Preclinical to phase II amyloid beta (A_β) peptide modulators under investigation for Alzheimer’s disease

References

• Sheng M, Sabatini BL, Sudhof TC. Synapses and Alzheimer’s disease. Cold Spring Harb Perspect Biol. 2012;4:1–18.
   Web of Science ®Google Scholar
• Selkoe DJ. Preventing Alzheimer’s disease. Science. 2012;337:1488–1492.
   PubMed Web of Science ®Google Scholar
• Citron M. Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov. 2010;9:387–398.
   PubMed Web of Science ®Google Scholar
• Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl). 1991;82:239–259.
   PubMed Web of Science ®Google Scholar
• Herrmann N, Chau SA, Kircanski I, et al. Current and emerging drug treatment options for Alzheimer’s disease: a systematic review. Drugs. 2011;71:2031–2065.
   PubMed Web of Science ®Google Scholar
• Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Am J Geriatr Psychiatry. 1907;64:146–148.
   Google Scholar
• Lesne S, Koh MT, Kotilinek L, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352–357.
   PubMed Web of Science ®Google Scholar
• Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–185.
   PubMed Web of Science ®Google Scholar
• Cappai R, Barnham KJ. Delineating the mechanism of Alzheimer’s disease A beta peptide neurotoxicity. Neurochem Res. 2008;33:526–532.
   PubMed Web of Science ®Google Scholar
• Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356.
   PubMed Web of Science ®Google Scholar
• Barghorn S, Nimmrich V, Striebinger A, et al. Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer’s disease. J Neurochem. 2005;95:834–847.
   PubMed Web of Science ®Google Scholar
• Lacor PN, Buniel MC, Furlow PW, et al. 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;27:796–807.
   PubMed Web of Science ®Google Scholar
• Wilcox KC, Lacor PN, Pitt J, et al. Abeta oligomer-induced synapse degeneration in Alzheimer’s disease. Cell Mol Neurobiol. 2011;31:939–948.
   PubMed Web of Science ®Google Scholar
• Sokolow S, Luu SH, Nandy K, et al. Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer’s disease cortex. Neurobiol Dis. 2011;45:381–387.
   PubMed Web of Science ®Google Scholar
• Kummer MP, Heneka MT. Truncated and modified amyloid-beta species. Alzheimer’s Research & Therapy. 2014;6:28.
   PubMed Web of Science ®Google Scholar
• Kummer MP, Hermes M, Delekarte A, et al. Nitration of Tyrosine 10 critically enhances amyloid beta aggregation and plaque formation. Neuron. 2011;71:833–844.
   PubMed Web of Science ®Google Scholar
• Schilling S, Lauber T, Schaupp M, et al. On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry. 2006;45:12393–12399.
   PubMed Web of Science ®Google Scholar
• Russo C, Violani E, Salis S, et al. Pyroglutamate-modified amyloid beta-peptides–AbetaN3(pE)–strongly affect cultured neuron and astrocyte survival. J Neurochem. 2002;82:1480–1489.
   PubMed Web of Science ®Google Scholar
• Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res. 2008;192:106–113.
   PubMed Web of Science ®Google Scholar
• De Felice FG, Velasco PT, Lambert MP, et al. 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;282:11590–11601.
   PubMed Web of Science ®Google Scholar
• Alberdi E, Sanchez-Gomez MV, Cavaliere F, et al. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium. 2010;47:264–272.
   PubMed Web of Science ®Google Scholar
• Bieschke J, Herbst M, Wiglenda T, et al. Small-molecule conversion of toxic oligomers to nontoxic b-sheet‚Äìrich amyloid fibrils. Nat Chem Biol 2011;8:93–101.
   Google Scholar
• Selkoe DJ. Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med. 2011;17:1060–1065.
   PubMed Web of Science ®Google Scholar
• Christensen DD. Alzheimer’s disease: progress in the development of anti-amyloid disease-modifying therapies. CNS Spectrums. 2007;12(113–116):119–123.
   Google Scholar
• Masters CL, Cappai R, Barnham KJ, et al. Molecular mechanisms for Alzheimer’s disease: implications for neuroimaging and therapeutics. J Neurochem. 2006;97:1700–1725.
   PubMed Web of Science ®Google Scholar
• Durham TB, Shepherd TA. Progress toward the discovery and development of efficacious BACE inhibitors. Curr Opin Drug Discov Devel. 2006;9:776–791.
   PubMed Web of Science ®Google Scholar
• Imbimbo BP. Therapeutic potential of gamma-secretase inhibitors and modulators. Curr Top Med Chem. 2008;8:54–61.
   PubMed Web of Science ®Google Scholar
• Evin G, Sernee MF, Masters CL. Inhibition of gamma-secretase as a therapeutic intervention for Alzheimer’s disease: prospects, limitations and strategies. CNS Drugs. 2006;20:351–372.
   PubMed Web of Science ®Google Scholar
• Olson RE, Albright CF. Recent progress in the medicinal chemistry of gamma-secretase inhibitors. Curr Top Med Chem. 2008;8:17–33.
   PubMed Web of Science ®Google Scholar
• Walker LC, Rosen RF. Alzheimer therapeutics-what after the cholinesterase inhibitors? Age Ageing. 2006;35:332–335.
   PubMed Web of Science ®Google Scholar
• Dominguez D, Tournoy J, Hartmann D, et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem. 2005;280:30797–30806.
   PubMed Web of Science ®Google Scholar
• Selkoe D, Kopan R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:565–597.
   PubMed Web of Science ®Google Scholar
• Puzzo D, Privitera L, Leznik E, et al. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci. 2008;28:14537–14545.
   PubMed Web of Science ®Google Scholar
• Abramov E, Dolev I, Fogel H, et al. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci. 2009;12:1567–1576.
   PubMed Web of Science ®Google Scholar
• Giuffrida ML, Caraci F, Pignataro B, et al. Beta-amyloid monomers are neuroprotective. J Neurosci. 2009;29:10582–10587.
   PubMed Web of Science ®Google Scholar
• Kumar DK, Choi SH, Washicosky KJ, et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med. 2016;8:340ra372.
   Web of Science ®Google Scholar
• Wolfe MS. gamma-Secretase in biology and medicine. Semin Cell Dev Biol. 2009;20:219–224.
   PubMed Web of Science ®Google Scholar
• Henley DB, May PC, Dean RA, et al. Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer’s disease. Expert Opin Pharmacother. 2009;10:1657–1664.
   PubMed Web of Science ®Google Scholar
• Bateman RJ, Siemers ER, Mawuenyega KG, et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009;66:48–54.
   PubMed Web of Science ®Google Scholar
• Fleisher AS, Raman R, Siemers ER, et al. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Arch Neurol. 2008;65:1031–1038.
   PubMed Web of Science ®Google Scholar
• Ross J, Sharma S, Winston J, et al. CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study. Curr Alzheimer Res. 2013;10:742–753.
   PubMed Web of Science ®Google Scholar
• Rogers K, Felsenstein KM, Hrdlicka L, et al. Modulation of gamma-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol Neurodegener. 2012;7:61.
   PubMed Web of Science ®Google Scholar
• Citron M, Teplow DB, Selkoe DJ. Generation of amyloid beta protein from its precursor is sequence specific. Neuron. 1995;14:661–670.
   PubMed Web of Science ®Google Scholar
• Evin G, Lessene G, Wilkins S. BACE inhibitors as potential drugs for the treatment of Alzheimer’s disease: focus on bioactivity. Recent Pat CNS Drug Discov. 2011;6:91–106.
   PubMedGoogle Scholar
• Probst G, Xu YZ. Small-molecule BACE1 inhibitors: a patent literature review (2006 – 2011). Expert opinion on therapeutic patents. 2012;22:511–540.
   Google Scholar
• Evin G. Future therapeutics in Alzheimer’s disease: development status of BACE inhibitors. BioDrugs. 2016;30:173–194.
   PubMed Web of Science ®Google Scholar
• Yan R, Vassar R. Targeting the beta secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol. 2014;13:319–329.
   PubMed Web of Science ®Google Scholar
• Menting KW, Claassen JA. beta-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease. Front Aging Neurosci. 2014;6:165.
   PubMed Web of Science ®Google Scholar
• Amijee H, Scopes DI. The quest for small molecules as amyloid inhibiting therapies for Alzheimer’s disease. J Alzheimers Dis. 2009;17:33–47.
   PubMed Web of Science ®Google Scholar
• De Strooper B, Chavez Gutierrez L. Learning by failing: ideas and concepts to tackle gamma-secretases in Alzheimer’s disease and beyond. Annu Rev Pharmacol Toxicol. 2015;55:419–437.
   PubMed Web of Science ®Google Scholar
• Neumann U, Rueeger H, Machauer R, et al. A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-beta and neuroinflammation in APP transgenic mice. Mol Neurodegener. 2015;10:44.
   PubMed Web of Science ®Google Scholar
• Shimshek DR, Jacobson LH, Kolly C, et al. Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice. Scientific Reports. 2016;6:21917.
   PubMed Web of Science ®Google Scholar
• Filser S, Ovsepian SV, Masana M, et al. Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol Psychiatry. 2015;77:729–739.
   PubMed Web of Science ®Google Scholar
• Zhu K, Xiang XFilser S, et al., Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6. Biol Psychiatry. 2016.
   Google Scholar
• Nisha CM, Kumar A, Nair P, et al. Molecular docking and in silico ADMET study reveals acylguanidine 7a as a potential inhibitor of beta-secretase. Adv Bioinformatics. 2016;2016:9258578.
   PubMedGoogle Scholar
• Atwal JK, Chen Y, Chiu C, et al. A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo. Sci Transl Med. 2011;3:84ra43.
   PubMed Web of Science ®Google Scholar
• Yu YJ, Zhang Y, Kenrick M, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med. 2011;3:84ra44.
   PubMed Web of Science ®Google Scholar
• Wang W, Liu Y, Lazarus RA. Allosteric inhibition of BACE1 by an exosite-binding antibody. Curr Opin Struct Biol. 2013;23:797–805.
   PubMed Web of Science ®Google Scholar
• Saftig P, Hetman M, Schmahl W, et al. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO Journal. 1995;14:3599–3608.
   PubMed Web of Science ®Google Scholar
• May PC, Willis BA, Lowe SL, et al. The potent BACE1 inhibitor LY2886721 elicits robust central Abeta pharmacodynamic responses in mice, dogs, and humans. J Neurosci. 2015;35:1199–1210.
   PubMed Web of Science ®Google Scholar
• Lai R, Albala B, Kaplow JM, et al. First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta-amyloid levels after single dosing. Alzheimers Dement. 2012;8:P96.
   Google Scholar
• Lai R, Albala B, Kaplow JM, et al. Novel BACE1 inhibitor E2609 reduces plasma and CSF amyloid in health subjects after 14 days oral administration. The 11th International Conference On Alzheimer’s & Parkinson’s Diseases, Florence, Italy., (2013).
   Google Scholar
• Timmers M, Broeck BV, Slemmon J, Profiling the dynamics of CSF and plasma Abeta reduction with JNJ-54861911, an oral BACE inhibitor. 12th international conference on Alzheimer’s and Parkinson’s diseases and related neurological disorders (AD/PD), (2015).
   Google Scholar
• Luo X, Yan R. Inhibition of BACE1 for therapeutic use in Alzheimer’s disease. Int J Clin Exp Pathol. 2010;3:618–628.
   PubMed Web of Science ®Google Scholar
• Forman M, Tseng J, Palcza J, et al. The Novel BACE Inhibitor MK-8931 Dramatically Lowers CSF Aβ Peptides in Healthy Subjects: Results from a Rising Single Dose Study. Neurology. 2012;78:PL02.004.
   Google Scholar
• Forman M, Kleijn H-J, Dockendorf M, et al. The novel BACE inhibitor MK-8931 dramatically lowers CSF beta-amyloid in patients with mild-to-moderate Alzheimer’s disease. Alzheimers Dement. 2013;9:P139.
   Google Scholar
• Postina R, Schroeder A, Dewachter I, et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest. 2004;113:1456–1464.
   PubMed Web of Science ®Google Scholar
• Vingtdeux V, Marambaud P. Identification and biology of alpha-secretase. J.Neurochem. 2012;120 Suppl 1:34–45.
   Google Scholar
• Desire L, Marcade M, Peillon H, et al. Clinical trials of EHT 0202, a neuroprotective and procognitive alpha-secretase stimulator for Alzheimer’s disease. Alzheimer’s & Dementia. 2009;5:P255–P256.
   Google Scholar
• Vellas B, Sol O, Snyder PJ, et al. EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study. Curr Alzheimer Res. 2011;8:203–212.
   PubMed Web of Science ®Google Scholar
• Nikolaev A, McLaughlin T, O’Leary DD, et al. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009;457:981–989.
   PubMed Web of Science ®Google Scholar
• Galvan V, Gorostiza OF, Banwait S, et al. Reversal of Alzheimer’s-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci U S A. 2006;103:7130–7135.
   PubMed Web of Science ®Google Scholar
• Harris JA, Devidze N, Halabisky B, et al. Many neuronal and behavioral impairments in transgenic mouse models of Alzheimer’s disease are independent of caspase cleavage of the amyloid precursor protein. J Neurosci. 2010;30:372–381.
   PubMed Web of Science ®Google Scholar
• Lahiri DK, Chen D, Maloney B, et al. The experimental Alzheimer’s disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther. 2007;320:386–396.
   PubMed Web of Science ®Google Scholar
• Maccecchini ML, Chang MY, Pan C, et al. Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-beta peptide and tau levels: target engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry. 2012;83:894–902.
   PubMed Web of Science ®Google Scholar
• Heneka MT, Landreth GE. PPARs in the brain. Biochim Biophys Acta. 2007;1771:1031–1045.
   PubMed Web of Science ®Google Scholar
• Combs CK, Johnson DE, Karlo JC, et al. Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci. 2000;20:558–567.
   PubMed Web of Science ®Google Scholar
• Kim EJ, Kwon KJ, Park JY, et al. Effects of peroxisome proliferator-activated receptor agonists on LPS-induced neuronal death in mixed cortical neurons: associated with iNOS and COX-2. Brain Res. 2002;941:1–10.
   PubMed Web of Science ®Google Scholar
• Luna-Medina R, Cortes-Canteli M, Alonso M, et al. Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation. J Biol Chem. 2005;280:21453–21462.
   PubMed Web of Science ®Google Scholar
• Pedersen WA, McMillan PJ, Kulstad JJ, et al. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol. 2006;199:265–273.
   PubMed Web of Science ®Google Scholar
• Escribano L, Simon AM, Perez-Mediavilla A, et al. Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer’s disease mouse model. Biochem Biophys Res Commun. 2009;379:406–410.
   PubMed Web of Science ®Google Scholar
• O’Reilly JA, Lynch M. Rosiglitazone improves spatial memory and decreases insoluble Abeta(1-42) in APP/PS1 mice. J Neuroimmune Pharmacol. 2012;7:140–144.
   PubMed Web of Science ®Google Scholar
• Xu S, Liu G, Bao X, et al. Rosiglitazone prevents amyloid-beta oligomer-induced impairment of synapse formation and plasticity via increasing dendrite and spine mitochondrial number. J Alzheimers Dis. 2014;39:239–251.
   PubMed Web of Science ®Google Scholar
• Xu S, Guan Q, Wang C, et al. Rosiglitazone prevents the memory deficits induced by amyloid-beta oligomers via inhibition of inflammatory responses. Neurosci Lett. 2014;578:7–11.
   PubMed Web of Science ®Google Scholar
• Yu Y, Li X, Blanchard J, et al. Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD mice. J Neural Transm. 2015;122:593–606.
   PubMed Web of Science ®Google Scholar
• Tzimopoulou S, Cunningham VJ, Nichols TE, et al. Multi-center randomized proof-of-concept clinical trial applying [(1)(8)F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer’s’ disease. J Alzheimers Dis. 2010;22:1241–1256.
   PubMed Web of Science ®Google Scholar
• Watson GS, Cholerton BA, Reger MA, et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry. 2005;13:950–958.
   PubMed Web of Science ®Google Scholar
• Risner ME, Saunders AM, Altman JF, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J. 2006;6:246–254.
   PubMed Web of Science ®Google Scholar
• Harrington C, Sawchak S, Chiang C, et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer’s disease: two phase 3 studies. Curr Alzheimer Res. 2011;8:592–606.
   PubMed Web of Science ®Google Scholar
• Gold M, Alderton C, Zvartau-Hind M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010;30:131–146.
   PubMed Web of Science ®Google Scholar
• Lunemann JD, Nimmerjahn F, Dalakas MC. Intravenous immunoglobulin in neurology–mode of action and clinical efficacy. Nat Rev Neurol. 2015;11:80–89.
   PubMed Web of Science ®Google Scholar
• Loeffler DA. Should development of Alzheimer’s disease-specific intravenous immunoglobulin be considered? J Neuroinflammation. 2014;11:198.
   PubMed Web of Science ®Google Scholar
• Gong Y, Chang L, Viola KL, et al. Alzheimer’s disease-affected brain: presence of oligomeric Abeta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A. 2003;100:10417–10422.
   PubMed Web of Science ®Google Scholar
• Lee EB, Leng LZ, Zhang B, et al. Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. J Biol Chem. 2006;281:4292–4299.
   PubMed Web of Science ®Google Scholar
• Hillen H, Barghorn S, Striebinger A, et al. Generation and therapeutic efficacy of highly oligomer-specific beta-amyloid antibodies. J Neurosci. 2010;30:10369–10379.
   PubMed Web of Science ®Google Scholar
• Zago W, Buttini M, Comery TA, et al. Neutralization of soluble, synaptotoxic amyloid beta species by antibodies is epitope specific. J Neurosci. 2012;32:2696–2702.
   PubMed Web of Science ®Google Scholar
• De Felice FG, Wu D, Lambert MP, et al. Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by Abeta oligomers. Neurobiol Aging. 2008;29:1334–1347.
   PubMed Web of Science ®Google Scholar
• Shughrue PJ, Acton PJ, Breese RS, et al. Anti-ADDL antibodies differentially block oligomer binding to hippocampal neurons. Neurobiol Aging. 2010;31:189–202.
   PubMed Web of Science ®Google Scholar
• Zameer A, Kasturirangan S, Emadi S, et al. Anti-oligomeric Abeta single-chain variable domain antibody blocks Abeta-induced toxicity against human neuroblastoma cells. J Mol Biol. 2008;384:917–928.
   PubMed Web of Science ®Google Scholar
• Venkataramani V, Wirths O, Budka H, et al. Antibody 9D5 recognizes oligomeric pyroglutamate amyloid-beta in a fraction of amyloid-beta deposits in Alzheimer’s disease without cross-reactivity with other protein aggregates. J Alzheimers Dis. 2012;29:361–371.
   PubMed Web of Science ®Google Scholar
• Tucker S, Moller C, Tegerstedt K, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-beta protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis. 2015;43:575–588.
   PubMed Web of Science ®Google Scholar
• Glabe CG. Structural classification of toxic amyloid oligomers. J Biol Chem. 2008;283:29639–29643.
   PubMed Web of Science ®Google Scholar
• Lambert MP, Barlow AK, Chromy BA, et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998;95:6448–6453.
   PubMed Web of Science ®Google Scholar
• Lacor PN, Buniel MC, Chang L, et al. Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci. 2004;24:10191–10200.
   PubMed Web of Science ®Google Scholar
• Bontempi, B., Silva, Alcino J. (Eds.) Memories: Molecules and CircuitsResearch and Perspectives in Neurosciences. 2007;155–179.
   Google Scholar
• Krafft GA, Klein WL. ADDLs and the signaling web that leads to Alzheimer’s disease. Neuropharmacology. 2010;59:230–242.
   PubMed Web of Science ®Google Scholar
• Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet. 2010;19:R12–R20.
   PubMed Web of Science ®Google Scholar
• Shankar GM, Li S, Mehta TH, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008;14:837–842.
   PubMed Web of Science ®Google Scholar
• Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem. 2007;282:33305–33312.
   PubMed Web of Science ®Google Scholar
• Klein WL, Krafft GA, Finch CE. Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci. 2001;24:219–224.
   PubMed Web of Science ®Google Scholar
• Dinamarca MC, Rios JA, Inestrosa NC. Postsynaptic receptors for amyloid-beta oligomers as mediators of neuronal damage in Alzheimer’s disease. Front Physiol. 2012;3:464.
   PubMed Web of Science ®Google Scholar
• Koffie RM, Hyman BT, Spires-Jones TL. Alzheimer’s disease: synapses gone cold. Mol Neurodegener. 2011;6:63.
   PubMed Web of Science ®Google Scholar
• Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007;8:101–112.
   PubMed Web of Science ®Google Scholar
• Cerpa W, Dinamarca MC, Inestrosa NC. Structure-function implications in Alzheimer’s disease: effect of Abeta oligomers at central synapses. Curr Alzheimer Res. 2008;5:233–243.
   PubMed Web of Science ®Google Scholar
• Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–539.
   PubMed Web of Science ®Google Scholar
• Rammes G, Hasenjager A, Sroka-Saidi K, et al. Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of beta-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. Neuropharmacology. 2011;60:982–990.
   PubMed Web of Science ®Google Scholar
• Hsieh H, Boehm J, Sato C, et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron. 2006;52:831–843.
   PubMed Web of Science ®Google Scholar
• Chang L, Bakhos L, Wang Z, et al. Femtomole immunodetection of synthetic and endogenous amyloid-beta oligomers and its application to Alzheimer’s disease drug candidate screening. J Mol Neurosci. 2003;20:305–313.
   PubMed Web of Science ®Google Scholar
• Westerman MA, Cooper-Blacketer D, Mariash A, et al. The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci. 2002;22:1858–1867.
   PubMed Web of Science ®Google Scholar
• Ashe KH. Mechanisms of memory loss in Abeta and tau mouse models. Biochem Soc Trans. 2005;33:591–594.
   PubMed Web of Science ®Google Scholar
• Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002;298:789–791.
   PubMed Web of Science ®Google Scholar
• Catalano SM, Dodson EC, Henze DA, et al. The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer’s disease. Curr Top Med Chem. 2006;6:597–608.
   PubMed Web of Science ®Google Scholar
• Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem. 2007;101:1172–1184.
   PubMed Web of Science ®Google Scholar
• Benilova I, Karran E, De Strooper B. The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15:349–357.
   PubMed Web of Science ®Google Scholar
• Brouillette J, Caillierez R, Zommer N, et al. Neurotoxicity and memory deficits induced by soluble low-molecular-weight amyloid-beta1-42 oligomers are revealed in vivo by using a novel animal model. J Neurosci. 2012;32:7852–7861.
   PubMed Web of Science ®Google Scholar
• Larson ME, Lesne SE. Soluble Abeta oligomer production and toxicity. J Neurochem. 2012;120(Suppl 1):125–139.
   PubMed Web of Science ®Google Scholar
• Parsons CG, Ruitenberg M, Freitag CE, et al. MRZ-99030 - A novel modulator of Abeta aggregation: I - Mechanism of action (MoA) underlying the potential neuroprotective treatment of Alzheimer’s disease, glaucoma and age-related macular degeneration (AMD). Neuropharmacology. 2015;92:158–169.
   PubMed Web of Science ®Google Scholar
• Rammes G, Gravius A, Ruitenberg M, et al. MRZ-99030 - A novel modulator of Abeta aggregation: II - Reversal of Abeta oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice. Neuropharmacology. 2015;92:170–182.
   PubMed Web of Science ®Google Scholar
• Gervais F, Paquette J, Morissette C, et al. Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging. 2007;28:537–547.
   PubMed Web of Science ®Google Scholar
• Aisen PS, Saumier D, Briand R, et al. A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease. Neurology. 2006;67:1757–1763.
   PubMed Web of Science ®Google Scholar
• Gauthier S, Aisen PS, Ferris SH, et al. Effect of tramiprosate in patients with mild-to-moderate Alzheimer’s disease: exploratory analyses of the MRI sub-group of the Alphase study. J Nutr Health Aging. 2009;13:550–557.
   PubMed Web of Science ®Google Scholar
• Salloway S, Sperling R, Keren R, et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011;77:1253–1262.
   PubMed Web of Science ®Google Scholar
• Adlard PA, Cherny RA, Finkelstein DI, et al. Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ. Neuron. 2008;59:43–55.
   PubMed Web of Science ®Google Scholar
• Sampson EL, Jenagaratnam L, McShane R. Metal protein attenuating compounds for the treatment of Alzheimer’s dementia. Cochrane Database Syst Rev. 2014;Cd005380. doi: 10.1002/14651858.CD005380.pub5.
   Google Scholar
• Mandel SA, Amit T, Weinreb O, et al. Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases. CNS Neurosci Ther. 2008;14:352–365.
   PubMed Web of Science ®Google Scholar
• Look GC, Jerecic J, Cherbavaz DB, et al. Discovery of ADDL–targeting small molecule drugs for Alzheimer’s disease. Curr Alzheimer Res. 2007;4:562–567.
   PubMed Web of Science ®Google Scholar
• Frydman-Marom A, Rechter M, Shefler I, et al. Cognitive-performance recovery of Alzheimer’s disease model mice by modulation of early soluble amyloidal assemblies. Angew Chem Int Ed Engl. 2009;48:1981–1986.
   PubMed Web of Science ®Google Scholar
• Lai ZW, Petrera A, Schilling O. Protein amino-terminal modifications and proteomic approaches for N-terminal profiling. Curr Opin Chem Biol. 2015;24:71–79.
   PubMed Web of Science ®Google Scholar
• Jawhar S, Wirths T, Bayer A. Pyroglutamate amyloid-beta (Aβ): a hatchet man in Alzheimer disease. J Biol Chem. 2011;286:38825–38832.
   PubMed Web of Science ®Google Scholar
• Frost JL, Le KX, Cynis H, et al. Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. Am J Pathol. 2013;183:369–381.
   PubMed Web of Science ®Google Scholar
• Cynis H, Schilling S, Bodnar M, et al. Inhibition of glutaminyl cyclase alters pyroglutamate formation in mammalian cells. Biochim Biophys Acta. 2006;1764:1618–1625.
   PubMed Web of Science ®Google Scholar
• Schilling S, Zeitschel U, Hoffmann T, et al. Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology. Nat Med. 2008;14:1106–1111.
   PubMed Web of Science ®Google Scholar
• Hofling C, Indrischek H, Hopcke T, et al. Mouse strain and brain region-specific expression of the glutaminyl cyclases QC and isoQC. Int J Dev Neurosci. 2014;36:64–73.
   PubMed Web of Science ®Google Scholar