摘要
阿尔茨海默病（AD）是一种与蛋白质错误折叠和聚集相关的神经退行性疾病。 AD的病理特征在于由细胞外淀粉样蛋白-β（Aβ）肽和由过度磷酸化的tau蛋白形成的细胞内神经原纤维缠结（NFT）形成的老年斑。 广泛的突触丧失和神经元变性是AD典型的记忆障碍，认知衰退和行为功能障碍的原因。淀粉样变性与乙酰胆碱合成和释放的抑制， N-甲基-D-天冬氨酸（NMDA）受体的过度活化和导致兴奋毒性神经元变性的细胞内钙水平升高有关。目前用于AD治疗的药物是胆碱酯酶抑制剂或NMDA受体拮抗剂;然而，它们仅提供症状缓解并且不改变疾病的进展。Aβ是β-淀粉酶和γ-分泌酶连续切割后淀粉样蛋白前体蛋白（APP）加工的产物，而α-分泌酶的APP蛋白水解产生非淀粉样蛋白产物。根据淀粉样蛋白级联假说，Aβ阻滞抑制导致Aβ积聚和聚集成可溶性低聚物和不溶性原纤维。前者是突触毒性的并且可以诱导tau过度磷酸化，而后者沉积在老年斑中并引发促炎反应，导致氧化应激，神经元变性和神经炎症。因此，Aβ-蛋白质靶向治疗策略是用于治疗和预防AD的有希望的疾病修饰方法。本综述总结了Aβ-蛋白靶向AD药物的最新发现，包括β-分泌酶抑制剂，γ-分泌酶抑制剂和调节剂，α-分泌酶激活剂，Aβ聚集的直接抑制剂和靶向Aβ的免疫疗法，主要集中在目前正在临床试验中的那些。
关键词: 阿尔茨海默病，淀粉样蛋白β，蛋白质聚集，疾病改善疗法，聚集抑制剂，免疫疗法。
[1]
Alzheimer’s Disease International. World Alzheimer Report 2015 The Global Impact of Dementia An analysis of prevalence, incidence, cost & trends. London: Alzheimer’s Disease International (2015).
[2]
Kumar A, Singh A. Ekavali. A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep 67(2): 195-203. (2015).
[3]
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet 377(9770): 1019-31. (2011).
[4]
Aguzzi A, O’Connor T. Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nat Rev Drug Discov 9(3): 237-48. (2010).
[5]
Faustino C, Rijo P, Reis CP. Nanotechnological strategies for nerve growth factor delivery: Therapeutic implications in Alzheimer’s disease. Pharmacol Res 120: 68-87. (2017).
[6]
Pinheiro L, Faustino C. Therapeutic strategies targeting tau protein: implications for Alzheimer’s disease. In: Alzheimer’s disease and treatment, MedDocs Publishers, pp 1-18 (2018).
[7]
Chen G, Chen P, Tan H, Ma D, Dou F, Feng J, et al. Regulation of the NMDA receptor-mediated synaptic response by acetylcholinesterase inhibitors and its impairment in an animal model of Alzheimer’s disease. Neurobiol Aging 29: 1795-804. (2008).
[8]
Nunes-Tavares N, Santos LE, Stutz B, Brito-Moreira J, Klein WL, Ferreira ST, et al. Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloid-β peptide oligomers. J Biol Chem 287: 19377-85. (2012).
[9]
Danysz W, Parsons CG. Alzheimer’s disease, β-amyloid, glutamate, NMDA receptors and memantine - searching for the connections. Br J Pharmacol 167(2): 324-52. (2012).
[10]
De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, et al. Aβ 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 282(15): 11590-601. (2007).
[11]
Kamat PK, Kalani A, Rai S, Swarnkar S, Tota S, Nath C, et al. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: understanding the therapeutic strategies. Mol Neurobiol 53(1): 648-61. (2016).
[12]
Chow VW, Mattson MP, Wong PC, Gleichmann M. An overview of APP processing enzymes and products. Neuromolecular Med 12(1): 1-12. (2010).
[13]
Jan A, Gokce O, Luthi-Carter R, Lashuel HA. The ratio of monomeric to aggregated forms of Aβ40 and Aβ42 is an important determinant of amyloid-β aggregation, fibrillogenesis, and toxicity. J Biol Chem 283(42): 28176-89. (2008).
[14]
Baranello RJ, Bharani KL, Padmaraju V, Chopra N, Lahiri DK, Greig NH, et al. Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease. Curr Alzheimer Res 12: 32-46. (2015).
[15]
Saido T, Leissring MA. Proteolytic degradation of amyloid β-protein. Cold Spring Harb Perspect Med 2: a006379. (2012).
[16]
Yoon S-S, Jo SA. Mechanisms of amyloid-β peptide clearance: potential therapeutic targets for Alzheimer’s disease. Biomol Ther 20(3): 245-55. (2012).
[17]
Jarosz-Griffiths HH, Noble E, Rushworth JV, Hooper XNM. Amyloid-β receptors: the good, the bad, and the prion protein. J Biol Chem 291(7): 3174-83. (2016).
[18]
Ramanathan A, Nelson AR, Sagare AP, Zlokovic BV. Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: the role, regulation and restoration of LRP1. Front Aging Neurosci 7: 136. (2015).
[19]
Wei W, Bodles-Brakhop AM, Barger SW. A role for P-glycoprotein in clearance of Alzheimer amyloid β-peptide from the brain. Curr Alzheimer Res 13(6): 615-20. (2016).
[20]
Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, Siegmund W, et al. Deposition of Alzheimer’s beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics 12(7): 535-41. (2002).
[21]
Hartz AM, Miller DS, Bauer B. Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-β in a mouse model of Alzheimer’s disease. Mol Pharmacol 77(5): 715-23. (2010).
[22]
Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, Deane R, et al. Transport pathways for clearance of human Alzheimer’s amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 27(5): 909-18. (2007).
[23]
Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, et al. ApoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J Clin Invest 118(12): 4002-13. (2008).
[24]
Grasso G, Giuffrida ML, Rizzarelli E. Metallostasis and amyloid β-degrading enzymes. Metallomics 4(9): 937-49. (2012).
[25]
Hamley IW. The amyloid beta peptide: a chemist’s perspective. Role in Alzheimer’s and fibrillization. Chem Rev 112(10): 5147-92. (2012).
[26]
Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43). Neuron 13(1): 45-53. (1994).
[27]
Kakuda N, Miyasaka T, Iwasaki N, Nirasawa T, Wada-Kakuda S, Takahashi-Fujigasaki J, et al. Distinct deposition of amyloid-β species in brains with Alzheimer’s disease pathology visualized with MALDI imaging mass spectrometry. Acta Neuropathol Commun 5(1): 73. (2017).
[28]
Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, et al. Neurotoxicity of Alzheimer’s disease Aβ peptides is induced by snall changes in the Aβ42 to Aβ40 ratio. EMBO J 29(19): 3408-20. (2010).
[29]
Fandos N, Pérez-Grijalba V, Pesini P, Olmos S, Bossa M, Villemagne VL, et al. Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals. Alzheimers Dement 8: 179-87. (2017).
[30]
Ferreira ST, Lourenço MV, Oliveira MM, De Felice FG. Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer’s disease. Front Cell Neurosci 9: 191. (2015).
[31]
Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, et al. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat Neurosci 8(1): 79-84. (2005).
[32]
Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid-β peptide. Nat Rev Mol Cell Biol 8(2): 101-12. (2007).
[33]
Sengupta U, Nilson AN, Kayed R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 6: 42-9. (2016).
[34]
Sheng M, Sabatini BL, Südhof TC. Synapses and Alzheimer’s disease. Cold Spring Harb Perspect Biol 4: a005777. (2012).
[35]
Sivanesan S, Tan A, Rajadas J. Pathogenesis of Abeta oligomers in synaptic failure. Curr Alzheimer Res 10(3): 316-23. (2013).
[36]
Tu S, Okamoto S, Liptom SA, Xu H. Oligomeric Aβ-induced synaptic dysfunction in Alzheimer’s disease. Mol Neurodegener 14: 9-48. (2014).
[37]
Mucke L, Selkoe DJ. Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2: a006338. (2012).
[38]
Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, et al. The relationship between Aβeta and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 22(5): 1858-67. (2002).
[39]
Forny-Germano L, Lyra e Silva NM, Batista AF, Brito-Moreira J, Gralle M, Boehnke SE, et al. Alzheimer’s disease-like pathology induced by amyloid-β oligomers in nonhuman primates. J Neurosci 34(41): 13629-43. (2014).
[40]
He Y, Zheng MM, Ma Y, Han XJ, Ma XQ, Qu CQ, et al. Soluble oligomers and fibrillary species of amyloid β-peptide differentially affect cognitive functions and hippocampal inflammatory response. Biochem Biophys Res Commun 429(3-4): 125-30. (2012).
[41]
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8): 837-42. (2008).
[42]
Müller-Schiffmann A, Herring A, Abdel-Hafiz L, Chepkova AN, Schäble S, Wedel D, et al. Amyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity. Brain 139(Pt 2): 509-25. (2016).
[43]
Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, et al. Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci USA 106(10): 4012-7. (2009).
[44]
Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, et al. Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 73(1): 104-19. (2013).
[45]
Esparza TJ, Gangolli M, Cairn NJ, Brody DL. Soluble amyloid-beta buffering by plaques in Alzheimer disease dementia versus high-pathology controls. PLoS One 13(7): e0200251. (2018).
[46]
Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62(6): 788-801. (2009).
[47]
Li S, Jin M, Koeglsperger T, Shepardson N, Shankar G, Selkoe D. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 31(18): 6627-38. (2011).
[48]
Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52(5): 831-43. (2006).
[49]
Hascup KN, Hascup ER. Soluble amyloid-β42 stimulates glutamate release through activation of the α7 nicotinic acetylcholine receptor. J Alzheimers Dis 53(1): 337-47. (2016).
[50]
Conejero-Goldberg C, Davies P, Ulloa L. Alpha7 nicotinic acetylcholine receptor: a link between inflammation and neurodegeneration. Neurosci Biobehav Rev 32(4): 693-706. (2008).
[51]
Nagele RG, D’Andrea MR, Anderson WJ, Wang HY. Intracellular accumulation of β-amyloid1–42 in neurons is facilitated by the α7 nicotinic acetylcholine receptor in Alzheimer’s disease. Neuroscience 110(2): 199-211. (2002).
[52]
Oz M, Lorke DE, Yang KH, Petroianu G. On the interaction of β-amyloid peptides and α7-nicotinic acetylcholine receptors in Alzheimer’s disease. Curr Alzheimer Res 10(6): 618-30. (2013).
[53]
Puzzo D, Privitera L, Leznik E, Fa M, Staniszewski A, Palmeri A, et al. Picomolar amyloid-β positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28: 14537-45. (2008).
[54]
Kroker KS, Moreth J, Kussmaul L, Rast G, Rosenbrock H. Restoring long-term potentiation impaired by amyloid-beta oligomers: comparison of an acetylcholinesterase inhibitor and selective neuronal nicotinic receptor agonists. Brain Res Bull 96: 28-38. (2013).
[55]
Wang HY, Li W, Benedetti NJ, Lee DH. α7 Nicotinic acetylcholine receptors mediate β-amyloid peptide-induced tau protein phosphorylation. J Biol Chem 278(34): 31547-53. (2003).
[56]
Hu M, Waring JF, Gopalakrishnan M, Li J. Role of GSK-3β activation and α7 nAChRs in Aβ1– 42-induced tau phosphorylation in PC12 cells. J Neurochem 106(3): 1371-7. (2008).
[57]
Egea J, Buendia I, Parada E, Navarro E, León R, Lopez MG. Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochem Pharmacol 97(4): 463-72. (2015).
[58]
Vallés AS, Borroni MV, Barrantes FJ. Targeting brain α7 nicotinic acetylcholine receptors in Alzheimer’s disease: rationale and current status. CNS Drugs 28: 975-87. (2014).
[59]
Russo P, Del Bufalo A, Frustaci A, Fini M, Cesario A. Beyond acetylcholinesterase inhibitors for treating Alzheimer’s disease: α7-nAChR agonists in human clinical trials. Curr Pharm Des 20: 6014-21. (2014).
[60]
Foucault-Fruchard L, Antier D. Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases. Neural Regen Res 12(9): 1418-21. (2017).
[61]
Cai Z, Hussain MD, Yan LJ. Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer’s disease. Int J Neurosci 124: 307-21. (2014).
[62]
Dá Mesquita S, Ferreira AC, Sousa JC, Correia-Neves M, Sousa N, Marques F. Insights on the pathophysiology of Alzheimer’s disease: the cross-talk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci Biobehav Rev 68: 547-62. (2016).
[63]
Ferrara D, Mazzaro N, Canale C, Gasparini L. Resting microglia react to Aβ42 fibrils but do not detect oligomers or oligomer-induced neuronal damage. Neurobiol Aging 35(11): 2444-57. (2014).
[64]
Minter MR, Taylor JM, Crack PJ. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J Neurochem 136(3): 457-74. (2016).
[65]
White JA, Manelli AM, Holmberg KH, Van Eldik LJ, Ladu MJ. Differential effects of oligomeric and fibrillary amyloid-β1–42 on astrocyte-mediated inflammation. Neurobiol Dis 18(3): 459-65. (2005).
[66]
Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement 4: 575-90. (2018).
[67]
Clayton KA, Van Enoo AA, Ikezu T. Alzheimer’s disease: the role of microglia in brain homestasis and proteopathy. Front Neurosci 11: 680. (2017).
[68]
Paranjape GS, Gouwens LK, Osborn DC, Nichols MR. Isolated amyloid-β1-42 protofibrils, but not isolated fibrils, are robust stimulators of microglia. ACS Chem Neurosci 3(4): 302-11. (2012).
[69]
Ferretti MT, Bruno MA, Ducatenzeiler A, Klein WL, Cuello AC. Intracellular Aβ-oligomers and early inflammation in a model of Alzheimer’s disease. Neurobiol Aging 33(7): 1329-42. (2012).
[70]
Zhang Y, Lu L, Jia J, Jia L, Geula C, Pei J, et al. A lifespan observation of a novel mouse model: in vivo evidence supports Aβ oligomer hypothesis. PLoS One 9: e85885. (2014).
[71]
Boza-Serrano A, Yang Y, Paulus A, Deierborg T. Innate immune alterations are elicited in microglial cells before plaque deposition in the Alzheimer’s disease mouse model 5xFAD. Sci Rep 8(1): 1550. (2018).
[72]
Van Eldik L, Carrillo MC, Cole PE, Feuerbach D, Greenberg BD, Hendrix JA, et al. The roles of inflammation and immune mechanisms in Alzheimer’s disease. Alzheimers Dement 2: 99-109. (2016).
[73]
Walters A, Phillips E, Zheng R, Biju M, Kuruvilla T. Evidence for neuroinflammation in Alzheimer’s disease. Prog Neurol Psychiatry 20(5): 25-31. (2016).
[74]
Bisht K, Sharma K, Tremblay M-E. Chronic stress as a risk factor for Alzheimer’s disease: roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress. Neurobiol Stress 9: 9-21. (2018).
[75]
Tejera D, Heneka MT. Microglia in Alzheimer’s disease: the good, the bad and the ugly. Curr Alzheimer Res 13(4): 370-80. (2016).
[76]
Regen F, Hellmann-Regen J, Constantini E, Reale M. Neuroinflammation and Alzheimer’s disease: implications for microglial activation. Curr Alzheimer Res 14(11): 1140-8. (2017).
[77]
Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, et al. TREM2 deficiency eliminates TREM21 inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med 212(3): 287-95. (2015).
[78]
Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Sci Acad USA 110(27): E2518-27. (2013).
[79]
Ahmad MH, Fatima M, Mondal AC. Influence of microglia and astrocyte activation in the neuroinflammatory pathogenesis of Alzheimer’s disease: rational insights for the therapeutic approaches. J Clin Neurosci 59: 6-11. (2019).
[80]
Lee M, Schwab C, Mcgeer PL. Astrocytes are GABAergic cells that modulate microglial activity. Glia 59(1): 152-65. (2011).
[81]
Hanzel CE, Pichet-Binette A, Pimentel LS, Iulita MF, Allard S, Ducatenzeiler A, et al. Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer’s disease. Neurobiol Aging 35(10): 2249-62. (2014).
[82]
Walker D, Lue LF, Paul G, Patel A, Sabbagh MN. Receptor for advanced glycation end product modulators: a new therapeutic target in Alzheimer’s disease. Expert Opin Investig Drugs 24(3): 939- 9 (2015).
[83]
Matrone C, Djelloul M, Taglialatela G, Perrone L. Inflammatory risk factors and pathologies promoting Alzheimer’s disease progression: is RAGE the key? Histol Histopathol 30(2): 125-39. (2015).
[84]
McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging 28(5): 639-47. (2007).
[85]
Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, et al. NSAIDs and enantiomers of flurbiprofen target y-secretase and lower Aβ42in vivo. J Clin Invest 112(3): 440-9. (2003).
[86]
Ronsisvalle N, Di Benedetto G, Parenti C, Amoroso S, Bernardini R, Cantarella G. CHF5074 protects SH-SY5Y human neuronal-like cells from amyloid β25–35 and tumor necrosis factor related apoptosis inducing ligand toxicity in vitro. Curr Alzheimer Res 11(7): 714-24. (2014).
[87]
Sivilia S, Lorenzini L, Giuliani A, Gusciglio M, Fernandez M, Baldassarro VA, et al. Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long-term treatment in Tg2576 mice. BMC Neurosci 14: 44. (2013).
[88]
Porrini V, Lanzillotta A, Branca C, Benarese M, Parrella E, Lorenzini L, et al. CHF5074 (CSP-1103) induces microglia alternative activation in plaque-free Tg2576 mice and primary glial cultures exposed to beta-amyloid. Neuroscience 302: 112-20. (2015).
[89]
ADAPT Research Group, Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JC, et al. Cognitive function over time in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol 65(7): 896-905. (2008).
[90]
Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimers Dement 7(4): 402-11. (2011).
[91]
Jaturapatporn D, Isaac MG, McCleery J, Tabet N. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease. Cochrane Database Syst Rev 15(2): CD006378. (2012).
[92]
Choi SH, Aid S, Bosetti F. The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci 30(4): 174-81. (2009).
[93]
Choi SH, Aid S, Caracciolo L, Minami SS, Niikura T, Matsuoka Y, et al. Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer’s disease. J Neurochem 124(1): 59-68. (2013).
[94]
Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW, et al. Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res 1368: 239-47. (2011).
[95]
Butchart J, Brook L, Hopkins V, Teeling J, Püntener U, Culliford D, et al. Etanercept in Alzheimer disease: a randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 84(21): 2161-8. (2015).
[96]
Shadfar S, Hwang CJ, Lim M-S, Choi D-Y, Hong JT. Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents. Arch Pharm Res 38(12): 2106-19. (2015).
[97]
Mandrekar-Colucci S, Karlo JC, Landreth GE. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J Neurosci 32(30): 10117-28. (2012).
[98]
Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging 32(9): 1626-33. (2011).
[99]
Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 4: e525. (2013).
[100]
Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer’s disease-like amyloid pathology. J Neuroinflammation 9: 62. (2012).
[101]
Parachikova A, Vasileko V, Cribbs DH, LaFerla FM, Green KN. Reductions in Aβ-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation. J Alzheimers Dis 21(2): 527-42. (2010).
[102]
Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12(10): 383-8. (1991).
[103]
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054): 184-5. (1992).
[104]
Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ. Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci USA 108(14): 5819-24. (2011).
[105]
Lei M, Xu H, Li Z, Wang Z, O’Malley TT, Zhang D, et al. Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance. Neurobiol Dis 85: 111-21. (2016).
[106]
Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med 18(5): 421-30. (2016).
[107]
Hatami A, Monjazeb S, Milton S, Glabe CG. Familial Alzheimer’s disease mutations within the amyloid precursor protein alter the aggregation and conformation of the amyloid-β peptide. J Biol Chem 292(8): 3172-85. (2017).
[108]
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488(7409): 96-9. (2012).
[109]
Maloney JA, Bainbridge T, Gustafson A, Zhang S, Kyauk R, Steiner P, et al. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J Biol Chem 289(45): 30990-1000. (2014).
[110]
Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS One 5: e13950. (2010).
[111]
Sakae N, Liu CC, Shinohara M, Frisch-Daiello J, Ma L, Yamazaki Y, et al. ABCA7 deficiency accelerates amyloid-β generation and Alzheimer’s neuronal pathology. J Neurosci 36(13): 3848-59. (2016).
[112]
Kim WS, Li H, Ruberu Chan KS, Elliott DA, Low JK, et al. Deletion of Abca7 increases cerebral amyloid‐β accumulation in the J20 mouse model of Alzheimer’s disease. J Neurosci 33(10): 4387-94. (2013).
[113]
Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 213(5): 667-75. (2016).
[114]
Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE. bRansohoff RM, et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J Neurosci 37(3): 637-47. (2017).
[115]
Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90(4): 724-39. (2016).
[116]
Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, et al. Genome‐wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet 83(5): 623-32. (2008).
[117]
Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome‐wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10): 1094-9. (2009).
[118]
Crehan J, Hardy J, Pocock J. Blockage of CR1 prevents activation of rodent microglia. Neurobiol Dis 54: 139-49. (2013).
[119]
Griciuc A, Serrano-Pozzo A, Parrado AR, Lesinski NA, Asselin CN, Mullin K. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78(4): 631-43. (2013).
[120]
Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains microglia response in an Alzheimer’s disease model. Cell 160(6): 1061-71. (2015).
[121]
Kleinberger G, Yamanishi Y, Suarez‐Calvet M, Czirr E, Lohmann E, Cuyvers E, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 6(243): 243ra286. (2014).
[122]
Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, et al. The neuronal sortilin‐related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39(2): 168-77. (2007).
[123]
Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K, et al. Central role for PICALM in amyloid‐β blood-brain barrier transcytosis and clearance. Nat Neurosci 18(7): 978-87. (2015).
[124]
Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, et al. Neuronal sorting protein‐related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci USA 102(38): 13461-6. (2005).
[125]
Young JE, Boulanger‐Weill J, Williams DA, Woodruff G, Buen F, Revilla AC, et al. Elucidating molecular phenotypes caused by the SORL1 Alzheimer’s disease genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell 16(4): 373-85. (2015).
[126]
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8(6): 595-608. (2016).
[127]
Reitz C. Alzheimer’s disease and the amyloid cascade hypothesis: a critical review. Int J Alzheimers Dis 2012: 369808. (2012).
[128]
Doig AJ, del Castillo-Frias MP, Berthoumieu O, Tarus B, Nasica-Labouze J, Sterpone F, et al. Why is research on amyloid-β failing to give new drugs for Alzheimer’s disease? ACS Chem Neurosci 8(7): 1435-7. (2017).
[130]
Cao J, Hou J, Ping J, Cai D. Advances in developing novel therapeutic strategies for Alzheimer’s disease. Mol Neurodegener 13(1): 64. (2018).
[131]
Lesné SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, et al. Brain amyloid-β oligomers in ageing and Alzheimer’s disease. Brain 136(Pt 5): 1383-98. (2013).
[132]
Cummings J, Lee G, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement (N Y) 4: 195-214. (2018).
[133]
Citron M. Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov 9(5): 387-98. (2010).
[134]
Hong-Qi Y, Zhi-Kun S, Sheng-Di C. Current advances in the treatment of Alzheimer’s disease: focused on considerations targeting Aβ and tau. Transl Neurodegener 1(1): 21. (2012).
[135]
Jia Q, Deng Y, Qing H. Potential therapeutic strategies for Alzheimer’s disease targeting or beyond β-amyloid: insights from clinical trials. BioMed Res Int 2014: 857157. (2014).
[136]
Liu Z, Zhang A, Sun H, Han Y, Kong L, Wang X. Two decades of new drug discovery and development for Alzheimer’s disease. RSC Advances 7: 6046-58. (2017).
[137]
Schenk D, Basi GS, Pangalos MN. Treatment strategies targeting amyloid-β protein. Cold Spring Harb Perspect Med 2: a006387. (2012).
[138]
Kandalepas PC, Sadleir KR, Eimer WA, Zhao J, Nicholson DA, Vassar R. The Alzheimer’s beta-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol 126(3): 329-52. (2013).
[139]
Luo Y, Bolon B, Damore MA, Fitzpatrick D, Liu H, Zhang J, et al. BACE1 (β-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol Dis 14(1): 81-8. (2003).
[140]
Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 280(35): 30797-806. (2005).
[141]
Voytyuk I, De Strooper B, Chávez-Gutiérrez L. Modulation of γ- and β-secretase as early prevention against Alzheimer’s disease. Biol Psychiatry 83(4): 320-7. (2018).
[142]
Nishitomi K, Sakaguchi G, Horikoshi Y, Gray AJ, Maeda M, Hirata-Fukae C, et al. BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. J Neurochem 99(6): 1555-63. (2006).
[143]
Rochin L, Hurbain I, Serneels L, Fort C, Watt B, Leblanc P, et al. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc Natl Acad Sci USA 110(26): 10658-63. (2013).
[144]
Hu X, Fan Q, Hou H, Yan R. Neurological dysfunctions associated with altered BACE1-dependent neuregulin-1 signaling. J Neurochem 136(2): 234-49. (2016).
[145]
Zhu K, Peters F, Filser S, Herms J. Consequences of pharmacological BACE inhibition on synaptic structure and function. Biol Psychiatry 84(7): 478-7. (2018).
[146]
Zhu K, Xiang X, Filser S, Marinkovic P, Dorostkar MM, Crux S, et al. Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6. Biol Psychiatry 83(5): 428-37. (2018).
[147]
Zuhl AM, Nolan CE, Brodney MA, Niessen S, Atchison K, Houle C, et al. Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors. Nat Commun 7: 13042. (2016).
[148]
Ghosh AK, Cárdenas EL, Osswald HL. The design, development, and evaluation of BACE1 inhibitors for the treatment of Alzheimer’s disease. Top Med Chem 24: 27-86. (2017).
[149]
Yan R. Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs. Transl Neurodegener 5: 13. (2016).
[150]
Yan R, Vassar R. Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol 13(3): 319-29. (2014).
[151]
Prati F, Bottegoni G, Bolognesi ML, Cavalli A. BACE-1 inhibitors: from recent single-target molecules to multi-target compounds for Alzheimer’s disease. J Med Chem 61(3): 619-37. (2018).
[152]
May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, et al. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci 31(46): 16507-16. (2011).
[153]
Barão S, Moechars D, Lichtenthaler SF, De Strooper B. BACE1 physiological functions may limit its use as therapeutic target for Alzheimer’s disease. Trends Neurosci 39(3): 158-69. (2016).
[154]
May PC, Willis BA, Lowe SL, Dean RA, Monk SA, Cocke PJ, et al. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J Neurosci 35(3): 1199-210. (2015).
[155]
Lahiri DK, Maloney B, Long JM, Grieg NH. Lessons from a BACE inhibitor trial: off-site but not off base. Alzheimers Dement 10(0): S411-9. (2014).
[156]
Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients. Sci Transl Med 8(363): 363ra150. (2016).
[157]
Hawkes CA, Ng V, McLaurin JA. Small molecule inhibitors of Aβ-aggregation and neurotoxicity. Drug Dev Res 70(2): 111-24. (2009).
[158]
Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 378(18): 1691-703. (2018).
[159]
Jeppson F, Eketjäll S, Janson J, Karlström S, Gustavsson S, Olsson LL, et al. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem 287(49): 41245-57. (2012).
[160]
Henley DB, May PC, Dean RA, Siemers ER. Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer’s disease. Expert Opin Pharmacother 10(10): 1657-64. (2009).
[161]
Swahn BM, Kolmodin K, Karlström S, von Berg S, Söderman P, Holenz J, et al. Design and synthesis of β-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of β-amyloid peptides. J Med Chem 55(21): 9346-61. (2012).
[162]
Cebers G, Lejeune T, Attalla B, Soderberg M, Alexander RC, Budd Haeberlein S, et al. Reversible and species-specific depigmentation effects of AZD3293, a BACE inhibitor for the treatment of Alzheimer’s disease, are related to BACE2 inhibition and confined to epidermis and hair. J Prev Alzheimers Dis 3(4): 202-18. (2016).
[163]
Cebers G, Alexander RC, Haeberlein SB, Han D, Goldwater R, Ereshefsky L, et al. AZD3293: pharmacokinetic and pharmacodynamic effects in healthy subjects and patients with Alzheimer’s disease. J Alzheimers Dis 55(3): 1039-53. (2017).
[164]
Sakamoto K, Matsuki S, Matsuguma K, Yoshihara T, Uchida N, Azuma F, et al. BACE1 inhibitor lanabecestat (AZD3293) in a phase 1 study of healthy Japanese subjects: pharmacokinetics and effects on plasma and cerebrospinal fluid Aβ peptides. J Clin Pharmacol 57(11): 1460-71. (2017).
[165]
Sims JR, Selzler KJ, Downing AM, Willis BA, Aluise CD, Zimmer J, et al. Development review of the BACE1 inhibitor lanabecestat (AZD3293/LY3314814). J Prev Alzheimers Dis 4(4): 247-54. (2017).
[166]
Eketjäll S, Janson J, Kaspersson K, Bogstedt A, Jepsson F, Fälting J, et al. AZD3293: a novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J Alzheimers Dis 50(4): 1109-23. (2016).
[167]
Timmers M, Streffer JR, Russu A, Tominaga Y, Shimizu H, Shiraishi A, et al. Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study. Alzheimers Res Ther 10(1): 85. (2018).
[168]
Timmers M, Van Broeck B, Ramael S, Slemmon J, De Waepenaert K, Russu A, et al. Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor. Alzheimers Dement (N Y) 2(3): 202-12. (2016).
[169]
Neumann U, Ufer M, Jacobson LH, Rouzade-Dominguez M-L, Huledal G, Kolly C, et al. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Mol Med 10: e9316. (2018).
[170]
Brendel M, Jaworska A, Overhoff F, Blume T, Probst F, Gildehaus FJ, et al. Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Aβ deposition rate and plaque burden at treatment initiation. Theranostics 8(18): 4957-68. (2018).
[171]
Panza F, Lozupone M, Solfrizzi V, Sardone R, Piccininni C, Dibello V, et al. BACE inhibitors in clinical development for the treatment of Alzheimer’s disease. Expert Rev Neurother 18(11): 847-57. (2018).
[172]
Volloch V, Rits S. Results of beta secretase-inhibitor clinical trials support amyloid precursor protein-independent generation of beta amyloid in sporadic Alzheimer’s disease. Med Sci 6(2): 45. (2018).
[173]
Dobrowolska Zakaria JA, Vassar RJ. A promising, novel, and unique BACE1 inhibitor emerges in the quest to prevent Alzheimer’s disease. EMBO Mol Med 10(11): e9717. (2018).
[174]
Lopez Lopez C, Caputo A, Liu F, Riviere ME, Rouzade-Dominguez ML, Thomas RG, et al. The Alzheimer’s Prevention Initiative Generation Program: evaluating CNP520 efficacy in the prevention of Alzheimer’s disease. J Prev Alzheimers Dis 4(4): 242-6. (2017).
[175]
Penninkilampi R, Brothers HM, Eslick GD. Pharmacological agents targeting γ-secretase increase risk of cancer and cognitive decline in Alzheimer’s disease patients: a systematic review and meta-analysis. J Alzheimers Dis 53(4): 1395-404. (2016).
[176]
Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369(4): 341-50. (2013).
[177]
Henley DB, Sundell KL, Sethuraman G, Dowsett SA, May PC. Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trials findings. Curr Med Res Opin 30(10): 2021-32. (2014).
[178]
Tagami S, Yanagida K, Kodama TS, Takami M, Mizuta N, Oyama H, et al. Semagacestat is a pseudo-inhibitor of γ-secretase. Cell Reports 21(1): 259-73. (2017).
[179]
Albright CF, Dockens RC, Meredith JE Jr, Olson RE, Slemmon R, Lentz KA, et al. Pharmacodynamics of selective inhibition of γ-secretase by avagacestat. J Pharmacol Exp Ther 344(3): 686-95. (2013).
[180]
Crump CJ, Castro SV, Wang F, Pozdnyakov N, Ballard TE, Sisodia SS, et al. BMS-708163 targets presenilin and lacks notch-sparing activity. Biochemistry 51(37): 7209-11. (2012).
[181]
Tong G, Castaneda L, Wang JS, Sverdlov O, Huang SP, Slemmon R, et al. Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aβ levels in healthy young men. Clin Drug Investig 32(11): 761-9. (2012).
[182]
Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, et al. Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther 34(3): 654-67. (2012).
[183]
Dockens R, Wang JS, Castaneda L, Sverdlov O, Huang SP, Slemmon R, et al. A placebo-controlled, multiple ascending dose study to evaluate the safety, pharmacokinetics and pharmacodynamics of avagacestat (BMS-708163) in healthy young and elderly subjects. Clin Pharmacokinet 51(10): 681-93. (2012).
[184]
Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, et al. A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat. Br J Clin Pharmacol 75(1): 136-45. (2013).
[185]
Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M, Richter RW, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol 69(11): 1430-40. (2012).
[186]
Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol 72(11): 1324-33. (2015).
[187]
Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, et al. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein γ-secretase for the treatment of Alzheimer’s disease. J Pharmacol Exp Ther 331(2): 598-608. (2009).
[188]
Mayer SC, Kreft AF, Harrison B, Abou-Gharbia M, Antane M, Aschmies S, et al. Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer’s disease. J Med Chem 51(23): 7348-51. (2008).
[189]
Probst G, Aubele DL, Bowers S, Dressen D, Garofalo AW, Hom RK, et al. Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolone (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridine-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (ELND007): metabolically stable γ-secretase inhibitors that selectively inhibit the production of amyloid-β over Notch. J Med Chem 56(13): 5261-74. (2013).
[190]
Hopkins CR. ACS chemical neuroscience molecule spotlight on ELND006: another γ-secretase inhibitor fails in the clinic. ACS Chem Neurosci 2(6): 279-80. (2011).
[191]
Sogorb-Esteve A, García-Ayllón MS, Llansola M, Felipo V, Blennow K, Sáez-Valero J. Inhibition of γ-secretase leads to an increase in presenilin-1. Mol Neurobiol 55(6): 5047-58. (2018).
[192]
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomized phase II trial. Lancet Neurol 7(6): 483-93. (2008).
[193]
Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 302(23): 2557-64. (2009).
[194]
Imbimbo BP, Del Giudice E, Colavito D, D’Arrigo A, Dalle Carbonate M, Villetti G, et al. 1-(3′,4′-Dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel γ-secretase modulator, reduces brain β-amyloid pathology in a transgenic mouse model of Alzheimer’s disease without causing peripheral toxicity. J Pharmacol Exp Ther 323(3): 822-30. (2007).
[195]
Imbimbo BP, Hutter-Paier B, Villetti G, Facchinetti F, Cenacchi V, Volta R, et al. CHF5074, a novel γ-secretase modulator, attenuates brain β-amyloid pathology and learning deficit in a mouse model of Alzheimer’s disease. Br J Pharmacol 156(6): 982-93. (2009).
[196]
Imbimbo BP, Frigerio E, Breda M, Fiorentini F, Fernandez M, Sivilia S, et al. Pharmacokinetics and pharmacodynamics of CHF5074 after short-term administration in healthy subjects. Alzheimer Dis Assoc Disord 27(3): 278-86. (2013).
[197]
Ross J, Sharma S, Winston J, Nunez M, Bottini G, Franceschi M, et al. CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study. Curr Alzheimer Res 10(7): 742-53. (2013).
[198]
Rogers K, Felsenstein KM, Hrdlicka L, Tu Z, Albayya F, Lee W, et al. Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol Neurodegener 7: 61. (2012).
[199]
Kounnas MZ, Lane-Donovan C, Nowakowski DW, Herz J, Comer WT. NGP 555, a γ-secretase modulator, lowers the amyloid biomarker, Aβ42, in cerebrospinal fluid while preventing Alzheimer’s disease cognitive decline in rodents. Alzheimers Dement (N Y) 3(1): 65-73. (2017).
[200]
Pitt J, Thorner M, Brautigan D, Larner J, Klein WL. Protection against the synaptic targeting and toxicity of Alzheimer’s-associated Aβ oligomers by insulin mimetic chiro-inositols. FASEB J 27(1): 199-207. (2013).
[201]
Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, et al. ADAM 10 is the physiologically relevant, constitutive α-secretase of the amyloid precursor protein in primary neurons. EMBO J 29(17): 3020-32. (2010).
[202]
Nelson TJ, Sun M-K, Lim C, Sen A, Khan T, Chirila FV, et al. Bryostatin effects on cognitive function and PKCε in Alzheimer’s disease phase IIa and expanded access trials. J Alzheimers Dis 58(2): 521-35. (2017).
[203]
Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, et al. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 25(38): 8807-14. (2005).
[204]
Lee JW, Lee YK, Ban JO, Ha TY, Yun YP, Han SB, et al. Green tea (−)-epigallocatechin-3-gallate inhibits β-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-κB pathways in mice. J Nutr 139(10): 1987-93. (2009).
[205]
Levites Y, Amit T, Mandel S, Youdim MB. Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol (−)-epigallocatechin-3-gallate. FASEB J 17(8): 952-4. (2003).
[206]
Obregon DF, Rezai-Zadeh K, Bai Y, Sun N, Hou H, Ehrhart J, et al. ADAM10 activation is required for green tea (−)-epigallocatechin-3-gallate-induced α-secretase cleavage of amyloid precursor protein. J Biol Chem 281(24): 16419-27. (2006).
[207]
Ehrnhoefer DE, Bieschke J, Boeddrich A, Herbst M, Masino L, Lurz R, et al. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat Struct Mol Biol 15(6): 558-66. (2008).
[208]
Marcade M, Bourdin J, Loiseau N, Peillon H, Rayer A, Drouin D, et al. Etazolate, a neuroprotective drug linking GABAA receptor pharmacology to amyloid precursor protein processing. J Neurochem 106(1): 392-404. (2008).
[209]
Drott J, Desire L, Drouin D, Pando M, Haun F. Etazolate improves performance in a foraging and homing task in aged rats. Eur J Pharmacol 634(1-3): 95-100. (2010).
[210]
Vellas B, Sol O, Snyder PJ, Ousset PJ, Haddad R, Maurin M, et al. EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res 8(2): 203-12. (2011).
[211]
Holthoewer D, Endres K, Schuck F, Hiemke C, Schmitt U, Fahrenholz F. Acitretin, an enhancer of alpha-secretase expression, crosses the blood-brain barrier and is not eliminated by P-glycoprotein. Neurodegener Dis 10(1-4): 224-8. (2012).
[212]
Endres K, Fahrenholz F, Lotz J, Hiemke C, Teipel S, Lieb K, et al. Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin. Neurology 83(21): 1930-5. (2014).
[213]
Opazo C, Luza S, Villemagne VL, Volitakis I, Rowe C, Barnham KJ, et al. Radioiodinated clioquinol as a biomarker for β-amyloid: Zn2+ complexes in Alzheimer’s disease. Aging Cell 5(1): 69-79. (2006).
[214]
Matlack KE, Tardiff DF, Narayan P, Hamamichi S, Caldwell KA, Caldwell GA, et al. Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity. Proc Natl Acad Sci USA 111(11): 4013-8. (2014).
[215]
Grossi C, Francese S, Casini A, Rosi MC, Luccarini I, Fiorentini A, et al. Clioquinol decreases amyloid-β burden and reduces working memory impairment in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis 17(2): 423-40. (2009).
[216]
Wang T, Wang CY, Shan ZY, Teng WP, Wang ZY. Clioquinol reduces zinc accumulation in neuritic plaques and inhibits the amyloidogenic pathway in AβPP/PS1 transgenic mouse brain. J Alzheimers Dis 29(3): 549-59. (2012).
[217]
Ritchie CW, Bush AI, Mackinnon A, MacFarlane S, Mastwyk M, MacGregor L, et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60(12): 1685-91. (2003).
[218]
Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, et al. Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ. Neuron 59(1): 43-55. (2008).
[219]
Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomized, placebo-controlled trial. Lancet Neurol 7(9): 779-86. (2008).
[220]
Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis A, Bedo J, et al. PBT2 rapidly improves cognition in Alzheimer’s disease: additional phase II analyses. J Alzheimers Dis 20(2): 509-16. (2010).
[221]
Re F, Airoldi C, Zona C, Masserini M, La Ferla B, Quattrocchi N, et al. Beta amyloid aggregation inhibitors: small molecules as candidate drugs for therapy of Alzheimer’s disease. Curr Med Chem 17(27): 2990-3006. (2010).
[222]
Ladiwala AR, Dordick JS, Tessier PM. Aromatic small molecules remodel toxic soluble oligomers of amyloid β through three independent pathways. J Biol Chem 286(5): 3209-18. (2011).
[223]
Giorgetti S, Greco C, Tortora P, Aprile FA. Targeting amyloid aggregation: an overview of strategies and mechanisms. Int J Mol Sci 19(9): 2677. (2018).
[224]
Yamada M, Ono K, Hamaguchi T, Noguchi-Shinohara M. Natural phenolic compounds as therapeutic and preventive agents for cerebral amyloidosis. Adv Exp Med Biol 863: 73-94. (2015).
[225]
Freyssin A, Page G, Fauconneau B, Rioux Bilan A. Natural polyphenols effects on protein aggregates in Alzheimer’s and Parkinson’s prion-like diseases. Neural Regen Res 13(6): 955-61. (2018).
[226]
Hamaguchi T, Ono K, Murase A, Yamada M. Phenolic compounds prevent Alzheimer’s pathology through different effects on the amyloid-β aggregation pathway. Am J Pathol 175(6): 2557-65. (2009).
[227]
Biancalana M, Koide S. Molecular mechanism of Thioflavin-T binding to amyloid fibrils. Biochim Biophys Acta 1804(7): 1405-12. (2010).
[228]
Xue C, Lin TY, Chang D, Guo Z. Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation. R Soc Open Sci 4(1): 160696. (2017).
[229]
Wu C, Biancalana M, Koide S, Shea JE. Binding modes of thioflavin-T to the single-layer β-sheet of the peptide self-assembly mimics. J Mol Biol 394(4): 627-33. (2009).
[230]
Pederson MO, Mikkelsen K, Behrens MA, Pedersen JS, Enghild JJ, Skrydstrup T, et al. NMR reveals two-step association of Congo Red to amyloid β in low-molecular-weight aggregates. J Phys Chem B 114(48): 16003-10. (2010).
[231]
Wu C, Scott J, Shea JE. Binding of Congo red to amyloid protofibrils of the Alzheimer Aβ9–40 peptide probed by molecular dynamics simulations. Biophys J 103(3): 550-7. (2012).
[232]
Bose PP, Chatterjee U, Xie L, Johansson J, Göthelid E, Arvidsson PI. Effects of Congo red on Aβ1–40 fibril formation process and morphology. ACS Chem Neurosci 1(4): 315-24. (2010).
[233]
Lendel C, Bolognesi B, Wahlström A, Dobson CM, Gräslund A. Detergent-like interaction of Congo red with the amyloid β peptide. Biochemistry 49(7): 1358-60. (2010).
[234]
Crowther DC, Kinghorn KJ, Miranda E, Page R, Curry JA, Duthie FA, et al. Intraneuronal Aβ, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer’s disease. Neuroscience 132(1): 123-35. (2005).
[235]
Necula M, Breydo L, Milton S, Kayed R, van der Veer WE, Tone P, et al. Methylene blue inhibits amyloid Aβ oligomerization by promoting fibrillization. Biochemistry 46(30): 8850-60. (2007).
[236]
Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, et al. Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280(7): 5892-901. (2005).
[237]
Rao PP, Mohamed T, Teckwani K, Tin G. Curcumin binding to beta amyloid: a computational study. Chem Biol Drug Des 86(4): 813-20. (2015).
[238]
Thapa A, Jett SD, Chi EY. Curcumin attenuates amyloid-β aggregate toxicity and modulates amyloid-β aggregation pathway. ACS Chem Neurosci 7(1): 56-68. (2016).
[239]
Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, et al. Oral curcumin for Alzheimer’s disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther 4(5): 43. (2012).
[240]
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 67(1): 27-37. (2006).
[241]
Reinke AA, Gestwicki JE. Structure-activity relationships of amyloid beta-aggregation inhibitors based on curcumin: influence of linker length and flexibility. Chem Biol Drug Des 70(3): 206-15. (2007).
[242]
Ge JF, Qiao JP, Qi CC, Wang CW, Zhou JN. The binding of resveratrol to monomer and fibril amyloid beta. Neurochem Int 61(7): 1192-201. (2012).
[242]
Ladiwala AR, Lin JC, Bale SS, Marcelino-Cruz AM, Bhattacharya M, Dordick JS, et al. Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Aβ into off-pathway conformers. J Biol Chem 285(31): 24228-37. (2010).
[244]
Granzotto A, Zatta P. Resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties against Aβ and Aβ-metal complexes toxicity. PLoS One 6(6): e21565. (2011).
[245]
Jia Y, Wang N, Liu X. Resveratrol and amyloid-beta: Mechanistic insights. Nutrients 9(10): 1122. (2017).
[246]
Feng X, Liang N, Zhu D, Gao Q, Peng L, Dong H, et al. Resveratrol inhibits β-amyloid-induced neuronal apoptosis through regulation of SIRT1-ROCK1 signaling pathway. PLoS One 8(3): e59888. (2013).
[247]
Ma T, Tan MS, Yu JT, Tan L. Resveratrol as a therapeutic agent for Alzheimer’s disease. BioMed Res Int 2014: 350516. (2014).
[248]
Zhu CW, Grossman H, Neugroschl J, Parker S, Burden A, Luo X, et al. A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer’s disease: a pilot study. Alzheimers Dement (N Y) 4: 609-16. (2018).
[249]
Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, et al. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J Neuroinflammation 14(1): 1. (2017).
[250]
Matsuzaki K, Noguch T, Wakabayashi M, Ikeda K, Okada T, Ohashi Y, et al. Inhibitors of amyloid β-protein aggregation mediated by GM1-containing raft-like membranes. Biochim Biophys Acta 1768(1): 122-30. (2007).
[251]
Iannuzzi C, Irace G, Sirangelo I. The effect of glycosaminoglycans (GAGs) on amyloid aggregation and toxicity. Molecules 20(2): 2510-28. (2015).
[252]
Gervais F, Paquette J, Morissette C, Krzywkowski P, Yu M, Azzi M, et al. Targeting soluble Aβ peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging 28(4): 537-47. (2007).
[253]
Aisen PS, Saumier D, Briand R, Laurin J, Gervais F, Tremblay P, et al. A phase II study targeting amyloid-β with 3APS in mild-to-moderate Alzheimer disease. Neurology 67(10): 1757-63. (2006).
[254]
Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D, Garceau D, et al. Tramiprosate in mild-to-moderate Alzheimer’s disease – a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Arch Med Sci 7(1): 102-11. (2011).
[255]
Kocis P, Tolar M, Yu J, Sinko W, Ray S, Blennow K, et al. Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer’s disease: integrating molecular analytical methods, pharmacokinetic and clinical data. CNS Drugs 31(6): 495-509. (2017).
[256]
Abushakra S, Porsteinsson A, Scheltens P, Sadowsky C, Vellas B, Cummings J, et al. Clinical effects of tramiprosate in APOE4/4 homozygous patients with mild Alzheimer’s disease suggest disease modification potential. J Prev Alzheimers Dis 4(3): 149-56. (2017).
[257]
Hey JA, Yu JY, Versavel M, Abushakra S, Kocis P, Power A, et al. M. Clinical pharmacokinetics and safety of ALZ-801, a novel prodrug of tramiprosate in development for the treatment of Alzheimer’s disease. CNS Drugs 57(3): 315-33. (2018).
[258]
Hey JA, Kocis P, Hort J, Abushakra S, Power A, Vyhnálek M, et al. Discovery and identification of an endogenous metabolite of tramiprosate and its prodrug ALZ-801 that inhibits beta amyloid oligomer formation in the human brain. CNS Drugs 32(9): 849-61. (2018).
[259]
McLaurin J, Kierstead ME, Brown ME, Hawkes CA, Lambermon MH, Phinney AL, et al. Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med 12(7): 801-8. (2006).
[260]
Ma K, Thomason LA, McLaurin J. scyllo-Inositol, preclinical, and clinical data for Alzheimer’s disease. Adv Pharmacol 64: 177-212. (2012).
[261]
Jin M, Selkoe DJ. Systematic analysis of time-dependent neural effects of soluble amyloid β oligomers in culture and in vivo: prevention by scyllo-inositol. Neurobiol Dis 82: 152-63. (2015).
[262]
Fenili D, Brown M, Rappaport R, McLaurin J. Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology. J Mol Med (Berl) 85(6): 603-11. (2007).
[263]
Liang E, Garzone P, Cedarbaum JM, Koller M, Tran T, Xu V, et al. Pharmacokinetic profile of orally administered scyllo-inositol (ELND005) in plasma, cerebrospinal fluid and brain, and corresponding effect on amyloid-beta in healthy subjects. Clin Pharmacol Drug Dev 2(2): 186-94. (2013).
[264]
Salloway S, Sperling R, Keren R, Porsteinsson AP, van Dyck CH, Tariot PN, et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology 77(13): 1253-62. (2011).
[265]
Lee D, Lee WS, Lim S, Kim YK, Jung HY, Das S, et al. A guanidine-appended scyllo-inositol derivative AAD-66 enhances brain delivery and ameliorates Alzheimer’s phenotypes. Sci Rep 7(1): 14125. (2017).
[266]
Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335(6075): 1503-6. (2012).
[267]
Fantini J, Di Scala C, Yahi N, Troadec J-D, Sadelli K, Chahinian H, et al. Bexarotene blocks calcium-permeable ion channels formed by neurotoxic Alzheimer’s β-amyloid peptides. ACS Chem Neurosci 5(3): 216-24. (2014).
[268]
Habchi J, Arosio P, Perni M, Costa AR, Yagi-Utsumi M, Joshi P, et al. An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease. Sci Adv 2(2): e1501244. (2016).
[269]
Cummings JL, Zhong K, Kinney JW, Heaney C, Moll-Tudla J, Joshi A, et al. Double-blind, placebo-controlled, proof-of-concept trial of bexarotene in moderate Alzheimer’s disease. Alzheimers Res Ther 8: 4. (2016).
[270]
Lannfelt L, Moller C, Basun H, Osswald G, Sehlin D, Satlin A, et al. Perspectives on future Alzheimer therapies: amyloid-b protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res Ther 6(2): 16. (2014).
[271]
Lacosta AM, Pascual-Lucas M, Pesini P, Casabona D, Perez-Grijalba V, Marcos-Campos I, et al. Safety, tolerability and immunogenicity of an active anti-Aβ40 vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res Ther 10(1): 12. (2018).
[272]
Sumner IL, Edwards RA, Asuni AA, Teeling JL. Antibody engineering for optimized immunotherapy in Alzheimer’s disease. Front Neurosci 12: 254. (2018).
[273]
Schilling S, Rahfeld J-U, Lues I, Lemere CA. Passive Aβ immunotherapy: current achievements and future perspectives. Molecules 23(5): 1068. (2018).
[274]
Bittar A, Sengupta U, Kayed R. Prospects for strain-specific immunotherapy in Alzheimer’s disease and tauopathies. NPJ Vaccines 3: 9. (2018).
[275]
van Dyck CH. Anti-amyloid-β monoclonal antibodies for Alzheimer’s disease: pitfalls and promise. Biol Psychiatry 83(4): 311-9. (2018).
[276]
Wang CH, Wang P-N, Chiu M-J, Finstad CL, Lin F, Lynn S, et al. UB-311, a novel UBITh® amyloid β peptide vaccine for mild Alzheimer’s disease. Alzheimers Dement 3(2): 262-72. (2017).
[277]
Folch J, Ettcheto M, Petrov D, Abad S, Pedrós I, Marin M, et al. Review of the advances in treatment for Alzheimer disease: strategies for combating β-amyloid protein. Neurologia 33(1): 47-58. (2018).
[278]
Delrieu J, Ousset PJ, Voisin T, Vellas B. Amyloid beta peptide immunotherapy in Alzheimer disease. Rev Neurol (Paris) 170(12): 739-48. (2014).
[280]
Cehlar O, Skrabana R, Revajova V, Novak M. Structural aspects of Alzheimer’s disease immunotherapy targeted against amyloid-beta peptide. Bratisl Med J 119(4): 201-4. (2018).
[281]
Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, et al. Clinical effects of Aβ immunization (AN1792) in patients with AD in a interrupted trial. Neurology 64(9): 1553-62. (2005).
[282]
Winblad B, Graf A, Riviere M-E, Andreasen N, Ryan JM. Active immunotherapy options for Alzheimer’s disease. Alzheimers Res Ther 6(1): 7. (2014).
[283]
Agadjanyan MG, Petrovsky N, Ghochikyan A. A fresh perspective from immunologists and vaccine researchers: Active vaccination strategies to prevent and reverse Alzheimer’s disease. Alzheimers Dement 11(10): 1246-59. (2015).
[284]
Vandenberghe R, Riviere M-E, Caputo A, Sovago J, Maguire RP, Farlow M, et al. Active Aβ immunotherapy CAD106 in Alzheimer’s disease: A phase 2b study. Alzheimers Dement 3(1): 10-22. (2017).
[285]
Pasquier F, Sadowsky C, Holstein A, Leterme GP, Peng Y, Jackson N, et al. Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate Alzheimer’s disease. J Alzheimers Dis 51(4): 1131-43. (2016).
[286]
Hull M, Sadowsky C, Arai H, Le Prince Leterme G, Holstein A, Booth K, et al. Long-term extensions of randomized vaccination trials of ACC-001 and QS-21 in mild to moderate Alzheimer’s disease. Curr Alzheimer Res 14(7): 696-708. (2017).
[287]
Kool M, Fierens K, Lambrecht BN. Alum adjuvant: some of the tricks of the oldest adjuvant. J Med Microbiol 61(Pt 7): 927-34. (2012).
[288]
Schneeberger A, Hendrix S, Mandler M, Ellison N, Bürger V, Brunner M, et al. Results from a phase II study to assess the clinical and immunological activity of AFFITOPE® AD02 in patients with early Alzheimer’s disease. J Prev Alzheimers Dis 2(2): 103-14. (2015).
[289]
Yu Y-Z, Xu Q. Prophylactic immunotherapy of Alzheimer’s disease using recombinant amyloid-β B-cell epitope chimeric protein as subunit vaccine. Hum Vaccin Immunother 12(11): 2801-4. (2016).
[290]
Tariot PN, Langbaum JB, Reinman EM. What are we willing to accept for preventing Alzheimer’s disease? – Investigators’ reply. Lancet Neurol 15(7): 660-1. (2016).
[291]
Tabarkiewicz J. Advances in active and passive immunotherapy for Alzheimer’s disease – a short review. Medical Review 14(1): 93-6. (2016).
[292]
Schneeberger A, Mandler M, Otawa O, Zauner W, Mattner F, Schmidt W. Development of AFFITOPE vaccines for Alzheimer’s disease (AD) – from concept to clinical testing. Alzheimers Dement 5(4): P257. (2009).
[293]
Schneeberger A, Mandler M, Mattner F, Schmidt W. AFFITOME® technology in neurodegenerative diseases: the doubling advantage. Hum Vaccin 6(11): 948-52. (2010).
[294]
Mandler M, Santic R, Gruber P, Cinar Y, Pichler D, Funke SA, et al. Tailoring the antibody response to aggregated Aβ using novel Alzheimer-vaccines. PLoS One 10(1): e0115237. (2015).
[295]
Hendrix S, Ellison N, Stanworth S, Tierney L, Mattner F, Schmidt W, et al. Methodological aspects of the phase II study AFF006 evaluating amyloid-beta -targeting vaccine AFFITOPE® AD02 in early Alzheimer’s disease - prospective use of novel composite scales. J Prev Alzheimers Dis 2(2): 91-102. (2015).
[296]
Hu Y-Z, Xu Q. Prophylactic immunotherapy of Alzheimer’s disease using recombinant amyloid-β B-cell epitope chimeric protein as subunit vaccine. Hum Vaccin Immunother 12(11): 2801-4. (2016).
[297]
Cynis H, Frost JL, Crehan H, Lemere CA. Immunotherapy targeting pyroglutamate-3 Aβ: prospects and challenges. Mol Neurodegener 11(1): 48. (2016).
[298]
Davtyan H, Ghochikyan A, Petrushina I, Hovakimyan A, Davtyan A, Poghosyan A, et al. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: Prelude to a clinical trial. J Neurosci 33(11): 4923-34. (2013).
[299]
Liu B, Frost JL, Sun J, Fu H, Grimes S, Blackburn P, et al. MER5101, a novel Aβ1-15:DT conjugate vaccine, generates a robust anti-Aβ antibody response and attenuated Aβ pathology and cognitive deficits in APPswe/PS1ΔE9 transgenic mice. J Neurosci 33(16): 7027-37. (2013).
[300]
Martins YA, Tsuchida CJ, Antoniassi P, Demarchi IG. Efficacy and safety of the immunization with DNA for Alzheimer’s disease in animal models: a systematic review from literature. J Alzheimer’s Dis Rep 1(1): 195-217. (2017).
[301]
Lambracht-Washington D, Fu M, Wight-Carter M, Riegel M, Rosenberg RN. Evaluation of a DNA Aβ42 vaccine in aged NZW rabbits: antibody kinetics and immune profile after intradermal immunization with full-length DNA Aβ42 trimer. J Alzheimers Dis 57(1): 97-112. (2017).
[302]
Matsumoto Y, Niimi N, Kohyama K. Development of a new DNA vaccine for Alzheimer disease targeting a wide range of Aβ species and amyloidogenic peptides. PLoS One 8(9): e75203. (2013).
[303]
Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann B, Brooks DJ, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 69(2): 198-207. (2012).
[304]
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4): 311-21. (2014).
[305]
Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4): 322-33. (2014).
[306]
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537(7618): 50-6. (2016).
[307]
Cummings JL, Cohen S, van Dyck CH, Brody M, Curtis G, Cho W, et al. ABBY-A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 90: e1889-97. (2018).
[308]
Landen JW, Andreasen N, Cronenberger CL, Schwartz PF, Börjesson-Hanson A, Östlund H, et al. Ponezumab in mild-to-moderate Alzheimer’s disease: randomized phase II PET-PIB study. Alzheimers Dement 3(3): 393-401. (2017).
[309]
Bouter Y, Lopez Noguerola JS, Tucholla P, Crespi GA, Parker MW, Wiltfang J, et al. Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against Ntruncated Abeta in sporadic Alzheimer disease cases and mouse models. Acta Neuropathol 130(5): 713-29. (2015).
[310]
Miles LA, Crespi GA, Doughty L, Parker MW. Bapineuzumab captures the N-terminus of the Alzheimer’s disease amyloid-β peptide in a helical conformation. Sci Rep 3: 1302. (2013).
[311]
Bard F, Fox M, Friedrich S, Seubert P, Schenk D, Kinney GG, et al. Sustained levels of antibodies against Aβ in amyloid-rich regions of the CNS following intravenous dosing in human APP transgenic mice. Exp Neurol 238: 38-43. (2012).
[312]
Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer’s disease. Neurology 73(24): 2061-70. (2009).
[313]
Vandenberghe R, Rinne JO, Boada M, Katayama S, Scheltens P, Vellas B, et al. Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther 8(1): 18. (2016).
[314]
Crespi GA, Hermans SJ, Parker MW, Miles LA. Molecular basis for mid-region amyloid-β capture by leading Alzheimer’s disease immunotherapies. Sci Rep 5: 9649. (2015).
[315]
Hefti F, Goure WF, Jerecic J, Iverson KS, Walicke PA, Krafft GA. The case for soluble Aβ oligomers as a drug target in Alzheimer’s disease. Trends Pharmacol Sci 34(5): 261-6. (2013).
[316]
Dodart JC, Bales KR, Gannon KS, Greene SJ, Demattos RB, Mathis C, et al. Immunization reverses memory deficits without reducing brain ab burden in Alzheimer’s disease model. Nat Neurosci 5(5): 45-7. (2002).
[317]
Wessels AM, Siemers ER, Yu P, Andersen SW, Holdrige KC, Sims JR, et al. A combined measure of cognition and function for clinical trials: the integrated Alzheimer’s Disease Rating Scale (iADRS). J Prev Alzheimers Dis 2(4): 227-41. (2015).
[318]
Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of Solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 378(4): 321-30. (2018).
[319]
Bales KR, O’Neill SM, Pozdnyakov N, Pan F, Caouette D, Pi Y, et al. Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity. Brain 139(2): 563-77. (2016).
[320]
Freeman GB, Brown TP, Wallace K, Bales KR. Chronic administration of an aglycosylated murine antibody of Ponezumab does not worsen microhemorrhages in aged Tg2576 mice. Curr Alzheimer Res 9(9): 1059-68. (2012).
[321]
Landen JW, Zhao Q, Cohen S, Borrie M, Woodward M, Billing CB Jr, et al. Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: A phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clin Neuropharmacol 36(1): 14-23. (2013).
[322]
Novakovic D, Feligioni M, Scaccianoce S, Caruso A, Piccinin S, Schepisi C, et al. Profile of gantenerumab and its potential in the treatment of Alzheimer’s disease. Drug Des Devel Ther 7: 1359-64. (2013).
[323]
Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J Alzheimers Dis 28(1): 49-69. (2012).
[324]
Scheltens P, Nikolcheva T, Lasser R, Ostrowitzki S, Boada M, Dubois B, et al. Biomarker Data from SCarlet RoAd – a Global
Phase 3 study of gantenerumab in patients with prodromal AD. The
Alzheimer’s association international conference (AAIC) (2015).
[cited 2018 September 25]. Available from: https://www. alz.org/aaic/abstracts/abstr-archives.aspI
[325]
Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nokolcheva T, et al. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 9(1): 95. (2017).
[326]
Tariot PN, Lopera F, Langbaum JB, Thomas RG, Hendrix S, Schneider LS, et al. The Alzheimer’s prevention initiative Autosomal-Dominant Alzheimer’s Disease Trial: a study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s disease, including a placebo-treated noncarrier cohort. Alzheimers Dement (N Y) 4: 150-60. (2018).
[327]
Blaettler T, Smith J, Smith J, Paul R, Asnaghi V, Fuji R, et al. Clinical trial design of CREAD: A randomized, double-blind, placebo-controlled, parallel-group phase 3 study to evaluate Crenezumab treatment in patients with prodromal-to-mild Alzheimer’s disease. Alzheimers Dement 12: 609. (2016).
[328]
Demattos RB, Lu J, Tang Y, Racke MM, Delong CA, Tzaferis JA, et al. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer’s disease mice. Neuron 76(5): 908-20. (2012).
[329]
Kastanenka KV, Bussiere T, Shakerdge N, Qian F, Weinreb PH, Rhodes K, et al. Immunotherapy with aducanumab restores calcium homeostasis in Tg2576 mice. J Neurosci 36(50): 12549-58. (2016).
[330]
Viglietta V, O’Gorman J, Williams L, Tian Y, Sandbrock A, Doody R, et al. Randomized, double-blind, placebo-controlled
studies to evaluate treatment with Aducanumab (BIIB037) in patients
with early Alzheimer’s disease: phase 3 study design
(S1.003). Neurology 86(16): S1.003 (2016).
[331]
Pradier L, Blanchard V, Debeir T, Barneoud P, Canton T, Menager J, et al. SAR228810: an antiprotofibrillar beta-amyloid antibody designed to reduce risk of amyloid-related imaging abnormalities (ARIA). Alzheimers Dement 9(4): 808-9. (2013).
[332]
Logovinsky V, Satlin A, Lai R, Swanson C, Kaplow J, Osswald G, et al. Safety and tolerability of BAN2401 - a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res Ther 8(1): 14. (2016).
[333]
Satlin A, Wang J, Logovinsky V, Berry S, Swanson C, Dhadda S, et al. Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer’s disease. Alzheimers Dement 2(1): 1-12. (2016).
[334]
Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, et al. The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Aβ protofibril formation. Nat Neurosci 4(9): 887-93. (2001).
[335]
Sölvander S, Nikitidou E, Gallasch L, Zyśk M, Söderberg L, Sehlin D, et al. The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neuron from Aβ-induced cell death. J Neuroinflammation 15(1): 98. (2018).
[336]
Andreasen N, Simeoni M, Ostlund H, Lisjo PI, Fladby T, Loercher AE, et al. First administration of the Fc-attenuated anti-β amyloid antibody GSK933776 to patients with mild Alzheimer’s disease: a randomized, placebo controlled study. PLoS One 10: e0098153. (2015).
[337]
Rosenfeld PJ, Berger B, Reichel E, Danis RP, Gress A, Ye L, et al. A randomized phase 2 study of an anti-amyloid β monoclonal antibody in geographic atrophy secondary to age-related macular degeneration. Ophthalmol Retina 2(10): 1028-40. (2018).
[338]
Delnomdedieu M, Duvvuri S, Li DJ, Atassi N, Lu M, Brashear HR, et al. First-in-human safety and long-term exposure data for AAB-003 (PF- 05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer’s disease. Alzheimers Res Ther 8(1): 12. (2016).
[339]
Montoliu-Gaya L, Villegas S. I mmunotherapy for neurodegenerative diseases: the Alzheimer’s disease paradigm. Curr Opin Chem Eng 19: 59-67. (2018).
[340]
Kaplan J, Silverman JM, Gibbs E, Wang J, Peng X, Plotkin SS, et al. Targeting of toxic amyloid-beta oligomer species by monoclonal antibody PMN310: precision drug design for Alzheimer’s disease. Alzheimers Dement 13(7): 952. (2017).
[341]
Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, et al. The DIAN-TU Next Generation Alzheimer’s prevention trial: Adaptive design and disease progression model. Alzheimers Dement 13: 8-19. (2017).
[342]
Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino G, Santamato A, et al. Immunotherapy for Alzheimer’s disease: from anti-β-amyloid to tau-based immunization strategies. Immunotherapy 4(2): 213-38. (2018).
[343]
Sperling R, Mormino E, Johnson K. The evolution of preclinical Alzheimer’s disease: implications for prevention trials. Neuron 84(3): 608-22. (2014).
[344]
Sperling RA, Rentz DM, Johnson KA, Karlawish J, Donohue DM, Salmon DP, et al. The A4 study: stopping AD before symptoms begin? Sci Transl Med 6(228): 228fs13. (2014).
[345]
Antonios G, Borgers H, Richard BC, Brauß A, Meißner J, Weggen S, et al. Alzheimer therapy with an antibody against N-terminal Ab 4-X and pyroglutamate Ab 3-X. Sci Rep 5: 17338. (2015).
[346]
Jin M, O’Nuallain B, Hong W, Boyd J, Lagomarsino VN, O’Malley TT, et al. An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease. Nat Commun 9(1): 2676. (2018).
Call for Papers in Thematic Issues
31 December, 2025
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
31 December, 2024
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
25 December, 2024
Early nutritional intervention and physical activity in the prevention of Alzheimer's disease and other dementias
The aim is to broaden the knowledge about the impact of the consumption of food ingredients, diet ingredients, methods of processing of food raw materials as well as the impact of composing of diets on the possibility of preventing Alzheimer's disease and other types of dementia at each stage of ...read more
31 December, 2025
Integrative Perspectives on Neurodegeneration and Aging: From Molecular Insights to Therapeutic Strategies
The increasing burden of age-related neurodegenerative diseases demands an immediate and pressing need for research in all aspects, from molecular mechanisms to therapeutic interventions. The special issue in Current Alzheimer Research "Integrative Perspectives on Neurodegeneration and Aging: From Molecular Insights to Therapeutic Strategies" aims to highlight the summary of state-of-the-art ...read more
Related Journals
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Diabetes Reviews
Current Neuropharmacology
Current Neurovascular Research
Central Nervous System Agents in Medicinal Chemistry
Current Respiratory Medicine Reviews
Current Pediatric Reviews
Infectious Disorders - Drug Targets
Endocrine, Metabolic & Immune Disorders - Drug Targets
Current Stem Cell Research & Therapy
Related Books
Frontiers in Clinical Drug Research-Dementia
COVID-19: Causes, Transmission, Diagnosis, and Treatment
Skeletal Muscle Health in Metabolic Diseases
Thyroid and Brain: Understanding the Actions of Thyroid Hormones in Brain Development and Function
Common Lip Diseases: A Clinical Guide
Interventional Pain Surgery
Endoscopy and Fetoscopy Techniques for the Brain and Neuroaxis
Frontiers in Stem Cell and Regenerative Medicine Research
Textbook of Advanced Dermatology: Pearls for Academia and Skin Clinics (Part 2)
Women’s Health: A Comprehensive Guide to Common Health Issues in Women
Article Metrics
294
24
1