia, B.; Kamboh, M.I.; Adamscampbell, L.L.; Bunker, C.H.; Nwankwo, M.; Majumder, P.P.; Ferrell, R.E. Genetic-studies of human apolipoproteins. 10. the effect of the apolipoprotein-e polymorphism on quantitative levels of lipoproteins in nigerian blacks. Am. J. Hum. Genet., 1989, 45(4), 586-591.
Notkola, I.L.; Sulkava, R.; Pekkanen, J.; Erkinjuntti, T.; Ehnholm, C.; Kivinen, P.; Tuomilehto, A.; Nissinen, A. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer’s disease. Neuroepidemiology, 1998, 17(1), 14-20.
Hauser, P.S.; Ryan, R.O. Impact of apolipoprotein E on Alzheimer’s disease. Curr. Alzheimer Res., 2013, 10(8), 809-817.
Stocker, H.; Mollers, T.; Perna, L.; Brenner, H. The genetic risk of Alzheimer’s disease beyond APOE epsilon 4: Systematic review of Alzheimer’s genetic risk scores. Transl. Psychiatry, 2018, 8, 166.
Yu, J.T.; Tan, L.; Hardy, J. Apolipoprotein E in Alzheimer’s disease: An update. Annu. Rev. Neurosci., 2014, 37, 79-100.
Han, S.H.; Park, J.C.; Mook-Jung, I. Amyloid beta-interacting partners in Alzheimer’s disease: From accomplices to possible therapeutic targets. Prog. Neurobiol., 2016, 137, 17-38.
Brandon, J.A.; Farmer, B.C.; Williams, H.C.; Johnson, L.A. APOE and Alzheimer’s disease: Neuroimaging of metabolic and cerebrovascular dysfunction. Front. Aging Neurosci., 2018, 10, 180.
Wolf, A.B.; Caselli, R.J.; Reiman, E.M.; Valla, J. APOE and neuroenergetics: An emerging paradigm in Alzheimer’s disease. Neurobiol. Aging, 2013, 34(4), 1007-1017.
Alata, W.; Ye, Y.; St-Amour, I.; Vandal, M.; Calon, F. Human apolipoprotein E epsilon 4 expression impairs cerebral vascularization and blood-brain barrier function in mice. J. Cereb. Blood Flow Metab., 2015, 35(1), 86-94.
Bell, R.D.; Winkler, E.A.; Singh, I.; Sagare, A.P.; Deane, R.; Wu, Z.H.; Holtzman, D.M.; Betsholtz, C.; Armulik, A.; Sallstrom, J.; Berk, B.C.; Zlokovic, B.V. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature, 2012, 485(7399), 512-516.
Nielsen, H.M.; Chen, K.W.; Lee, W.; Chen, Y.H.; Bauer, R.J.; Reiman, E.; Caselli, R.; Bu, G.J. Peripheral apoE isoform levels in cognitively normal APOE epsilon 3/epsilon 4 individuals are associated with regional gray matter volume and cerebral glucose metabolism. Alzheimers Res. Ther., 2017, 9(1), 5.
Huynh, T.V.; Davis, A.A.; Ulrich, J.D.; Holtzman, D.M. Apolipoprotein E and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-beta and other amyloidogenic proteins. J. Lipid Res., 2017, 58(5), 824-836.
Holtzman, D.M.; Bales, K.R.; Tenkova, T.; Fagan, A.M.; Parsadanian, M.; Sartorius, L.J.; Mackey, B.; Olney, J.; McKeel, D.; Wozniak, D.; Paul, S.M. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 2000, 97(6), 2892-2897.
Buttini, M.; Yu, G.Q.; Shockley, K.; Huang, Y.D.; Jones, B.; Masliah, E.; Mallory, M.; Yeo, T.; Longo, F.M.; Mucke, L. Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. J. Neurosci., 2002, 22(24), 10539-10548.
Fagan, A.M.; Watson, M.; Parsadanian, M.; Bales, K.R.; Paul, S.M.; Holtzman, D.M. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer’s disease. Neurobiol. Dis., 2002, 9(3), 305-318.
Kim, J.; Basak, J.M.; Holtzman, D.M. The role of apolipoprotein E in Alzheimer’s disease. Neuron, 2009, 63(3), 287-303.
Kuszczyk, M.A.; Sanchez, S.; Pankiewicz, J.; Kim, J.; Duszczyk, M.; Guridi, M.; Asuni, A.A.; Sullivan, P.M.; Holtzman, D.M.; Sadowski, M.J. Blocking the interaction between apolipoprotein E and A beta reduces intraneuronal accumulation of A beta and inhibits synaptic degeneration. Am. J. Pathol., 2013, 182(5), 1750-1768.
Berridge, M.J. Calcium regulation of neural rhythms, memory and Alzheimer’s disease. J. Physiol., 2014, 592(2), 281-293.
Ferreira, A. Calpain dysregulation in Alzheimer’s disease. ISRN Biochem., 2012, 2012, 728571.
McBrayer, M.; Nixon, R.A. Lysosome and calcium dysregulation in Alzheimer’s disease: Partners in crime. Biochem. Soc. Trans., 2013, 41, 1495-1502.
Kurbatskaya, K.; Phillips, E.C.; Croft, C.L.; Dentoni, G.; Hughes, M.M.; Wade, M.A.; Al-Sarraj, S.; Troakes, C.; O’Neill, M.J.; Perez-Nievas, B.G.; Hanger, D.P.; Noble, W. Upregulation of calpain activity precedes tau phosphorylation and loss of synaptic proteins in Alzheimer’s disease brain. Acta Neuropathol. Commun., 2016, 4, 34.
Yamashima, T. Reconsider Alzheimer’s disease by the ‘calpain-cathepsin hypothesis’-A perspective review. Prog. Neurobiol., 2013, 105, 1-23.
Ahmad, F.; Das, D.; Kommaddi, R.P.; Diwakar, L.; Gowaikar, R.; Rupanagudi, K.V.; Bennett, D.A.; Ravindranath, V. Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer’s disease mice and correlates with memory deficits in human subjects. Sci. Rep., 2018, 8, 13119.
Ashraf, J.; Ahmad, J.; Ali, A.; Ul-Haq, Z. Analyzing the behavior of neuronal pathways in Alzheimer’s disease using petri net modeling approach. Front. Neuroinform., 2018, 12, 26.
Ittner, A.; Chua, S.W.; Bertz, J.; Volkerling, A.; van der Hoven, J.; Gladbach, A.; Przybyla, M.; Bi, M.; van Hummel, A.; Stevens, C.H.; Ippati, S.; Suh, L.S.; Macmillan, A.; Sutherland, G.; Kril, J.J.; Silva, A.P.G.; Mackay, J.; Poljak, A.; Delerue, F.; Ke, Y.D.; Ittner, L.M. Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer’s mice. Science, 2016, 354(6314), 904-908.
Nygaard, H.B. Targeting fyn kinase in Alzheimer’s disease. Biol. Psychiatry, 2018, 83(4), 369-376.
Tharp, W.G.; Sarkar, I.N. Origins of amyloid-beta. BMC Genomics, 2013, 14, 290.
Brothers, H.M.; Gosztyla, M.L.; Robinson, S.R. The physiological roles of amyloid-beta peptide hint at new ways to treat Alzheimer’s disease. Front. Aging Neurosci., 2018, 10, 118.
Soscia, S.J.; Kirby, J.E.; Washicosky, K.J.; Tucker, S.M.; Ingelsson, M.; Hyman, B.; Burton, M.A.; Goldstein, L.E.; Duong, S.; Tanzi, R.E.; Moir, R.D. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One, 2010, 5(3), 9505.
Wildburger, N.C.; Esparza, T.J.; LeDuc, R.D.; Fellers, R.T.; Thomas, P.M.; Cairns, N.J.; Kelleher, N.L.; Bateman, R.J.; Brody, D.L. Diversity of amyloid-beta proteoforms in the Alzheimer’s disease brain. Sci. Rep., 2017, 7(1), 9520.
Masters, C.L.; Simms, G.; Weinman, N.A.; Multhaup, G.; Mcdonald, B.L.; Beyreuther, K. Amyloid plaque core protein in Alzheimer-disease and down syndrome. Proc. Natl. Acad. Sci. USA, 1985, 82(12), 4245-4249.
Roche, J.; Shen, Y.; Lee, J.H.; Ying, J.; Bax, A. Monomeric Abeta(1-40) and Abeta(1-42) peptides in solution adopt very similar ramachandran map distributions that closely resemble random coil. Biochemistry, 2016, 55(5), 762-775.
Wei, G.H.; Shea, J.E. Effects of solvent on the structure of the Alzheimer amyloid-beta(25-35) peptide. Biophys. J., 2006, 91(5), 1638-1647.
Zheng, W.H.; Tsai, M.Y.; Wolynes, P.G. Comparing the aggregation free energy landscapes of amyloid beta(1-42) and amyloid beta(1-40). J. Am. Chem. Soc., 2017, 139(46), 16666-16676.
Condello, C.; Stoehr, J. Abeta propagation and strains: Implications for the phenotypic diversity in Alzheimer's disease. Neurobiol.Dis 2018. 109(Pt B), 191-200.
Chiti, F.; Dobson, C.M. Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade. Annu. Rev. Biochem., 2017, 86, 27-68.
Viola, K.L.; Klein, W.L. Amyloid beta oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol., 2015, 129(2), 183-206.
Klein, W.L.; Krafft, G.A.; Finch, C.E. Targeting small A beta oligomers: The solution to an Alzheimer’s disease conundrum? Trends Neurosci., 2001, 24(4), 219-224.
Lambert, M.P.; Barlow, A.K.; Chromy, B.A.; Edwards, C.; Freed, R.; Liosatos, M.; Morgan, T.E.; Rozovsky, I.; Trommer, B.; Viola, K.L.; Wals, P.; Zhang, C.; Finch, C.E.; Krafft, G.A.; Klein, W.L. Diffusible, nonfibrillar ligands derived from A beta(1-42) are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA, 1998, 95(11), 6448-6453.
Hayden, E.Y.; Teplow, D.B. Amyloid beta-protein oligomers and Alzheimer’s disease. Alzheimers Res. Ther., 2013, 5(6), 60.
Mucke, L.; Selkoe, D.J. Neurotoxicity of amyloid beta-protein: Synaptic and network dysfunction. Cold Spring Harb. Perspect. Med., 2012, 2(7), 006338.
Ferreira, S.T.; Klein, W.L. The Abeta oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol. Learn. Mem., 2011, 96(4), 529-543.
Kayed, R.; Head, E.; Thompson, J.L.; McIntire, T.M.; Milton, S.C.; Cotman, C.W.; Glabe, C.G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science, 2003, 300(5618), 486-489.
Gong, Y.; Chang, L.; Viola, K.L.; Lacor, P.N.; Lambert, M.P.; Finch, C.E.; Krafft, G.A.; Klein, W.L. Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc. Natl. Acad. Sci. USA, 2003, 100(18), 10417-10422.
Walsh, D.M.; Klyubin, I.; Fadeeva, J.V.; Cullen, W.K.; Anwyl, R.; Wolfe, M.S.; Rowan, M.J.; Selkoe, D.J. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 2002, 416(6880), 535-539.
Ladiwala, A.R.A.; Litt, J.; Kane, R.S.; Aucoin, D.S.; Smith, S.O.; Ranjan, S.; Davis, J.; Van Nostrand, W.E.; Tessier, P.M. Conformational differences between two amyloid beta oligomers of similar size and dissimilar toxicity. J. Biol. Chem., 2012, 287(29), 24765-24773.
Klyubin, I.; Cullen, W.K.; Hu, N.W.; Rowan, M.J. Alzheimer’s disease A beta assemblies mediating rapid disruption of synaptic plasticity and memory. Mol. Brain, 2012, 5, 25.
Choi, M.L.; Gandhi, S. Crucial role of protein oligomerization in the pathogenesis of Alzheimer’s and Parkinson’s diseases. FEBS J., 2018, 285(19), 3631-3644.
Pickett, E.K.; Koffie, R.M.; Wegmann, S.; Henstridge, C.M.; Herrmann, A.G.; Colom-Cadena, M.; Lleo, A.; Kay, K.R.; Vaught, M.; Soberman, R.; Walsh, D.M.; Hyman, B.T.; Spires-Jones, T.L. Non-fibrillar oligomeric amyloid-beta within synapses. J. Alzheimers Dis., 2016, 53(3), 787-800.
Gouras, G.K.; Tampellini, D.; Takahashi, R.H.; Capetillo-Zarate, E. Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta Neuropathol., 2010, 119(5), 523-541.
Georganopoulou, D.G.; Chang, L.; Nam, J.M.; Thaxton, C.S.; Mufson, E.J.; Klein, W.L.; Mirkin, C.A. Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 2005, 102(7), 2273-2276.
Oddo, S.; Caccamo, A.; Tran, L.; Lambert, M.P.; Glabe, C.G.; Klein, W.L.; LaFerla, F.M. Temporal profile of amyloid-beta (A beta) oligomerization in an in vivo model of Alzheimer disease - A link between A beta and tau pathology. J. Biol. Chem., 2006, 281(3), 1599-1604.
Campioni, S.; Mannini, B.; Zampagni, M.; Pensalfini, A.; Parrini, C.; Evangelisti, E.; Relini, A.; Stefani, M.; Dobson, C.M.; Cecchi, C.; Chiti, F. A causative link between the structure of aberrant protein oligomers and their toxicity. Nat. Chem. Biol., 2010, 6(2), 140-147.
Hamdan, N.; Kritsiligkou, P.; Grant, C.M. ER stress causes widespread protein aggregation and prion formation. J. Cell Biol., 2017, 216(8), 2295-2304.
Horrocks, M.H.; Lee, S.F.; Gandhi, S.; Magdalinou, N.K.; Chen, S.W.; Devine, M.J.; Tosatto, L.; Kjaergaard, M.; Beckwith, J.S.; Zetterberg, H.; Iljina, M.; Cremades, N.; Dobson, C.M.; Wood, N.W.; Klenerman, D. Single-molecule imaging of individual amyloid protein aggregates in human biofluids. ACS Chem. Neurosci., 2016, 7(3), 399-406.
Lesne, S.; Koh, M.T.; Kotilinek, L.; Kayed, R.; Glabe, C.G.; Yang, A.; Gallagher, M.; Ashe, K.H. A specific amyloid-beta protein assembly in the brain impairs memory. Nature, 2006, 440(7082), 352-357.
Wolff, M.; Zhang-Haagen, B.; Decker, C.; Barz, B.; Schneider, M.; Biehl, R.; Radulescu, A.; Strodel, B.; Willbold, D.; Nagel-Steger, L. Abeta42 pentamers/hexamers are the smallest detectable oligomers in solution. Sci. Rep., 2017, 7(1), 2493.
Ahmed, M.; Davis, J.; Aucoin, D.; Sato, T.; Ahuja, S.; Aimoto, S.; Elliott, J.I.; Van Nostrand, W.E.; Smith, S.O. Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils. Nat. Struct. Mol. Biol., 2010, 17(5), 561-567.
Shigemitsu, Y.; Iwaya, N.; Goda, N.; Matsuzaki, M.; Tenno, T.; Narita, A.; Hoshi, M.; Hiroaki, H. Nuclear magnetic resonance evidence for the dimer formation of beta amyloid peptide 1-42 in 1,1,1,3,3,3-hexafluoro-2-propanol. Anal. Biochem., 2016, 498, 59-67.
Brinet, D.; Gaie-Levrel, F.; Delatour, V.; Kaffy, J.; Ongeri, S.; Taverna, M. In vitro monitoring of amyloid beta-peptide oligomerization by Electrospray differential mobility analysis: An alternative tool to evaluate Alzheimer’s disease drug candidates. Talanta, 2017, 165, 84-91.
Acosta, D.M.A.V.; Vega, B.C.; Basurto, J.C.; Morales, L.G.F.; Hernandez, M.C.R. Recent advances by in silico and in vitro studies of amyloid-β 1-42 fibril depicted a s-shape conformation. Int. J. Mol. Sci., 2018, 19(8), E2415.
Tycko, R. Amyloid polymorphism: Structural basis and neurobiological relevance. Neuron, 2015, 86(3), 632-645.
Chiti, F.; Dobson, C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem., 2006, 75, 333-366.
Galzitskaya, O.V.; Selivanova, O.M. Rosetta stone for amyloid fibrils: The key role of ring-like oligomers in amyloidogenesis. J. Alzheimers Dis., 2017, 59(3), 785-795.
Cohen, S.I.; Linse, S.; Luheshi, L.M.; Hellstrand, E.; White, D.A.; Rajah, L.; Otzen, D.E.; Vendruscolo, M.; Dobson, C.M.; Knowles, T.P. Proliferation of amyloid-beta42 aggregates occurs through a secondary nucleation mechanism. Proc. Natl. Acad. Sci. USA, 2013, 110(24), 9758-9763.
Kovacs, G.G.; Lutz, M.I.; Ricken, G.; Strobel, T.; Hoftberger, R.; Preusser, M.; Regelsberger, G.; Honigschnabl, S.; Reiner, A.; Fischer, P.; Budka, H.; Hainfellner, J.A. Dura mater is a potential source of A beta seeds. Acta Neuropathol., 2016, 131(6), 911-923.
Dovidchenko, N.V.; Glyakina, A.V.; Selivanova, O.M.; Grigorashvili, E.I.; Suvorina, M.Y.; Dzhus, U.F.; Mikhailina, A.O.; Shiliaev, N.G.; Marchenkov, V.V.; Surin, A.K.; Galzitskaya, O.V. One of the possible mechanisms of amyloid fibrils formation based on the sizes of primary and secondary folding nuclei of Abeta40 and Abeta42. J. Struct. Biol., 2016, 194(3), 404-414.
Nielsen, E.H.; Nybo, M.; Svehag, S.E. Electron microscopy of prefibrillar structures and amyloid fibrils. Methods Enzymol., 1999, 309, 491-496.
Barz, B.; Strodel, B. Understanding amyloid-beta oligomerization at the molecular level: The role of the fibril surface. Chemistry, 2016, 22(26), 8768-8772.
Linse, S. Monomer-dependent secondary nucleation in amyloid formation. Biophys. Rev., 2017, 9(4), 329-338.
Tornquist, M.; Michaels, T.C.T.; Sanagavarapu, K.; Yang, X.; Meisl, G.; Cohen, S.I.A.; Knowles, T.P.J.; Linse, S. Secondary nucleation in amyloid formation. Chem. Commun. (Camb.), 2018, 54(63), 8667-8684.
Qiang, W.; Kelley, K.; Tycko, R. Polymorph-specific kinetics and thermodynamics of beta-amyloid fibril growth. J. Am. Chem. Soc., 2013, 135(18), 6860-6871.
Sunde, M.; Blake, C. The structure of amyloid fibrils by electron microscopy and X-ray diffraction. Adv. Protein Chem., 1997, 50, 123-159.
Ruggeri, F.S.; Habchi, J.; Cerreta, A.; Dietler, G. AFM-based single molecule techniques: unraveling the amyloid pathogenic species. Curr. Pharm. Des., 2016, 22(26), 3950-3970.
Lomont, J.P.; Rich, K.L.; Maj, M.; Ho, J.J.; Ostrander, J.S.; Zanni, M.T. Spectroscopic signature for stable beta-amyloid fibrils versus beta-sheet-rich oligomers. J. Phys. Chem. B, 2018, 122(1), 144-153.
Colvin, M.T.; Silvers, R.; Ni, Q.Z.; Can, T.V.; Sergeyev, I.; Rosay, M.; Donovan, K.J.; Michael, B.; Wall, J.; Linse, S.; Griffin, R.G. Atomic resolution structure of monomorphic a beta(42) amyloid fibrils. J. Am. Chem. Soc., 2016, 138(30), 9663-9674.
Lu, J.X.; Qiang, W.; Yau, W.M.; Schwieters, C.D.; Meredith, S.C.; Tycko, R. Molecular structure of beta-amyloid fibrils in Alzheimer’s disease brain tissue. Cell, 2013, 154(6), 1257-1268.
Walti, M.A.; Ravotti, F.; Arai, H.; Glabe, C.G.; Wall, J.S.; Bockmann, A.; Guntert, P.; Meier, B.H.; Riek, R. Atomic-resolution structure of a disease-relevant A beta(1-42) amyloid fibril. Proc. Natl. Acad. Sci. USA, 2016, 113(34), 4976-4984.
Luhrs, T.; Ritter, C.; Adrian, M.; Riek-Loher, D.; Bohrmann, B.; Doeli, H.; Schubert, D.; Riek, R. 3D structure of Alzheimer’s amyloid-beta(1-42) fibrils. Proc. Natl. Acad. Sci. USA, 2005, 102(48), 17342-17347.
Grasso, G.; Rebella, M.; Muscat, S.; Morbiducci, U.; Tuszynski, J.; Danani, A.; Deriu, M.A. Conformational dynamics and stability of U-shaped and s-shaped amyloid beta assemblies. Int. J. Mol. Sci., 2018, 19(2), 571.
Qiang, W.; Yau, W.M.; Lu, J.X.; Collinge, J.; Tycko, R. Structural variation in amyloid-beta fibrils from Alzheimer’s disease clinical subtypes. Nature, 2017, 541(7636), 217-221.
Watanabe-Nakayama, T.; Ono, K.; Itami, M.; Takahashi, R.; Teplow, D.B.; Yamada, M. High-speed atomic force microscopy reveals structural dynamics of amyloid beta1-42 aggregates. Proc. Natl. Acad. Sci. USA, 2016, 113(21), 5835-5840.
Cohen, M.L.; Kim, C.; Haldiman, T.; ElHag, M.; Mehndiratta, P.; Pichet, T.; Lissemore, F.; Shea, M.; Cohen, Y.; Chen, W.; Blevins, J.; Appleby, B.S.; Surewicz, K.; Surewicz, W.K.; Sajatovic, M.; Tatsuoka, C.; Zhang, S.L.; Mayo, P.; Butkiewicz, M.; Haines, J.L.; Lerner, A.J.; Safar, J.G. Rapidly progressive Alzheimer’s disease features distinct structures of amyloid-beta. Brain, 2015, 138, 1009-1022.
Treusch, S.; Cyr, D.M.; Lindquist, S. Amyloid deposits: Protection against toxic protein species? Cell Cycle, 2009, 8(11), 1668-1674.
Stroo, E.; Koopman, M.; Nollen, E.A.; Mata-Cabana, A. Cellular regulation of amyloid formation in aging and disease. Front. Neurosci., 2017, 11, 64.
Liu, P.; Reed, M.N.; Kotilinek, L.A.; Grant, M.K.; Forster, C.L.; Qiang, W.; Shapiro, S.L.; Reichl, J.H.; Chiang, A.C.; Jankowsky, J.L.; Wilmot, C.M.; Cleary, J.P.; Zahs, K.R.; Ashe, K.H. Quaternary structure defines a large class of amyloid-beta oligomers neutralized by sequestration. Cell Reports, 2015, 11(11), 1760-1771.
Yang, X.; Meisl, G.; Frohm, B.; Thulin, E.; Knowles, T.P.J.; Linse, S. On the role of sidechain size and charge in the aggregation of A beta 42 with familial mutations. Proc. Natl. Acad. Sci. USA, 2018, 115(26), 5849-5858.
Hatami, A.; Monjazeb, S.; Milton, S.; Glabe, C.G. Familial Alzheimer’s disease mutations within the amyloid precursor protein alter the aggregation and conformation of the amyloid-beta peptide. J. Biol. Chem., 2017, 292(8), 3172-3185.
Di Fede, G.; Catania, M.; Morbin, M.; Rossi, G.; Suardi, S.; Mazzoleni, G.; Merlin, M.; Giovagnoli, A.R.; Prioni, S.; Erbetta, A.; Falcone, C.; Gobbi, M.; Colombo, L.; Bastone, A.; Beeg, M.; Manzoni, C.; Francescucci, B.; Spagnoli, A.; Cantu, L.; Del Favero, E.; Levy, E.; Salmona, M.; Tagliavini, F. A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science, 2009, 323(5920), 1473-1477.
Janssen, J.C.; Beck, J.A.; Campbell, T.A.; Dickinson, A.; Fox, N.C.; Harvey, R.J.; Houlden, H.; Rossor, M.N.; Collinge, J. Early onset familial Alzheimer’s disease - Mutation frequency in 31 families. Neurology, 2003, 60(2), 235-239.
Ono, K.; Condron, M.M.; Teplow, D.B. Effects of the English (H6R) and Tottori (D7N) familial Alzheimer disease mutations on amyloid beta-protein assembly and toxicity. J. Biol. Chem., 2010, 285(30), 23184-23195.
Wakutani, Y.; Watanabe, K.; Adachi, Y.; Wada-Isoe, K.; Urakami, K.; Ninomiya, H.; Saido, T.C.; Hashimoto, T.; Iwatsubo, T.; Nakashima, K. Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry, 2004, 75(7), 1039-1042.
Chen, W.T.; Hong, C.J.; Lin, Y.T.; Chang, W.H.; Huang, H.T.; Liao, J.Y.; Chang, Y.J.; Hsieh, Y.F.; Cheng, C.Y.; Liu, H.C.; Chen, Y.R.; Cheng, I.H. Amyloid-beta (A beta) D7H mutation increases oligomeric A beta 42 and alters properties of a beta-zinc/copper assemblies. PLoS One, 2012, 7(4), e35807.
Zhou, L.; Brouwers, N.; Benilova, I.; Vandersteen, A.; Mercken, M.; Van Laere, K.; Van Damme, P.; Demedts, D.; Van Leuven, F.; Sleegers, K.; Broersen, K.; Van Broeckhoven, C.; Vandenberghe, R.; De Strooper, B. Amyloid precursor protein mutation E682K at the alternative beta-secretase cleavage beta '-site increases A beta generation. EMBO Mol. Med., 2011, 3(5), 291-302.
Hendriks, L.; van Duijn, C.M.; Cras, P.; Cruts, M.; Van Hul, W.; van Harskamp, F.; Warren, A.; McInnis, M.G.; Antonarakis, S.E.; Martin, J.J. et al.Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat. Genet., 1992, 1(3), 218-221.
Nilsberth, C.; Westlind-Danielsson, A.; Eckman, C.B.; Condron, M.M.; Axelman, K.; Forsell, C.; Stenh, C.; Luthman, J.; Teplow, D.B.; Younkin, S.G.; Naslund, J.; Lannfelt, L. The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat. Neurosci., 2001, 4(9), 887-893.
Levy, E.; Carman, M.D.; Fernandez-Madrid, I.J.; Power, M.D.; Lieberburg, I.; van Duinen, S.G.; Bots, G.T.; Luyendijk, W.; Frangione, B. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science, 1990, 248(4959), 1124-1126.
Miravalle, L.; Tokuda, T.; Chiarle, R.; Giaccone, G.; Bugiani, O.; Tagliavini, F.; Frangione, B.; Ghiso, J. Substitutions at codon 22 of Alzheimer’s A beta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J. Biol. Chem., 2000, 275(35), 27110-27116.
Grabowski, T.J.; Cho, H.S.; Vonsattel, J.P.G.; Rebeck, G.W.; Greenberg, S.M. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann. Neurol., 2001, 49(6), 697-705.
Kumar-Singh, S.; Cras, P.; Wang, R.; Kros, J.M.; van Swieten, J.; Lubke, U.; Ceuterick, C.; Serneels, S.; Vennekens, K.; Timmermans, J.P.; Van Marck, E.; Martin, J.J.; van Duijn, C.M.; Van Broeckhoven, C. Dense-core senile plaques in the Flemish variant of Alzheimer’s disease are vasocentric. Am. J. Pathol., 2002, 161(2), 507-520.
Roks, G.; Van Harskamp, F.; De Koning, I.; Cruts, M.; De Jonghe, C.; Kumar-Singh, S.; Tibben, A.; Tanghe, H.; Niermeijer, M.F.; Hofman, A.; Van Swieten, J.C.; Van Broeckhoven, C.; Van Duijn, C.M. Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692). Brain, 2000, 123, 2130-2140.
Yagi-Utsumi, M.; Dobson, C.M. Conformational effects of the A21G flemish mutation on the aggregation of amyloid beta peptide. Biol. Pharm. Bull., 2015, 38(10), 1668-1672.
Tomiyama, T.; Nagata, T.; Shimada, H.; Teraoka, R.; Fukushima, A.; Kanemitsu, H.; Takuma, H.; Kuwano, R.; Imagawa, M.; Ataka, S.; Wada, Y.; Yoshioka, E.; Nishizaki, T.; Watanabe, Y.; Mori, H. A new amyloid mu variant favoring oligomerization in Alzheimer’s-type dementia. Ann. Neurol., 2008, 63(3), 377-387.
Obici, L.; Demarchi, A.; de Rosa, G.; Bellotti, V.; Marciano, S.; Donadei, S.; Arbustini, E.; Palladini, G.; Diegoli, M.; Genovese, E.; Ferrari, G.; Coverlizza, S.; Merlini, G. A novel A beta PP mutation exclusively associated with cerebral amyloid angiopathy. Ann. Neurol., 2005, 58(4), 639-644.
De Strooper, B.; Karran, E. The cellular phase of Alzheimer’s disease. Cell, 2016, 164(4), 603-615.
Penke, B.; Toth, A.M.; Foldi, I.; Szucs, M.; Janaky, T. Intraneuronal beta-amyloid and its interactions with proteins and subcellular organelles. Electrophoresis, 2012, 33(24), 3608-3616.
Amadoro, G.; Corsetti, V.; Atlante, A.; Florenzano, F.; Capsoni, S.; Bussani, R.; Mercanti, D.; Calissano, P. Interaction between NH2-tau fragment and A beta in Alzheimer's disease mitochondria contributes to the synaptic deterioration.Neurobiol. Aging, 2012. 33(4), 833.el-833.e25
Schneider, A.; Biernat, J.; von Bergen, M.; Mandelkow, E.; Mandelkow, E.M. Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry, 1999, 38(12), 3549-3558.
Tanimukai, H.; Grundke-Iqbal, I.; Iqbal, K. Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease. Am. J. Pathol., 2005, 166(6), 1761-1771.
Wang, Y.P.; Martinez-Vicente, M.; Kruger, U.; Kaushik, S.; Wong, E.; Mandelkow, E.M.; Cuervo, A.M.; Mandelkow, E. Tau fragmentation, aggregation and clearance: The dual role of lysosomal processing. Hum. Mol. Genet., 2009, 18(21), 4153-4170.
Mukrasch, M.D.; Biernat, J.; von Bergen, M.; Griesinger, C.; Mandelkow, E.; Zweckstetter, M. Sites of tau important for aggregation populate beta-structure and bind to microtubules and polyanions. J. Biol. Chem., 2005, 280(26), 24978-24986.
Wegmann, S.; Jung, Y.J.; Chinnathambi, S.; Mandelkow, E.M.; Mandelkow, E.; Muller, D.J. Human tau isoforms assemble into ribbon-like fibrils that display polymorphic structure and stability. J. Biol. Chem., 2010, 285(35), 27302-27313.
Perez, M.J.; Jara, C.; Quintanilla, R.A. Contribution of tau pathology to mitochondrial impairment in neurodegeneration. Front. Neurosci., 2018, 12, 441.
Chang, H.Y.; Sang, T.K.; Chiang, A.S. Untangling the Tauopathy for Alzheimer’s disease and parkinsonism. J. Biomed. Sci., 2018, 25(1), 54.
Cieri, D.; Vicario, M.; Vallese, F.; D’Orsi, B.; Berto, P.; Grinzato, A.; Catoni, C.; De Stefani, D.; Rizzuto, R.; Brini, M.; Cali, T. Tau localises within mitochondrial sub-compartments and its caspase cleavage affects ER-mitochondria interactions and cellular Ca2+ handling. BBA-Mol. Basis. Dis., 2018, 1864(10), 3247-3256.
Ittner, A.; Ittner, L.M. Dendritic tau in Alzheimer’s disease. Neuron, 2018, 99(1), 13-27.
Ittner, L.M.; Ke, Y.D.; Delerue, F.; Bi, M.A.; Gladbach, A.; van Eersel, J.; Wolfing, H.; Chieng, B.C.; Christie, M.J.; Napier, I.A.; Eckert, A.; Staufenbiel, M.; Hardeman, E.; Gotz, J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell, 2010, 142(3), 387-397.
Lam, B.; Masellis, M.; Freedman, M.; Stuss, D.T.; Black, S.E. Clinical, imaging, and pathological heterogeneity of the Alzheimer’s disease syndrome. Alzheimers Res. Ther., 2013, 5(1), 1.
Reiman, E.M.; Langbaum, J.B.S.; Tariot, P.N. Alzheimer’s prevention initiative: A proposal to evaluate presymptomatic treatments as quickly as possible. Biomarkers Med., 2010, 4(1), 3-14.
Villemagne, V.L.; Dore, V.; Burnham, S.C.; Masters, C.L.; Rowe, C.C. Imaging tau and amyloid-beta proteinopathies in Alzheimer disease and other conditions. Nat. Rev. Neurol., 2018, 14(4), 225-236.
Kantarci, K.; Lowe, V.J.; Boeve, B.F.; Senjem, M.L.; Tosakulwong, N.; Lesnick, T.G.; Spychalla, A.J.; Gunter, J.L.; Fields, J.A.; Graff-Radford, J.; Ferman, T.J.; Jones, D.T.; Murray, M.E.; Knopman, D.S.; Jack, C.R., Jr; Petersen, R.C. AV-1451 tau and beta-amyloid positron emission tomography imaging in dementia with Lewy bodies. Ann. Neurol., 2017, 81(1), 58-67.
Fagan, A.M.; Mintun, M.A.; Mach, R.H.; Lee, S.Y.; Dence, C.S.; Shah, A.R.; LaRossa, G.N.; Spinner, M.L.; Klunk, W.E.; Mathis, C.A.; DeKosky, S.T.; Morris, J.C.; Holtzman, D.M. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann. Neurol., 2006, 59(3), 512-519.
Morris, J.C.; Roe, C.M.; Xiong, C.; Fagan, A.M.; Goate, A.M.; Holtzman, D.M.; Mintun, M.A. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol., 2010, 67(1), 122-131.
Jack, C.R., Jr; Wiste, H.J.; Vemuri, P.; Weigand, S.D.; Senjem, M.L.; Zeng, G.; Bernstein, M.A.; Gunter, J.L.; Pankratz, V.S.; Aisen, P.S.; Weiner, M.W.; Petersen, R.C.; Shaw, L.M.; Trojanowski, J.Q.; Knopman, D.S. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease. Brain, 2010, 133(11), 3336-3348.
Nakamura, A.; Kaneko, N.; Villemagne, V.L.; Kato, T.; Doecke, J.; Dore, V.; Fowler, C.; Li, Q.X.; Martins, R.; Rowe, C.; Tomita, T.; Matsuzaki, K.; Ishii, K.; Ishii, K.; Arahata, Y.; Iwamoto, S.; Ito, K.; Tanaka, K.; Masters, C.L.; Yanagisawa, K. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature, 2018, 554(7691), 249-254.
Nabers, A.; Perna, L.; Lange, J.; Mons, U.; Schartner, J.; Guldenhaupt, J.; Saum, K.U.; Janelidze, S.; Holleczek, B.; Rujescu, D.; Hansson, O.; Gerwert, K.; Brenner, H. Amyloid blood biomarker detects Alzheimer’s disease. EMBO Mol. Med., 2018, 10(5), 8763.
Teich, A.F.; Arancio, O. Is the amyloid hypothesis of Alzheimer’s disease therapeutically relevant? Biochem. J., 2012, 446, 165-177.
Luo, J.H.; Warmlander, S.K.T.S.; Graslund, A.; Abrahams, J.P. Cross-interactions between the Alzheimer disease amyloid-beta peptide and other amyloid proteins: A further aspect of the amyloid cascade hypothesis. J. Biol. Chem., 2016, 291(32), 16485-16493.
Salazar, S.V.; Strittmatter, S.M. Cellular prion protein as a receptor for amyloid-beta oligomers in Alzheimer’s disease. Biochem. Biophys. Res. Commun., 2017, 483(4), 1143-1147.
Jembrek, M.J.; Slade, N.; Hof, P.R.; Simic, G. The interactions of p53 with tau and A beta as potential therapeutic targets for Alzheimer’s disease. Prog. Neurobiol., 2018, 168, 104-127.
Mesulam, M.M. Neuroplasticity failure in Alzheimer’s disease: Bridging the gap between plaques and tangles. Neuron, 1999, 24(3), 521-529.
Kuperstein, I.; Broersen, K.; Benilova, I.; Rozenski, J.; Jonekheere, W.; Debulpaep, M.; Vandersteen, A.; Segers-Nolten, I.; Van der Werf, K.; Subramaniam, V.; Braeken, D.; Callewaert, G.; Bartic, C.; D’Hooge, R.; Martins, I.C.; Rousseau, F.; Schymkowitz, J.; De Strooper, B. Neurotoxicity of Alzheimer’s disease A beta peptides is induced by small changes in the A beta(42) to A beta(40) ratio. EMBO J., 2010, 29(19), 3408-3420.
Szaruga, M.; Veugelen, S.; Benurwar, M.; Lismont, S.; Sepulveda-Falla, D.; Lleo, A.; Ryan, N.S.; Lashley, T.; Fox, N.C.; Murayama, S.; Gijsen, H.; De Strooper, B.; Chavez-Gutierrez, L. Qualitative changes in human gamma-secretase underlie familial Alzheimer’s disease. J. Exp. Med., 2015, 212(12), 2003-2013.
Labbadia, J.; Morimoto, R.I. The biology of proteostasis in aging and disease. Annu. Rev. Biochem., 2015, 84, 435-464.
Crary, J.F.; Trojanowski, J.Q.; Schneider, J.A.; Abisambra, J.F.; Abner, E.L.; Alafuzoff, I.; Arnold, S.E.; Attems, J.; Beach, T.G.; Bigio, E.H.; Cairns, N.J.; Dickson, D.W.; Gearing, M.; Grinberg, L.T.; Hof, P.R.; Hyman, B.T.; Jellinger, K.; Jicha, G.A.; Kovacs, G.G.; Knopman, D.S.; Kofler, J.; Kukull, W.A.; Mackenzie, I.R.; Masliah, E.; McKee, A.; Montine, T.J.; Murray, M.E.; Neltner, J.H.; Santa-Maria, I.; Seeley, W.W.; Serrano-Pozo, A.; Shelanski, M.L.; Stein, T.; Takao, M.; Thal, D.R.; Toledo, J.B.; Troncoso, J.C.; Vonsattel, J.P.; White, C.L.; Wisniewski, T.; Woltjer, R.L.; Yamada, M.; Nelson, P.T. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol., 2014, 128(6), 755-766.
Khan, U.A.; Liu, L.; Provenzano, F.A.; Berman, D.E.; Profaci, C.P.; Sloan, R.; Mayeux, R.; Duff, K.E.; Small, S.A. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease. Nat. Neurosci., 2014, 17(2), 304-311.
Karran, E.; Mercken, M.; De Strooper, B. The amyloid cascade hypothesis for Alzheimer’s disease: An appraisal for the development of therapeutics. Nat. Rev. Drug Discov., 2011, 10(9), 698-712.
Pignataro, A.; Middei, S. Trans-synaptic spread of amyloid-beta in Alzheimer’s disease: Paths to beta-amyloidosis. Neural Plast., 2017, 2017, 5281829.
Perea, J.R.; Llorens-Martin, M.; Avila, J.; Bolos, M. The role of microglia in the spread of tau: relevance for tauopathies. Front. Cell. Neurosci., 2018, 12, 172.
Iaccarino, L.; Tammewar, G.; Ayakta, N.; Baker, S.L.; Bejanin, A.; Boxer, A.L.; Gorno-Tempini, M.L.; Janabi, M.; Kramer, J.H.; Lazaris, A.; Lockhart, S.N.; Miller, B.L.; Miller, Z.A.; O’Neil, J.P.; Ossenkoppele, R.; Rosen, H.J.; Schonhaut, D.R.; Jagust, W.J.; Rabinovici, G.D. Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer’s Disease. Neuroimage Clin., 2018, 17, 452-464.
Scannevin, R.H. Therapeutic strategies for targeting neurodegenerative protein misfolding disorders. Curr. Opin. Chem. Biol., 2018, 44, 66-74.
Mullard, A. Alzheimer amyloid hypothesis lives on. Nat. Rev. Drug Discov., 2017, 16(1), 3-5.
Cummings, J.; Lee, G.; Mortsdorf, T.; Ritter, A.; Zhong, K. Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement. (N. Y.), 2017, 3(3), 367-384.
Cummings, J.; Lee, G.; Ritter, A.; Zhong, K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement. (N. Y.), 2018, 4, 195-214.
Kumar, D.; Ganeshpurkar, A.; Kumar, D.; Modi, G.; Gupta, S.K.; Singh, S.K. Secretase inhibitors for the treatment of Alzheimer’s disease: Long road ahead. Eur. J. Med. Chem., 2018, 148, 436-452.
Peron, R.; Vatanabe, I.P.; Manzine, P.R.; Camins, A.; Cominetti, M.R. Alpha-secretase ADAM10 regulation: Insights into Alzheimer’s disease treatment. Pharmaceuticals, 2018, 11(1), 12.
van Dyck, C.H. Anti-amyloid-beta monoclonal antibodies for Alzheimer’s disease: Pitfalls and promise. Biol. Psychiatry, 2018, 83(4), 311-319.
Lannfelt, L.; Moller, C.; Basun, H.; Osswald, G.; Sehlin, D.; Satlin, A.; Logovinsky, V.; Gellerfors, P. Perspectives on future Alzheimer therapies: Amyloid-beta protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res. Ther., 2014, 6(2), 16.
Vounatsos, M.; Naito, H. Recent developments in Therapeutics. Alzheimer’s Association International Conference, 2018, pp. (20-26 Jul), Presentation number:DT-01-07.
Parsons, C.G.; Rammes, G. Preclinical to phase II amyloid beta (A) peptide modulators under investigation for Alzheimer’s disease. Expert Opin. Investig. Drugs, 2017, 26(5), 579-591.
Congdon, E.E.; Sigurdsson, E.M. Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol., 2018, 14(7), 399-415.
Khan, R.I.; Nirzhor, S.S.R.; Rashid, B. A closer look into the role of protein Tau in the identification of promising therapeutic targets for Alzheimer’s disease. Brain Sci., 2018, 8(9), 162.
Medina, M. An overview on the clinical development of tau-based therapeutics. Int. J. Mol. Sci., 2018, 19(4), 1160.
Sahoo, A.K.; Dandapat, J.; Dash, U.C.; Kanhar, S. Features and outcomes of drugs for combination therapy as multi-targets strategy to combat Alzheimer’s disease. J. Ethnopharmacol., 2018, 6(215), 42-73.
Zhang, Z.; Nie, S.; Chen, L. Targeting prion-like protein spreading in neurodegenerative diseases. Neural Regen. Res., 2018, 13(11), 1875-1878.
Kasza, A.; Hunya, A.; Frank, Z.; Fulop, F.; Torok, Z.; Balogh, G.; Santha, M.; Bernath, S.; Blundell, K.L.I.M.; Prodromou, C.; Horvath, I.; Zeiler, H.J.; Hooper, P.L.; Vigh, L.; Penke, B. Dihydropyridine derivatives modulate heat shock responses and have a neuroprotective effect in a transgenic mouse model of Alzheimer’s disease. J. Alzheimers Dis., 2016, 53(2), 557-571.
Carrillo, M.C.; Dean, R.A.; Nicolas, F.; Miller, D.S.; Berman, R.; Khachaturian, Z.; Bain, L.J.; Schindler, R.; Knopman, D. Revisiting the framework of the National Institute on Aging-Alzheimer’s Association diagnostic criteria. Alzheimers Dement., 2013, 9(5), 594-601.
Hickman, R.A.; Faustin, A.; Wisniewski, T. Alzheimer disease and its growing epidemic risk factors, biomarkers, and the urgent need for therapeutics. Neurol. Clin., 2016, 34(4), 941-953.
Sweeney, M.D.; Sagare, A.P.; Zlokovic, B.V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol., 2018, 14(3), 133-150.
Peacock, M.L.; Warren, J.T.; Roses, A.D.; Fink, J.K. Novel polymorphism in the a4-region of the amyloid precursor protein gene in a patient without Alzheimers-disease. Neurology, 1993, 43(6), 1254-1256.
Petersen, A.J.; Wassarman, D.A. Drosophila innate immune response pathways moonlight in neurodegeneration. Fly , 2012, 6(3), 169-172.
Kamino, K.; Orr, H.T.; Payami, H.; Wijsman, E.M.; Alonso, M.E.; Pulst, S.M.; Anderson, L.; Odahl, S.; Nemens, E.; White, J.A.; Sadovnick, A.D.; Ball, M.J.; Kaye, J.; Warren, A.; Mcinnis, M.; Antonarakis, S.E.; Korenberg, J.R.; Sharma, V.; Kukull, W.; Larson, E.; Heston, L.L.; Martin, G.M.; Bird, T.D.; Schellenberg, G.D. Linkage and mutational analysis of familial Alzheimer-disease kindreds for the APP gene region. Am. J. Hum. Genet., 1992, 51(5), 998-1014.

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Year: 2019
Page: [577 - 599]
Pages: 23
DOI: 10.2174/1389203720666190103123434
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