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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

The Pathogenesis Mechanism, Structure Properties, Potential Drugs and Therapeutic Nanoparticles against the Small Oligomers of Amyloid-β

Author(s): Ke Wang, Liu Na and Mojie Duan*

Volume 21, Issue 2, 2021

Published on: 16 September, 2020

Page: [151 - 167] Pages: 17

DOI: 10.2174/1568026620666200916123000

Price: $65


Alzheimer’s Disease (AD) is a devastating neurodegenerative disease that affects millions of people in the world. The abnormal aggregation of amyloid β protein (Aβ) is regarded as the key event in AD onset. Meanwhile, the Aβ oligomers are believed to be the most toxic species of Aβ. Recent studies show that the Aβ dimers, which are the smallest form of Aβ oligomers, also have the neurotoxicity in the absence of other oligomers in physiological conditions. In this review, we focus on the pathogenesis, structure and potential therapeutic molecules against small Aβ oligomers, as well as the nanoparticles (NPs) in the treatment of AD. In this review, we firstly focus on the pathogenic mechanism of Aβ oligomers, especially the Aβ dimers. The toxicity of Aβ dimer or oligomers, which attributes to the interactions with various receptors and the disruption of membrane or intracellular environments, were introduced. Then the structure properties of Aβ dimers and oligomers are summarized. Although some structural information such as the secondary structure content is characterized by experimental technologies, detailed structures are still absent. Following that, the small molecules targeting Aβ dimers or oligomers are collected; nevertheless, all of these ligands have failed to come into the market due to the rising controversy of the Aβ-related “amyloid cascade hypothesis”. At last, the recent progress about the nanoparticles as the potential drugs or the drug delivery for the Aβ oligomers are present.

Keywords: Alzheimer's disease, Amyloid-β, Oligomer, Dimer, Senile plaques, Pathogenesis.

Graphical Abstract
Prince, M. World alzheimer report 2015: the global impact of dementia, 2015. Available from:
Blennow, K.; de Leon, M.J.; Zetterberg, H. Alzheimer’s disease. Lancet, 2006, 368(9533), 387-403.
[] [PMID: 16876668]
Alzheimer’s Association. 2014 Alzheimer’s disease facts and figures. Alzheimers Dement., 2014, 10(2), 47-92.
Awasthi, M.; Singh, S.; Pandey, V.P.; Dwivedi, U.N. Alzheimer’s disease: An overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products. J. Neurol. Sci., 2016, 361, 256-271.
[] [PMID: 26810552]
Murphy, M.P.; LeVine, H., III Alzheimer’s disease and the amyloid-beta peptide. J. Alzheimers Dis., 2010, 19(1), 311-323.
[] [PMID: 20061647]
Blennow, K.; De Meyer, G.; Hansson, O.; Minthon, L.; Wallin, A.; Zetterberg, H.; Lewczuk, P.; Vanderstichele, H.; Vanmechelen, E.; Kornhuber, J.; Wiltfang, J.; Heuser, I.; Maier, W.; Luckhaus, C.; Rüther, E.; Hüll, M.; Jahn, H.; Gertz, H.J.; Frölich, L.; Hampel, H.; Pernetzki, R. KND-Study Group. Evolution of Abeta42 and Abeta40 levels and Abeta42/Abeta40 ratio in plasma during progression of Alzheimer’s disease: a multicenter assessment. J. Nutr. Health Aging, 2009, 13(3), 205-208.
[] [PMID: 19262954]
Jan, A.; Gokce, O.; Luthi-Carter, R.; Lashuel, H.A. The ratio of monomeric to aggregated forms of Abeta40 and Abeta42 is an important determinant of amyloid-beta aggregation, fibrillogenesis, and toxicity. J. Biol. Chem., 2008, 283(42), 28176-28189.
[] [PMID: 18694930]
Chabrier, M.A.; Blurton-Jones, M.; Agazaryan, A.A.; Nerhus, J.L.; Martinez-Coria, H.; LaFerla, F.M. Soluble aβ promotes wild-type tau pathology in vivo. J. Neurosci., 2012, 32(48), 17345-17350.
[] [PMID: 23197725]
Sondag, C.M.; Dhawan, G.; Combs, C.K. Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J. Neuroinflammation, 2009, 6, 1.
[] [PMID: 19123954]
Cheignon, C.; Tomas, M.; Bonnefont-Rousselot, D.; Faller, P.; Hureau, C.; Collin, F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol., 2018, 14, 450-464.
[] [PMID: 29080524]
Selkoe, D.J. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav. Brain Res., 2008, 192(1), 106-113.
[] [PMID: 18359102]
Dinamarca, M.C.; Ríos, J.A.; Inestrosa, N.C. Postsynaptic receptors for arnyloid-beta oligomers as mediators of neuronal damage in Alzheimer’s disease. Front. Physiol., 2012, 3, 464.
[] [PMID: 23267328]
Ferreira, S.T.; Klein, W.L. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol. Learn. Mem., 2011, 96(4), 529-543.
[] [PMID: 21914486]
De Felice, F.G.; Velasco, P.T.; Lambert, M.P.; Viola, K.; Fernandez, S.J.; Ferreira, S.T.; Klein, W.L. Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem., 2007, 282(15), 11590-11601.
[] [PMID: 17308309]
Zempel, H.; Luedtke, J.; Kumar, Y.; Biernat, J.; Dawson, H.; Mandelkow, E.; Mandelkow, E.M. Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. EMBO J., 2013, 32(22), 2920-2937.
[] [PMID: 24065130]
Larson, M.E.; Lesné, S.E. Soluble Aβ oligomer production and toxicity. J. Neurochem., 2012, 120(Suppl. 1), 125-139.
[] [PMID: 22121920]
Müller-Schiffmann, A.; Herring, A.; Abdel-Hafiz, L.; Chepkova, A.N.; Schäble, S.; Wedel, D.; Horn, A.H.; Sticht, H.; de Souza Silva, M.A.; Gottmann, K.; Sergeeva, O.A.; Huston, J.P.; Keyvani, K.; Korth, C. Amyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity. Brain, 2016, 139(Pt 2), 509-525.
[] [PMID: 26657517]
Shankar, G.M.; Bloodgood, B.L.; Townsend, M.; Walsh, D.M.; Selkoe, D.J.; Sabatini, B.L. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci., 2007, 27(11), 2866-2875.
[] [PMID: 17360908]
Shankar, G.M.; Li, S.; Mehta, T.H.; Garcia-Munoz, A.; Shepardson, N.E.; Smith, I.; Brett, F.M.; Farrell, M.A.; Rowan, M.J.; Lemere, C.A.; Regan, C.M.; Walsh, D.M.; Sabatini, B.L.; Selkoe, D.J. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med., 2008, 14(8), 837-842.
[] [PMID: 18568035]
Jin, M.; Shepardson, N.; Yang, T.; Chen, G.; Walsh, D.; Selkoe, D.J. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl. Acad. Sci. USA, 2011, 108(14), 5819-5824.
[] [PMID: 21421841]
Bloom, G.S. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol., 2014, 71(4), 505-508.
[] [PMID: 24493463]
Shaw, L.M.; Vanderstichele, H.; Knapik-Czajka, M.; Clark, C.M.; Aisen, P.S.; Petersen, R.C.; Blennow, K.; Soares, H.; Simon, A.; Lewczuk, P.; Dean, R.; Siemers, E.; Potter, W.; Lee, V.M.; Trojanowski, J.Q. Alzheimer’s Disease Neuroimaging Initiative. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann. Neurol., 2009, 65(4), 403-413.
[] [PMID: 19296504]
Sperling, R.A.; Aisen, P.S.; Beckett, L.A.; Bennett, D.A.; Craft, S.; Fagan, A.M.; Iwatsubo, T.; Jack, C.R., Jr; Kaye, J.; Montine, T.J.; Park, D.C.; Reiman, E.M.; Rowe, C.C.; Siemers, E.; Stern, Y.; Yaffe, K.; Carrillo, M.C.; Thies, B.; Morrison-Bogorad, M.; Wagster, M.V.; Phelps, C.H. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement., 2011, 7(3), 280-292.
[] [PMID: 21514248]
McKhann, G.M.; Knopman, D.S.; Chertkow, H.; Hyman, B.T.; Jack, C.R., Jr; Kawas, C.H.; Klunk, W.E.; Koroshetz, W.J.; Manly, J.J.; Mayeux, R.; Mohs, R.C.; Morris, J.C.; Rossor, M.N.; Scheltens, P.; Carrillo, M.C.; Thies, B.; Weintraub, S.; Phelps, C.H. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement., 2011, 7(3), 263-269.
[] [PMID: 21514250]
Fagan, A.M.; Mintun, M.A.; Shah, A.R.; Aldea, P.; Roe, C.M.; Mach, R.H.; Marcus, D.; Morris, J.C.; Holtzman, D.M. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer’s disease. EMBO Mol. Med., 2009, 1(8-9), 371-380.
[] [PMID: 20049742]
Hardy, J.; Selkoe, D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 2002, 297(5580), 353-356.
[] [PMID: 12130773]
Hardy, J.A.; Higgins, G.A. Alzheimer’s disease: the amyloid cascade hypothesis. Science, 1992, 256(5054), 184-185.
[] [PMID: 1566067]
Kim, A.C.; Lim, S.; Kim, Y.K. Metal Ion Effects on Aβ and Tau Aggregation. Int. J. Mol. Sci., 2018, 19(1), E128.
[] [PMID: 29301328]
Sadigh-Eteghad, S.; Sabermarouf, B.; Majdi, A.; Talebi, M.; Farhoudi, M.; Mahmoudi, J. Amyloid-beta: a crucial factor in Alzheimer’s disease. Med. Princ. Pract., 2015, 24(1), 1-10.
[] [PMID: 25471398]
Minter, M.R.; Taylor, J.M.; Crack, P.J. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J. Neurochem., 2016, 136(3), 457-474.
[] [PMID: 26509334]
Drechsel, D.N.; Hyman, A.A.; Cobb, M.H.; Kirschner, M.W. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol. Biol. Cell, 1992, 3(10), 1141-1154.
[] [PMID: 1421571]
Weingarten, M.D.; Lockwood, A.H.; Hwo, S.Y.; Kirschner, M.W. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA, 1975, 72(5), 1858-1862.
[] [PMID: 1057175]
Zhang, X.; Gao, F.; Wang, D.; Li, C.; Fu, Y.; He, W.; Zhang, J. Tau pathology in Parkinson’s. Disease. Front. Neurol., 2018, 42(11), 177-1778.
Iqbal, K.; Liu, F.; Gong, C.X.; Grundke-Iqbal, I. Tau in Alzheimer disease and related tauopathies. Curr. Alzheimer Res., 2010, 7(8), 656-664.
[] [PMID: 20678074]
Grill, J.D.; Cummings, J.L. Novel targets for Alzheimer’s disease treatment. Expert Rev. Neurother., 2010, 10(5), 711-728.
[] [PMID: 20420492]
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.
[] [PMID: 29299792]
Dolan, P.J.; Johnson, G.V. The role of tau kinases in Alzheimer’s disease. Curr. Opin. Drug Discov. Devel., 2010, 13(5), 595-603.
[PMID: 20812151]
Stoothoff, W.H. Tau phosphorylation: physiological and pathological consequences. Biochim. Biophys. Acta Biomembr., 2005, 1739, 280-297.
Amar, F.; Sherman, M.A.; Rush, T.; Larson, M.; Boyle, G.; Chang, L.; Götz, J.; Buisson, A.; Lesné, S.E. The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci. Signal., 2017, 10(478), eaal2021.
[] [PMID: 28487416]
Sharma, P.; Srivastava, P.; Seth, A.; Tripathi, P.N.; Banerjee, A.G.; Shrivastava, S.K. Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies. Prog. Neurobiol., 2019, 174, 53-89.
[] [PMID: 30599179]
Bertram, L.; Lill, C.M.; Tanzi, R.E. The genetics of Alzheimer disease: back to the future. Neuron, 2010, 68(2), 270-281.
[] [PMID: 20955934]
Carmona, S.; Hardy, J.; Guerreiro, R. The genetic landscape of Alzheimer disease. Handb. Clin. Neurol., 2018, 148, 395-408.
[] [PMID: 29478590]
Bloom, G.S.; Lazo, J.S.; Norambuena, A. Reduced brain insulin signaling: A seminal process in Alzheimer’s disease pathogenesis. Neuropharmacology,, 2018, 136(Pt B), 192-195.
[] [PMID: 28965829]
Sims-Robinson, C.; Kim, B.; Rosko, A.; Feldman, E.L. How does diabetes accelerate Alzheimer disease pathology? Nat. Rev. Neurol., 2010, 6(10), 551-559.
[] [PMID: 20842183]
Steen, E.; Terry, B.M.; Rivera, E.J.; Cannon, J.L.; Neely, T.R.; Tavares, R.; Xu, X.J.; Wands, J.R.; de la Monte, S.M. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease--is this type 3 diabetes? J. Alzheimers Dis., 2005, 7(1), 63-80.
[] [PMID: 15750215]
Kepp, K.P. Alzheimer’s disease: How metal ions define beta-amyloid function. Coord. Chem. Rev., 2017, 351, 127-159.
González-Reyes, R.E.; Nava-Mesa, M.O.; Vargas-Sánchez, K.; Ariza-Salamanca, D.; Mora-Muñoz, L. Involvement of astrocytes in alzheimer’s disease from a neuroinflammatory and oxidative stress perspective. Front. Mol. Neurosci., 2017, 10, 427.
[] [PMID: 29311817]
Calsolaro, V.; Edison, P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement., 2016, 12(6), 719-732.
[] [PMID: 27179961]
Kepp, K.P. Alzheimer’s disease due to loss of function: A new synthesis of the available data. Prog. Neurobiol., 2016, 143, 36-60.
[] [PMID: 27327400]
Savage, M.J.; Kalinina, J.; Wolfe, A.; Tugusheva, K.; Korn, R.; Cash-Mason, T.; Maxwell, J.W.; Hatcher, N.G.; Haugabook, S.J.; Wu, G.; Howell, B.J.; Renger, J.J.; Shughrue, P.J.; McCampbell, A. A sensitive aβ oligomer assay discriminates Alzheimer’s and aged control cerebrospinal fluid. J. Neurosci., 2014, 34(8), 2884-2897.
[] [PMID: 24553930]
Koffie, R.M.; Meyer-Luehmann, M.; Hashimoto, T.; Adams, K.W.; Mielke, M.L.; Garcia-Alloza, M.; Micheva, K.D.; Smith, S.J.; Kim, M.L.; Lee, V.M.; Hyman, B.T.; Spires-Jones, T.L. Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc. Natl. Acad. Sci. USA, 2009, 106(10), 4012-4017.
[] [PMID: 19228947]
Mucke, L.; Masliah, E.; Yu, G.Q.; Mallory, M.; Rockenstein, E.M.; Tatsuno, G.; Hu, K.; Kholodenko, D.; Johnson-Wood, K.; McConlogue, L. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci., 2000, 20(11), 4050-4058.
[] [PMID: 10818140]
Balducci, C.; Tonini, R.; Zianni, E.; Nazzaro, C.; Fiordaliso, F.; Salio, M.; Vismara, L.; Gardoni, F.; Di Luca, M.; Carli, M.; Forloni, G. Cognitive deficits associated with alteration of synaptic metaplasticity precede plaque deposition in AβPP23 transgenic mice. J. Alzheimers Dis., 2010, 21(4), 1367-1381.
[] [PMID: 21504138]
Forny-Germano, L.; Lyra e Silva, N.M.; Batista, A.F.; Brito-Moreira, J.; Gralle, M.; Boehnke, S.E.; Coe, B.C.; Lablans, A.; Marques, S.A.; Martinez, A.M.; Klein, W.L.; Houzel, J.C.; Ferreira, S.T.; Munoz, D.P.; De Felice, F.G. Alzheimer’s disease-like pathology induced by amyloid-β oligomers in nonhuman primates. J. Neurosci., 2014, 34(41), 13629-13643.
[] [PMID: 25297091]
Brouillette, J.; Caillierez, R.; Zommer, N.; Alves-Pires, C.; Benilova, I.; Blum, D.; De Strooper, B.; Buée, L. Neurotoxicity and memory deficits induced by soluble low-molecular-weight amyloid-β1-42 oligomers are revealed in vivo by using a novel animal model. J. Neurosci., 2012, 32(23), 7852-7861.
[] [PMID: 22674261]
Zhao, W.Q.; De Felice, F.G.; Fernandez, S.; Chen, H.; Lambert, M.P.; Quon, M.J.; Krafft, G.A.; Klein, W.L. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J., 2008, 22(1), 246-260.
[] [PMID: 17720802]
Arbel-Ornath, M.; Hudry, E.; Boivin, J.R.; Hashimoto, T.; Takeda, S.; Kuchibhotla, K.V.; Hou, S.; Lattarulo, C.R.; Belcher, A.M.; Shakerdge, N.; Trujillo, P.B.; Muzikansky, A.; Betensky, R.A.; Hyman, B.T.; Bacskai, B.J. Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. Mol. Neurodegener., 2017, 12(1), 27.
[] [PMID: 28327181]
Shin, W.S.; Di, J.; Cao, Q.; Li, B.; Seidler, P.M.; Murray, K.A.; Bitan, G.; Jiang, L. Amyloid β-protein oligomers promote the uptake of tau fibril seeds potentiating intracellular tau aggregation. Alzheimers Res. Ther., 2019, 11(1), 86.
[] [PMID: 31627745]
Selkoe, D.J.; Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med., 2016, 8(6), 595-608.
[] [PMID: 27025652]
Kayed, R.; Lasagna-Reeves, C.A. Molecular mechanisms of amyloid oligomers toxicity. J. Alzheimers Dis., 2013, 33(Suppl. 1), S67-S78.
[] [PMID: 22531422]
Cline, E.N.; Bicca, M.A.; Viola, K.L.; Klein, W.L. The amyloid-β oligomer hypothesis: beginning of the third decade. J. Alzheimers Dis., 2018, 64(s1), S567-S610.
[] [PMID: 29843241]
Snyder, E.M.; Nong, Y.; Almeida, C.G.; Paul, S.; Moran, T.; Choi, E.Y.; Nairn, A.C.; Salter, M.W.; Lombroso, P.J.; Gouras, G.K.; Greengard, P. Regulation of NMDA receptor trafficking by amyloid-beta. Nat. Neurosci., 2005, 8(8), 1051-1058.
[] [PMID: 16025111]
Lacor, P.N.; Buniel, M.C.; Furlow, P.W.; Clemente, A.S.; Velasco, P.T.; Wood, M.; Viola, K.L.; Klein, W.L. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J. Neurosci., 2007, 27(4), 796-807.
[] [PMID: 17251419]
Li, S.; Jin, M.; Koeglsperger, T.; Shepardson, N.E.; Shankar, G.M.; Selkoe, D.J. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J. Neurosci., 2011, 31(18), 6627-6638.
[] [PMID: 21543591]
Bartolotti, N.; Bennett, D.A.; Lazarov, O. Reduced pCREB in Alzheimer’s disease prefrontal cortex is reflected in peripheral blood mononuclear cells. Mol. Psychiatry, 2016, 21(9), 1158-1166.
[] [PMID: 27480489]
Saura, C.A.; Valero, J. The role of CREB signaling in Alzheimer’s disease and other cognitive disorders. Rev. Neurosci., 2011, 22(2), 153-169.
[] [PMID: 21476939]
García-Osta, A.; Cuadrado-Tejedor, M.; García-Barroso, C.; Oyarzábal, J.; Franco, R. Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem. Neurosci., 2012, 3(11), 832-844.
[] [PMID: 23173065]
Canale, C.; Seghezza, S.; Vilasi, S.; Carrotta, R.; Bulone, D.; Diaspro, A.; San Biagio, P.L.; Dante, S. Different effects of Alzheimer’s peptide Aβ(1-40) oligomers and fibrils on supported lipid membranes. Biophys. Chem., 2013, 182, 23-29.
[] [PMID: 23998637]
Gunn, A.P.; Wong, B.X.; Johanssen, T.; Griffith, J.C.; Masters, C.L.; Bush, A.I.; Barnham, K.J.; Duce, J.A.; Cherny, R.A. Amyloid-β peptide aβ3pe-42 induces lipid peroxidation, membrane permeabilization, and calcium influx in neurons. J. Biol. Chem., 2016, 291(12), 6134-6145.
[] [PMID: 26697885]
LaFerla, F.M.; Green, K.N.; Oddo, S. Intracellular amyloid-beta in Alzheimer’s disease. Nat. Rev. Neurosci., 2007, 8(7), 499-509.
[] [PMID: 17551515]
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.
[] [PMID: 20354705]
Puzzo, D.; Piacentini, R.; Fá, M.; Gulisano, W.; Li, Puma 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 Aβ and Tau oligomers is APP-dependent. eLife, 2017, 6, e26991.
[] [PMID: 28696204]
Enya, M.; Morishima-Kawashima, M.; Yoshimura, M.; Shinkai, Y.; Kusui, K.; Khan, K.; Games, D.; Schenk, D.; Sugihara, S.; Yamaguchi, H.; Ihara, Y. Appearance of sodium dodecyl sulfate-stable amyloid beta-protein (Abeta) dimer in the cortex during aging. Am. J. Pathol., 1999, 154(1), 271-279.
[] [PMID: 9916941]
Garzon-Rodriguez, W.; Sepulveda-Becerra, M.; Milton, S.; Glabe, C.G. Soluble amyloid Abeta-(1-40) exists as a stable dimer at low concentrations. J. Biol. Chem., 1997, 272(34), 21037-21044.
[] [PMID: 9261105]
Kim, B-H.; Lyubchenko, Y.L. Nanoprobing of misfolding and interactions of amyloid β 42 protein. Nanomedicine (Lond.), 2014, 10(4), 871-878.
[] [PMID: 24333588]
Barz, B.; Liao, Q.; Strodel, B. Pathways of amyloid-β aggregation depend on oligomer shape. J. Am. Chem. Soc., 2018, 140(1), 319-327.
[] [PMID: 29235346]
Tjernberg, L.O.; Callaway, D.J.; Tjernberg, A.; Hahne, S.; Lilliehöök, C.; Terenius, L.; Thyberg, J.; Nordstedt, C. A molecular model of Alzheimer amyloid beta-peptide fibril formation. J. Biol. Chem., 1999, 274(18), 12619-12625.
[] [PMID: 10212241]
O’Malley, T.T.; Witbold, W.M., III; Linse, S.; Walsh, D.M. The aggregation paths and products of aβ42 dimers are distinct from those of the aβ42 monomer. Biochemistry, 2016, 55(44), 6150-6161.
[] [PMID: 27750419]
O’Malley, T.T.; Oktaviani, N.A.; Zhang, D.; Lomakin, A.; O’Nuallain, B.; Linse, S.; Benedek, G.B.; Rowan, M.J.; Mulder, F.A.; Walsh, D.M. Aβ dimers differ from monomers in structural propensity, aggregation paths and population of synaptotoxic assemblies. Biochem. J., 2014, 461(3), 413-426.
[] [PMID: 24785004]
Roher, A.E.; Chaney, M.O.; Kuo, Y.M.; Webster, S.D.; Stine, W.B.; Haverkamp, L.J.; Woods, A.S.; Cotter, R.J.; Tuohy, J.M.; Krafft, G.A.; Bonnell, B.S.; Emmerling, M.R. Morphology and toxicity of Abeta-(1-42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer’s disease. J. Biol. Chem., 1996, 271(34), 20631-20635.
[] [PMID: 8702810]
Yamaguchi, T.; Yagi, H.; Goto, Y.; Matsuzaki, K.; Hoshino, M. A disulfide-linked amyloid-beta peptide dimer forms a protofibril-like oligomer through a distinct pathway from amyloid fibril formation. Biochemistry, 2010, 49(33), 7100-7107.
[] [PMID: 20666485]
O’Nuallain, B.; Freir, D.B.; Nicoll, A.J.; Risse, E.; Ferguson, N.; Herron, C.E.; Collinge, J.; Walsh, D.M. Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrils. J. Neurosci., 2010, 30(43), 14411-14419.
[] [PMID: 20980598]
Zott, B.; Simon, M.M.; Hong, W.; Unger, F.; Chen-Engerer, H.J.; Frosch, M.P.; Sakmann, B.; Walsh, D.M.; Konnerth, A. A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science, 2019, 365(6453), 559-565.
[] [PMID: 31395777]
Irie, Y.; Murakami, K.; Hanaki, M.; Hanaki, Y.; Suzuki, T.; Monobe, Y.; Takai, T.; Akagi, K.I.; Kawase, T.; Hirose, K.; Irie, K. Synthetic models of quasi-stable amyloid β40 oligomers with significant neurotoxicity. ACS Chem. Neurosci., 2017, 8(4), 807-816.
[] [PMID: 28026168]
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.
[] [PMID: 12702875]
Lesné, 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.
[] [PMID: 16541076]
Kirkitadze, M.D.; Bitan, G.; Teplow, D.B. Paradigm shifts in Alzheimer’s disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J. Neurosci. Res., 2002, 69(5), 567-577.
[] [PMID: 12210822]
Lesné, S.E.; Sherman, M.A.; Grant, M.; Kuskowski, M.; Schneider, J.A.; Bennett, D.A.; Ashe, K.H. Brain amyloid-β oligomers in ageing and Alzheimer’s disease. Brain, 2013, 136(Pt 5), 1383-1398.
[] [PMID: 23576130]
Sengupta, U.; Nilson, A.N.; Kayed, R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine, 2016, 6, 42-49.
[] [PMID: 27211547]
Huang, T.H.J.; Yang, D.S.; Plaskos, N.P.; Go, S.; Yip, C.M.; Fraser, P.E.; Chakrabartty, A. Structural studies of soluble oligomers of the Alzheimer beta-amyloid peptide. J. Mol. Biol., 2000, 297(1), 73-87.
[] [PMID: 10704308]
Lashuel, H.A.; Hartley, D.M.; Petre, B.M.; Wall, J.S.; Simon, M.N.; Walz, T.; Lansbury, P.T., Jr Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores. J. Mol. Biol., 2003, 332(4), 795-808.
[] [PMID: 12972252]
Mastrangelo, I.A.; Ahmed, M.; Sato, T.; Liu, W.; Wang, C.; Hough, P.; Smith, S.O. High-resolution atomic force microscopy of soluble Abeta42 oligomers. J. Mol. Biol., 2006, 358(1), 106-119.
[] [PMID: 16499926]
Economou, N.J.; Giammona, M.J.; Do, T.D.; Zheng, X.; Teplow, D.B.; Buratto, S.K.; Bowers, M.T. Amyloid β-protein assembly and alzheimer’s disease: dodecamers of aβ42, but not of aβ40, seed fibril formation. J. Am. Chem. Soc., 2016, 138(6), 1772-1775.
[] [PMID: 26839237]
Fu, Z.; Aucoin, D.; Ahmed, M.; Ziliox, M.; Van Nostrand, W.E.; Smith, S.O. Capping of aβ42 oligomers by small molecule inhibitors. Biochemistry, 2014, 53(50), 7893-7903.
[] [PMID: 25422864]
Ono, K.; Condron, M.M.; Teplow, D.B. Structure-neurotoxicity relationships of amyloid beta-protein oligomers. Proc. Natl. Acad. Sci. USA, 2009, 106(35), 14745-14750.
[] [PMID: 19706468]
Ono, K. Alzheimer’s disease as oligomeropathy. Neurochem. Int., 2018, 119, 57-70.
[] [PMID: 28821400]
Viola, K.L.; Klein, W.L. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol., 2015, 129(2), 183-206.
[] [PMID: 25604547]
Benilova, I.; Karran, E.; De Strooper, B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat. Neurosci., 2012, 15(3), 349-357.
[] [PMID: 22286176]
Kłoniecki, M.; Jabłonowska, A.; Poznański, J.; Langridge, J.; Hughes, C.; Campuzano, I.; Giles, K.; Dadlez, M. Ion mobility separation coupled with MS detects two structural states of Alzheimer’s disease Aβ1-40 peptide oligomers. J. Mol. Biol., 2011, 407(1), 110-124.
[] [PMID: 21237171]
Kim, S.; Takeda, T.; Klimova, D.K. Globular state in the oligomers formed by A beta peptides. J. Chem. Phys., 2010, 132(22)
Yu, L.; Edalji, R.; Harlan, J.E.; Holzman, T.F.; Lopez, A.P.; Labkovsky, B.; Hillen, H.; Barghorn, S.; Ebert, U.; Richardson, P.L.; Miesbauer, L.; Solomon, L.; Bartley, D.; Walter, K.; Johnson, R.W.; Hajduk, P.J.; Olejniczak, E.T. Structural characterization of a soluble amyloid beta-peptide oligomer. Biochemistry, 2009, 48(9), 1870-1877.
[] [PMID: 19216516]
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.
[] [PMID: 20383142]
Schmechel, A.; Zentgraf, H.; Scheuermann, S.; Fritz, G.; Pipkorn, R.; Reed, J.; Beyreuther, K.; Bayer, T.A.; Multhaup, G. Alzheimer beta-amyloid homodimers facilitate A beta fibrillization and the generation of conformational antibodies. J. Biol. Chem., 2003, 278(37), 35317-35324.
[] [PMID: 12840025]
Bernstein, S.L.; Dupuis, N.F.; Lazo, N.D.; Wyttenbach, T.; Condron, M.M.; Bitan, G.; Teplow, D.B.; Shea, J.E.; Ruotolo, B.T.; Robinson, C.V.; Bowers, M.T. Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat. Chem., 2009, 1(4), 326-331.
[] [PMID: 20703363]
Zheng, X.; Liu, D.; Klärner, F.G.; Schrader, T.; Bitan, G.; Bowers, M.T. Amyloid β-protein assembly: The effect of molecular tweezers CLR01 and CLR03. J. Phys. Chem. B, 2015, 119(14), 4831-4841.
[] [PMID: 25751170]
Dunker, A.K.; Lawson, J.D.; Brown, C.J.; Williams, R.M.; Romero, P.; Oh, J.S.; Oldfield, C.J.; Campen, A.M.; Ratliff, C.M.; Hipps, K.W.; Ausio, J.; Nissen, M.S.; Reeves, R.; Kang, C.; Kissinger, C.R.; Bailey, R.W.; Griswold, M.D.; Chiu, W.; Garner, E.C.; Obradovic, Z. Intrinsically disordered protein. J. Mol. Graph. Model., 2001, 19(1), 26-59.
[] [PMID: 11381529]
Kosol, S.; Contreras-Martos, S.; Cedeño, C.; Tompa, P. Structural characterization of intrinsically disordered proteins by NMR spectroscopy. Molecules, 2013, 18(9), 10802-10828.
[] [PMID: 24008243]
Istrate, A.N.; Tsvetkov, P.O.; Mantsyzov, A.B.; Kulikova, A.A.; Kozin, S.A.; Makarov, A.A.; Polshakov, V.I. NMR solution structure of rat aβ(1-16): toward understanding the mechanism of rats’ resistance to Alzheimer’s disease. Biophys. J., 2012, 102(1), 136-143.
[] [PMID: 22225807]
Tarus, B.; Tran, T.T.; Nasica-Labouze, J.; Sterpone, F.; Nguyen, P.H.; Derreumaux, P. Structures of the alzheimer’s wild-type aβ1-40 dimer from atomistic simulations. J. Phys. Chem. B, 2015, 119(33), 10478-10487.
[] [PMID: 26228450]
Zhang, Y.; Hashemi, M.; Lv, Z.; Lyubchenko, Y.L. Self-assembly of the full-length amyloid Aβ42 protein in dimers. Nanoscale, 2016, 8(45), 18928-18937.
[] [PMID: 27714140]
Sun, Y.; Qian, Z.; Wei, G. The inhibitory mechanism of a fullerene derivative against amyloid-β peptide aggregation: an atomistic simulation study. Phys. Chem. Chem. Phys., 2016, 18(18), 12582-12591.
[] [PMID: 27091578]
Cao, Y.; Jiang, X.; Han, W. Self-assembly pathways of β-sheet-rich amyloid-β(1-40) dimers: markov state model analysis on millisecond hybrid-resolution simulations. J. Chem. Theory Comput., 2017, 13(11), 5731-5744.
[] [PMID: 29019683]
Man, V.H.; Nguyen, P.H.; Derreumaux, P. Conformational ensembles of the wild-type and s8c aβ1-42 dimers. J. Phys. Chem. B, 2017, 121(11), 2434-2442.
[] [PMID: 28245647]
Jin, Y.; Sun, Y.; Chen, Y.; Lei, J.; Wei, G. Molecular dynamics simulations reveal the mechanism of graphene oxide nanosheet inhibition of Aβ1-42 peptide aggregation. Phys. Chem. Chem. Phys., 2019, 21(21), 10981-10991.
[] [PMID: 31111835]
Smith, M.D.; Srinivasa Rao, J.; Cruz, L. Spontaneous dimer states of the Aβ(21-30) decapeptide. Phys. Chem. Chem. Phys., 2014, 16(26), 13069-13073.
[] [PMID: 24888358]
Pouplana, R.; Campanera, J.M. Energetic contributions of residues to the formation of early amyloid-β oligomers. Phys. Chem. Chem. Phys., 2015, 17(4), 2823-2837.
[] [PMID: 25503571]
Lu, Y.; Shi, X.F.; Salsbury, F.R., Jr; Derreumaux, P. Influence of electric field on the amyloid-β(29-42) peptides embedded in a membrane bilayer. J. Chem. Phys., 2018, 148(4), 045105.
[] [PMID: 29390813]
Liao, Q.; Owen, M.C.; Bali, S.; Barz, B.; Strodel, B. Aβ under stress: the effects of acidosis, Cu2+-binding, and oxidation on amyloid β-peptide dimers. Chem. Commun. (Camb.), 2018, 54(56), 7766-7769.
[] [PMID: 29947363]
Yi, X.; Zhang, Y.; Gong, M.; Yu, X.; Darabedian, N.; Zheng, J.; Zhou, F. Ca(2+) interacts with glu-22 of aβ(1-42) and phospholipid bilayers to accelerate the aβ(1-42) aggregation below the critical micelle concentration. Biochemistry, 2015, 54(41), 6323-6332.
[] [PMID: 26426973]
Menon, S.; Sengupta, N. Influence of hyperglycemic conditions on self-association of the alzheimer’s amyloid β (aβ1-42) peptide. ACS Omega, 2017, 2(5), 2134-2147.
[] [PMID: 30023655]
Brown, A.M.; Bevan, D.R. Molecular dynamics simulations of amyloid β-peptide (1-42): tetramer formation and membrane interactions. Biophys. J., 2016, 111(5), 937-949.
[] [PMID: 27602722]
Chong, S-H.; Ham, S. Distinct role of hydration water in protein misfolding and aggregation revealed by fluctuating thermodynamics analysis. Acc. Chem. Res., 2015, 48(4), 956-965.
[] [PMID: 25844814]
van der Munnik, N.P.; Sajib, M.S.J.; Moss, M.A.; Wei, T.; Uline, M.J. Determining the potential of mean force for amyloid-β dimerization: combining self-consistent field theory with molecular dynamics simulation. J. Chem. Theory Comput., 2018, 14(5), 2696-2704.
[] [PMID: 29562134]
Zhang, T.; Xu, W.; Mu, Y.; Derreumaux, P. Atomic and dynamic insights into the beneficial effect of the 1,4-naphthoquinon-2-yl-L-tryptophan inhibitor on Alzheimer’s Aβ1-42 dimer in terms of aggregation and toxicity. ACS Chem. Neurosci., 2014, 5(2), 148-159.
[] [PMID: 24246047]
Boopathi, S.; Kolandaivel, P. Study on the inter- and intra-peptide salt-bridge mechanism of Aβ23-28 oligomer interaction with small molecules: QM/MM method. Mol. Biosyst., 2015, 11(7), 2031-2041.
[] [PMID: 25973904]
Xu, L.; Shan, S.; Chen, Y.; Wang, X.; Nussinov, R.; Ma, B. Coupling of zinc-binding and secondary structure in nonfibrillar aβ40 peptide oligomerization. J. Chem. Inf. Model., 2015, 55(6), 1218-1230.
[] [PMID: 26017140]
de Almeida, N.E.C.; Do, T.D.; Tro, M.; LaPointe, N.E.; Feinstein, S.C.; Shea, J.E.; Bowers, M.T. Opposing effects of cucurbit[7]uril and 1,2,3,4,6-penta-o-galloyl-β-d-glucopyranose on amyloid β25-35 assembly. ACS Chem. Neurosci., 2016, 7(2), 218-226.
[] [PMID: 26629788]
Mittal, S.; Bravo-Rodriguez, K.; Sanchez-Garcia, E. Mechanism of inhibition of beta amyloid toxicity by supramolecular tweezers. J. Phys. Chem. B, 2018, 122(15), 4196-4205.
[] [PMID: 29630377]
Zou, Y.; Qian, Z.; Chen, Y.; Qian, H.; Wei, G.; Zhang, Q. Norepinephrine inhibits alzheimer’s amyloid-β peptide aggregation and destabilizes amyloid-β protofibrils: a molecular dynamics simulation study. ACS Chem. Neurosci., 2019, 10(3), 1585-1594.
[] [PMID: 30605312]
Ngo, S.T.; Hung, H.M.; Truong, D.T.; Nguyen, M.T. Replica exchange molecular dynamics study of the truncated amyloid beta (11-40) trimer in solution. Phys. Chem. Chem. Phys., 2017, 19(3), 1909-1919.
[] [PMID: 28004051]
Viet, M.H.; Nguyen, P.H.; Derreumaux, P.; Li, M.S. Effect of the English familial disease mutation (H6R) on the monomers and dimers of Aβ40 and Aβ42. ACS Chem. Neurosci., 2014, 5(8), 646-657.
[] [PMID: 24949887]
Blinov, N.; Khorvash, M.; Wishart, D.S.; Cashman, N.R.; Kovalenko, A. Initial structural models of the aβ42 dimer from replica exchange molecular dynamics simulations. ACS Omega, 2017, 2(11), 7621-7636.
[] [PMID: 31457321]
Man, V.H.; Nguyen, P.H.; Derreumaux, P. High-resolution structures of the amyloid-β 1-42 dimers from the comparison of four atomistic force fields. J. Phys. Chem. B, 2017, 121(24), 5977-5987.
[] [PMID: 28538095]
Watts, C.R.; Gregory, A.; Frisbie, C.; Lovas, S. Effects of force fields on the conformational and dynamic properties of amyloid β(1-40) dimer explored by replica exchange molecular dynamics simulations. Proteins, 2018, 86(3), 279-300.
[] [PMID: 29235155]
Fändrich, M. On the structural definition of amyloid fibrils and other polypeptide aggregates. Cell. Mol. Life Sci., 2007, 64(16), 2066-2078.
[] [PMID: 17530168]
Schmidt, M.; Sachse, C.; Richter, W.; Xu, C.; Fändrich, M.; Grigorieff, N. Comparison of Alzheimer Abeta(1-40) and Abeta(1-42) amyloid fibrils reveals similar protofilament structures. Proc. Natl. Acad. Sci. USA, 2009, 106(47), 19813-19818.
[] [PMID: 19843697]
Fändrich, M.; Schmidt, M.; Grigorieff, N. Recent progress in understanding Alzheimer’s β-amyloid structures. Trends Biochem. Sci., 2011, 36(6), 338-345.
[] [PMID: 21411326]
Sachse, C.; Fändrich, M.; Grigorieff, N. Paired β-sheet structure of an Aβ(1-40) amyloid fibril revealed by electron microscopy. PNAS, 2008, 105(21), 7462-7466.
Zhang, R.; Hu, X.; Khant, H.; Ludtke, S.J.; Chiu, W.; Schmid, M.F.; Frieden, C.; Lee, J.M. Interprotofilament interactions between Alzheimer’s Abeta1-42 peptides in amyloid fibrils revealed by cryoEM. Proc. Natl. Acad. Sci. USA, 2009, 106(12), 4653-4658.
[] [PMID: 19264960]
Lopez del Amo, J.M.; Schmidt, M.; Fink, U.; Dasari, M.; Fändrich, M.; Reif, B. An asymmetric dimer as the basic subunit in Alzheimer’s disease amyloid β fibrils. Angew. Chem. Int. Ed. Engl., 2012, 51(25), 6136-6139.
Schütz, A.K.; Vagt, T.; Huber, M. Atomic-resolution three-dimensional structure of amyloid β fibrils bearing the osaka mutation. Angew. Chem. Int. Ed. Engl., 2015, 54(1), 331-335.
Schmidt, M.; Rohou, A.; Lasker, K.; Yadav, J.K.; Schiene-Fischer, C.; Fändrich, M.; Grigorieff, N. Peptide dimer structure in an Aβ(1-42) fibril visualized with cryo-EM. Proc. Natl. Acad. Sci. USA, 2015, 112(38), 11858-11863.
[] [PMID: 26351699]
Gremer, L.; Schölzel, D.; Schenk, C.; Reinartz, E.; Labahn, J.; Ravelli, R.B.G.; Tusche, M.; Lopez-Iglesias, C.; Hoyer, W.; Heise, H.; Willbold, D.; Schröder, G.F. Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Science, 2017, 358(6359), 116-119.
[] [PMID: 28882996]
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 aβ42 amyloid fibrils. J. Am. Chem. Soc., 2016, 138(30), 9663-9674.
[] [PMID: 27355699]
Cummings, J.; Aisen, P.S.; DuBois, B.; Frölich, L.; Jack, C.R., Jr; Jones, R.W.; Morris, J.C.; Raskin, J.; Dowsett, S.A.; Scheltens, P. Drug development in Alzheimer’s disease: the path to 2025. Alzheimers Res. Ther., 2016, 8, 39.
[] [PMID: 27646601]
Gaugler, J. 2019 Alzheimer’s disease facts and figures. Alzheimers Dement., 2019, 15(3), 321-387.
Chen, G.F.; Xu, T.H.; Yan, Y.; Zhou, Y.R.; Jiang, Y.; Melcher, K.; Xu, H.E. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin., 2017, 38(9), 1205-1235.
[] [PMID: 28713158]
Du, X.; Wang, X.; Geng, M. Alzheimer’s disease hypothesis and related therapies. Transl. Neurodegener., 2018, 7, 2.
[] [PMID: 29423193]
Hung, S-Y.; Fu, W-M. Drug candidates in clinical trials for Alzheimer’s disease. J. Biomed. Sci., 2017, 24(1), 47.
[] [PMID: 28720101]
Menting, K.W.; Claassen, J.A.H.R. β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease. Front. Aging Neurosci., 2014, 6, 165.
[] [PMID: 25100992]
Wolfe, M.S. γ-Secretase inhibitors and modulators for Alzheimer’s disease. J. Neurochem., 2012, 120(Suppl. 1), 89-98.
[] [PMID: 22122056]
Sevigny, J.; Chiao, P.; Bussière, T.; Weinreb, P.H.; Williams, L.; Maier, M.; Dunstan, R.; Salloway, S.; Chen, T.; Ling, Y.; O’Gorman, J.; Qian, F.; Arastu, M.; Li, M.; Chollate, S.; Brennan, M.S.; Quintero-Monzon, O.; Scannevin, R.H.; Arnold, H.M.; Engber, T.; Rhodes, K.; Ferrero, J.; Hang, Y.; Mikulskis, A.; Grimm, J.; Hock, C.; Nitsch, R.M.; Sandrock, A. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature, 2016, 537(7618), 50-56.
[] [PMID: 27582220]
Honig, L.S.; Vellas, B.; Woodward, M.; Boada, M.; Bullock, R.; Borrie, M.; Hager, K.; Andreasen, N.; Scarpini, E.; Liu-Seifert, H.; Case, M.; Dean, R.A.; Hake, A.; Sundell, K.; Poole Hoffmann, V.; Carlson, C.; Khanna, R.; Mintun, M.; DeMattos, R.; Selzler, K.J.; Siemers, E. Trial of solanezumab for mild dementia due to alzheimer’s disease. N. Engl. J. Med., 2018, 378(4), 321-330.
[] [PMID: 29365294]
Panza, F.; Lozupone, M.; Logroscino, G.; Imbimbo, B.P. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat. Rev. Neurol., 2019, 15(2), 73-88.
[] [PMID: 30610216]
Lakey-Beitia, J.; Berrocal, R.; Rao, K.S.; Durant, A.A. Polyphenols as therapeutic molecules in Alzheimer’s disease through modulating amyloid pathways. Mol. Neurobiol., 2015, 51(2), 466-479.
[] [PMID: 24826916]
Porat, Y.; Abramowitz, A.; Gazit, E. Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem. Biol. Drug Des., 2006, 67(1), 27-37.
[] [PMID: 16492146]
Kametani, F.; Hasegawa, M. Reconsideration of amyloid hypothesis and tau hypothesis in alzheimer’s disease. Front. Neurosci., 2018, 12, 25.
[] [PMID: 29440986]
Congdon, E.E.; Sigurdsson, E.M. Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol., 2018, 14(7), 399-415.
[] [PMID: 29895964]
Panza, F. Tau-centric targets and drugs in clinical development for the treatment of alzheimer’s disease. BioMed Res. Int., 2016.
Gerson, J.E.; Cascio, F.L.; Kayed, R. The potential of small molecules in preventing tau oligomer ormation and toxicity. In: Neuroprotection in Alzheimer’s Disease; Elsevier: Amsterdam, 2017; pp. 97-121.
Zhang, B.; Carroll, J.; Trojanowski, J.Q.; Yao, Y.; Iba, M.; Potuzak, J.S.; Hogan, A.M.; Xie, S.X.; Ballatore, C.; Smith, A.B., III; Lee, V.M.; Brunden, K.R. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J. Neurosci., 2012, 32(11), 3601-3611.
[] [PMID: 22423084]
Wobst, H.J.; Sharma, A.; Diamond, M.I.; Wanker, E.E.; Bieschke, J. The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett., 2015, 589(1), 77-83.
[] [PMID: 25436420]
Li, C.; Götz, J. Tau-based therapies in neurodegeneration: opportunities and challenges. Nat. Rev. Drug Discov., 2017, 16(12), 863-883.
[] [PMID: 28983098]
Crowe, A.; James, M.J.; Lee, V.M.; Smith, A.B., III; Trojanowski, J.Q.; Ballatore, C.; Brunden, K.R. Aminothienopyridazines and methylene blue affect Tau fibrillization via cysteine oxidation. J. Biol. Chem., 2013, 288(16), 11024-11037.
[] [PMID: 23443659]
Wojsiat, J.; Zoltowska, K.M.; Laskowska-Kaszub, K.; Wojda, U. Oxidant/antioxidant imbalance in alzheimer’s disease: therapeutic and diagnostic prospects. Oxid. Med. Cell. Longev., 2018, 2018, 6435861.
[] [PMID: 29636850]
Shal, B.; Ding, W.; Ali, H.; Kim, Y.S.; Khan, S. Anti-neuroinflammatory potential of natural products in attenuation of alzheimer’s disease. Front. Pharmacol., 2018, 9, 548.
[] [PMID: 29896105]
Hampel, H.; Mesulam, M.M.; Cuello, A.C.; Farlow, M.R.; Giacobini, E.; Grossberg, G.T.; Khachaturian, A.S.; Vergallo, A.; Cavedo, E.; Snyder, P.J.; Khachaturian, Z.S. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 2018, 141(7), 1917-1933.
[] [PMID: 29850777]
Wang, X.; Sun, G.; Feng, T.; Zhang, J.; Huang, X.; Wang, T.; Xie, Z.; Chu, X.; Yang, J.; Wang, H.; Chang, S.; Gong, Y.; Ruan, L.; Zhang, G.; Yan, S.; Lian, W.; Du, C.; Yang, D.; Zhang, Q.; Lin, F.; Liu, J.; Zhang, H.; Ge, C.; Xiao, S.; Ding, J.; Geng, M. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res., 2019, 29(10), 787-803.
[] [PMID: 31488882]
Villarreal, S.; Zhao, F.; Hyde, L.A.; Holder, D.; Forest, T.; Sondey, M.; Chen, X.; Sur, C.; Parker, E.M.; Kennedy, M.E. Chronic verubecestat treatment suppresses amyloid accumulation in advanced aged tg2576-aβppswe mice without inducing microhemorrhage. J. Alzheimers Dis., 2017, 59(4), 1393-1413.
[] [PMID: 28800329]
Yang, T.; Dang, Y.; Ostaszewski, B.; Mengel, D.; Steffen, V.; Rabe, C.; Bittner, T.; Walsh, D.M.; Selkoe, D.J. Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid. Ann. Neurol., 2019, 86(2), 215-224.
[] [PMID: 31168802]
Domínguez, J.M.; Fuertes, A.; Orozco, L.; del Monte-Millán, M.; Delgado, E.; Medina, M. Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib. J. Biol. Chem., 2012, 287(2), 893-904.
[] [PMID: 22102280]
Dong, H.; Yuede, C.M.; Coughlan, C.; Lewis, B.; Csernansky, J.G. Effects of memantine on neuronal structure and conditioned fear in the Tg2576 mouse model of Alzheimer’s disease. Neuropsychopharmacology, 2008, 33(13), 3226-3236.
[] [PMID: 18418360]
Digiacomo, M.; Chen, Z.; Wang, S.; Lapucci, A.; Macchia, M.; Yang, X.; Chu, J.; Han, Y.; Pi, R.; Rapposelli, S. Synthesis and pharmacological evaluation of multifunctional tacrine derivatives against several disease pathways of AD. Bioorg. Med. Chem. Lett., 2015, 25(4), 807-810.
[] [PMID: 25597007]
Jann, M.W. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacotherapy, 2000, 20(1), 1-12.
[] [PMID: 10641971]
Rogers, S.L.; Friedhoff, L.T. The donepezil study group. the efficacy and safety of donepezil in patients with alzheimer’s disease: results of a us multicentre, randomized, double-blind, placebo-controlled trial. Dementia, 1996, 7(6), 293-303.
[PMID: 8915035]
Jiang, S.; Zhao, Y.; Zhang, T.; Lan, J.; Yang, J.; Yuan, L.; Zhang, Q.; Pan, K.; Zhang, K. Galantamine inhibits β-amyloid-induced cytostatic autophagy in PC12 cells through decreasing ROS production. Cell Prolif., 2018, 51(3), e12427.
[] [PMID: 29292543]
Heneka, M.T.; Sastre, M.; Dumitrescu-Ozimek, L.; Hanke, A.; Dewachter, I.; Kuiperi, C.; O’Banion, K.; Klockgether, T.; Van Leuven, F.; Landreth, G.E. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain, 2005, 128(Pt 6), 1442-1453.
[] [PMID: 15817521]
Burstein, A.H. Development of azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild alzheimer’s disease. jpad-. J. Prev. Alzheimers Dis., 2018, 5(2), 149-154.
[PMID: 29616709]
Malouf, R.; Collins, H. Tramiprosate (alzhemed) for alzheimer’s disease. Cochrane Database Syst. Rev., 2009, 2018(8), CD007549.
Morris, M.C.; Beckett, L.A.; Scherr, P.A.; Hebert, L.E.; Bennett, D.A.; Field, T.S.; Evans, D.A. Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. Alzheimer Dis. Assoc. Disord., 1998, 12(3), 121-126.
[] [PMID: 9772012]
Saharan, S.; Mandal, P.K.P.K. The emerging role of glutathione in Alzheimer’s disease. J. Alzheimers Dis., 2014, 40(3), 519-529.
[] [PMID: 24496077]
Su, T.; Xie, S.; Wei, H.; Yan, J.; Huang, L.; Li, X. Synthesis and biological evaluation of berberine-thiophenyl hybrids as multi-functional agents: Inhibition of acetylcholinesterase, butyrylcholinesterase, and Aβ aggregation and antioxidant activity. Bioorg. Med. Chem., 2013, 21(18), 5830-5840.
[] [PMID: 23932451]
Fradinger, E.A.; Monien, B.H.; Urbanc, B.; Lomakin, A.; Tan, M.; Li, H.; Spring, S.M.; Condron, M.M.; Cruz, L.; Xie, C.W.; Benedek, G.B.; Bitan, G. C-terminal peptides coassemble into Abeta42 oligomers and protect neurons against Abeta42-induced neurotoxicity. Proc. Natl. Acad. Sci. USA, 2008, 105(37), 14175-14180.
[] [PMID: 18779585]
Li, H.; Monien, B.H.; Lomakin, A.; Zemel, R.; Fradinger, E.A.; Tan, M.; Spring, S.M.; Urbanc, B.; Xie, C.W.; Benedek, G.B.; Bitan, G. Mechanistic investigation of the inhibition of Abeta42 assembly and neurotoxicity by Abeta42 C-terminal fragments. Biochemistry, 2010, 49(30), 6358-6364.
[] [PMID: 20568734]
Gessel, M.M.; Wu, C.; Li, H.; Bitan, G.; Shea, J.E.; Bowers, M.T. Aβ(39-42) modulates Aβ oligomerization but not fibril formation. Biochemistry, 2012, 51(1), 108-117.
[] [PMID: 22129303]
Hyung, S-J.; DeToma, A.S.; Brender, J.R.; Lee, S.; Vivekanandan, S.; Kochi, A.; Choi, J.S.; Ramamoorthy, A.; Ruotolo, B.T.; Lim, M.H. Insights into antiamyloidogenic properties of the green tea extract (-)-epigallocatechin-3-gallate toward metal-associated amyloid-β species. Proc. Natl. Acad. Sci. USA, 2013, 110(10), 3743-3748.
[] [PMID: 23426629]
Bieschke, J.; Russ, J.; Friedrich, R.P.; Ehrnhoefer, D.E.; Wobst, H.; Neugebauer, K.; Wanker, E.E. EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc. Natl. Acad. Sci. USA, 2010, 107(17), 7710-7715.
[] [PMID: 20385841]
Ehrnhoefer, D.E.; Bieschke, J.; Boeddrich, A.; Herbst, M.; Masino, L.; Lurz, R.; Engemann, S.; Pastore, A.; Wanker, E.E. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat. Struct. Mol. Biol., 2008, 15(6), 558-566.
[] [PMID: 18511942]
Zhang, T.; Zhang, J.; Derreumaux, P.; Mu, Y. Molecular mechanism of the inhibition of EGCG on the Alzheimer Aβ(1-42) dimer. J. Phys. Chem. B, 2013, 117(15), 3993-4002.
[] [PMID: 23537203]
Yang, F.; Lim, G.P.; Begum, A.N.; Ubeda, O.J.; Simmons, M.R.; Ambegaokar, S.S.; Chen, P.P.; Kayed, R.; Glabe, C.G.; Frautschy, S.A.; Cole, G.M. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem., 2005, 280(7), 5892-5901.
[] [PMID: 15590663]
Ono, K.; Hasegawa, K.; Naiki, H.; Yamada, M. Curcumin has potent anti-amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro. J. Neurosci. Res., 2004, 75(6), 742-750.
[] [PMID: 14994335]
Hamaguchi, T.; Ono, K.; Yamada, M. REVIEW: Curcumin and Alzheimer’s disease. CNS Neurosci. Ther., 2010, 16(5), 285-297.
[] [PMID: 20406252]
Ono, K.; Condron, M.M.; Ho, L.; Wang, J.; Zhao, W.; Pasinetti, G.M.; Teplow, D.B. Effects of grape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity. J. Biol. Chem., 2008, 283(47), 32176-32187.
[] [PMID: 18815129]
Hayden, E.Y.; Yamin, G.; Beroukhim, S.; Chen, B.; Kibalchenko, M.; Jiang, L.; Ho, L.; Wang, J.; Pasinetti, G.M.; Teplow, D.B. Inhibiting amyloid β-protein assembly: Size-activity relationships among grape seed-derived polyphenols. J. Neurochem., 2015, 135(2), 416-430.
[] [PMID: 26228682]
Rao, P.P.N.; Mohamed, T.; Teckwani, K.; Tin, G. Curcumin Binding to Beta Amyloid: A Computational Study. Chem. Biol. Drug Des., 2015, 86(4), 813-820.
[] [PMID: 25776887]
McLaurin, J.; Golomb, R.; Jurewicz, A.; Antel, J.P.; Fraser, P.E. Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit abeta -induced toxicity. J. Biol. Chem., 2000, 275(24), 18495-18502.
[] [PMID: 10764800]
McLaurin, J.; Kierstead, M.E.; Brown, M.E.; Hawkes, C.A.; Lambermon, M.H.; Phinney, A.L.; Darabie, A.A.; Cousins, J.E.; French, J.E.; Lan, M.F.; Chen, F.; Wong, S.S.; Mount, H.T.; Fraser, P.E.; Westaway, D.; St George-Hyslop, P. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat. Med., 2006, 12(7), 801-808.
[] [PMID: 16767098]
Scherzer-Attali, R.; Pellarin, R.; Convertino, M.; Frydman-Marom, A.; Egoz-Matia, N.; Peled, S.; Levy-Sakin, M.; Shalev, D.E.; Caflisch, A.; Gazit, E.; Segal, D. Complete phenotypic recovery of an Alzheimer’s disease model by a quinone-tryptophan hybrid aggregation inhibitor. PLoS One, 2010, 5(6), e11101.
[] [PMID: 20559435]
Attar, A.; Rahimi, F.; Bitan, G. Modulators of amyloid protein aggregation and toxicity: egcg and clr01. Transl. Neurosci., 2013, 4(4), 385-409.
Jang, J.H.; Surh, Y.J. Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death. Free Radic. Biol. Med., 2003, 34(8), 1100-1110.
[] [PMID: 12684095]
Zheng, X.; Gessel, M.M.; Wisniewski, M.L.; Viswanathan, K.; Wright, D.L.; Bahr, B.A.; Bowers, M.T. Z-phe-ala-diazomethylketone (padk) disrupts and remodels early oligomer states of the alzheimer disease aβ42 protein. J. Biol. Chem., 2012, 287(9), 6084-6088.
[] [PMID: 22253440]
Huy, P.D.Q.; Thai, N.Q.; Bednarikova, Z.; Phuc, L.H.; Linh, H.Q.; Gazova, Z.; Li, M.S. Bexarotene does not clear amyloid beta plaques but delays fibril growth: molecular mechanisms. ACS Chem. Neurosci., 2017, 8(9), 1960-1969.
[] [PMID: 28689412]
Jin, Y.; Sun, Y.; Lei, J.; Wei, G. Dihydrochalcone molecules destabilize Alzheimer’s amyloid-β protofibrils through binding to the protofibril cavity. Phys. Chem. Chem. Phys., 2018, 20(25), 17208-17217.
[] [PMID: 29900443]
Fonseca-Santos, B.; Gremião, M.P.D.; Chorilli, M. Nanotechnology-based drug delivery systems for the treatment of Alzheimer’s disease. Int. J. Nanomedicine, 2015, 10, 4981-5003.
[] [PMID: 26345528]
Zheng, X.; Zhang, C.; Guo, Q.; Wan, X.; Shao, X.; Liu, Q.; Zhang, Q. Dual-functional nanoparticles for precise drug delivery to Alzheimer’s disease lesions: Targeting mechanisms, pharmacodynamics and safety. Int. J. Pharm., 2017, 525(1), 237-248.
[] [PMID: 28432017]
Liao, Y-H. Negatively charged gold nanoparticles inhibit alzheimer’s amyloid- β fibrillization, induce fibril dissociation, and mitigate neurotoxicity. Small, 2012, 8(23), 3631-3639.
Kayed, R.; Glabe, C.G. Conformation-dependent anti-amyloid oligomer antibodies. Methods Enzymol., 2006, 413, 326-344.
[] [PMID: 17046404]
Kim, H.Y.; Choi, I. Ultrafast colorimetric determination of predominant protein structure evolution with gold nanoplasmonic particles. Nanoscale, 2016, 8(4), 1952-1959.
[] [PMID: 26500087]
Javed, I.; Peng, G.; Xing, Y.; Yu, T.; Zhao, M.; Kakinen, A.; Faridi, A.; Parish, C.L.; Ding, F.; Davis, T.P.; Ke, P.C.; Lin, S. Inhibition of amyloid beta toxicity in zebrafish with a chaperone-gold nanoparticle dual strategy. Nat. Commun., 2019, 10(1), 3780.
[] [PMID: 31439844]
Gladytz, A.; Abel, B.; Risselada, H.J. Gold-induced fibril growth: the mechanism of surface-facilitated amyloid aggregation. Angew. Chem. Int. Ed. Engl., 2016, 55(37), 11242-11246.
[] [PMID: 27513605]
Song, M.; Sun, Y.; Luo, Y.; Zhu, Y.; Liu, Y.; Li, H. Exploring the mechanism of inhibition of au nanoparticles on the aggregation of amyloid-β(16-22) peptides at the atom level by all-atom molecular dynamics. Int. J. Mol. Sci., 2018, 19(6), E1815.
[] [PMID: 29925792]
Robinson, M.; Lee, B.Y.; Leonenko, Z. Drugs and drug delivery systems targeting amyloid-β in Alzheimer’s disease. Molecular Science, 2015, 2(3), 332-358.
Gao, N.; Sun, H.; Dong, K.; Ren, J.; Qu, X. Gold-nanoparticle-based multifunctional amyloid-β inhibitor against Alzheimer’s disease. Chemistry, 2015, 21(2), 829-835.
[] [PMID: 25376633]
Praça, C.; Rai, A.; Santos, T.; Cristovão, A.C.; Pinho, S.L.; Cecchelli, R.; Dehouck, M.P.; Bernardino, L.; Ferreira, L.S. A nanoformulation for the preferential accumulation in adult neurogenic niches. J. Control. Release, 2018, 284, 57-72.
[] [PMID: 29902485]

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