Generic placeholder image

Current Drug Targets


ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

Review Article

Amyloid Beta Hypothesis in Alzheimer's Disease: Major Culprits and Recent Therapeutic Strategies

Author(s): Dileep Vijayan* and Remya Chandra

Volume 21 , Issue 2 , 2020

Page: [148 - 166] Pages: 19

DOI: 10.2174/1389450120666190806153206

Price: $65


Alzheimer’s disease (AD) is one of the most common forms of dementia and has been a global concern for several years. Due to the multi-factorial nature of the disease, AD has become irreversible, fatal and imposes a tremendous socio-economic burden. Even though experimental medicines suggested moderate benefits, AD still lacks an effective treatment strategy for the management of symptoms or cure. Among the various hypotheses that describe development and progression of AD, the amyloid hypothesis has been a long-term adherent to the AD due to the involvement of various forms of Amyloid beta (Aβ) peptides in the impairment of neuronal and cognitive functions. Hence, majority of the drug discovery approaches in the past have focused on the prevention of the accumulation of Aβ peptides. Currently, there are several agents in the phase III clinical trials that target Aβ or the various macromolecules triggering Aβ deposition. In this review, we present the state of the art knowledge on the functional aspects of the key players involved in the amyloid hypothesis. Furthermore, we also discuss anti-amyloid agents present in the Phase III clinical trials.

Keywords: Beta secretase, gamma secretase, glutaminyl cyclase, RAGE, , amyloid hypothesis, Alzheimer's disease.

Graphical Abstract
Burns A, Iliffe S. Alzheimer’s disease. BMJ 2009; 338: b158.
[] [PMID: 19196745]
Markesbery WR. Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 1997; 23(1): 134-47.
[] [PMID: 9165306]
Galvin JE, Fu Q, Nguyen JT, Glasheen C, Scharff DP. Psychosocial determinants of intention to screen for Alzheimer’s disease. Alzheimers Dement 2008; 4(5): 353-60.
[] [PMID: 18790462]
Duthey B. Alzheimer disease and other dementias. A Public Health Approach to Innovation 2013; 20: 1-74.
Burke M. Why Alzheimer’s drugs keep failing. Sci Am 2014 2014.
Braak H, de Vos RA, Jansen EN, Bratzke H, Braak E. Neuropathological hallmarks of Alzheimer’s and Parkinson’s diseases. Prog Brain Res 1998; 117: 267-85.
[] [PMID: 9932414]
Niedowicz DM, Nelson PT, Murphy MP. Alzheimer’s disease: pathological mechanisms and recent insights. Curr Neuropharmacol 2011; 9(4): 674-84.
[] [PMID: 22654725]
Casey DA, Antimisiaris D, O’Brien J. Drugs for Alzheimer’s disease: are they effective? P&T 2010; 35(4): 208-11.
[PMID: 20498822]
Cummings J, Lee G, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement (N Y) 2018; 4: 195-214.
[] [PMID: 29955663]
Raskin J, Cummings J, Hardy J, Schuh K, Dean RA. A Dean R. Neurobiology of Alzheimer’s disease: integrated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Curr Alzheimer Res 2015; 12(8): 712-22.
[] [PMID: 26412218]
Bharadwaj PR, Dubey AK, Masters CL, Martins RN, Macreadie IG. Abeta aggregation and possible implications in Alzheimer’s disease pathogenesis. J Cell Mol Med 2009; 13(3): 412-21.
[] [PMID: 19374683]
Sperling R, Mormino E, Johnson K. The evolution of preclinical Alzheimer’s disease: implications for prevention trials. Neuron 2014; 84(3): 608-22.
[] [PMID: 25442939]
Brody DL, Jiang H, Wildburger N, Esparza TJ. Non-canonical soluble amyloid-beta aggregates and plaque buffering: controversies and future directions for target discovery in Alzheimer’s disease. Alzheimers Res Ther 2017; 9(1): 62.
[] [PMID: 28818091]
Jin S, Kedia N, Illes-Toth E, et al. Amyloid-β (1–42) aggregation initiates its cellular uptake and cytotoxicity. J Biol Chem 2016; 291(37): 19590-606.
[] [PMID: 27458018]
Do TD, Economou NJ, Chamas A, Buratto SK, Shea JE, Bowers MT. Interactions between amyloid-β and Tau fragments promote aberrant aggregates: implications for amyloid toxicity. J Phys Chem B 2014; 118(38): 11220-30.
[] [PMID: 25153942]
Li H, Rahimi F, Bitan G. Modulation of amyloid β-protein (Aβ) assembly by homologous C-terminal fragments as a strategy for inhibiting aβ toxicity. ACS Chem Neurosci 2016; 7(7): 845-56.
[] [PMID: 27322435]
Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron 2014; 81(4): 740-54.
[] [PMID: 24559670]
Yang SH, Lee DK, Shin J, et al. Nec-1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in APP/PS1 mice. EMBO Mol Med 2017; 9(1): 61-77.
[] [PMID: 27861127]
Bouter Y, Dietrich K, Wittnam JL, et al. N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits. Acta Neuropathol 2013; 126(2): 189-205.
[] [PMID: 23685882]
O’Malley TT, Witbold WM III, Linse S, Walsh DM. The aggregation paths and products of Aβ42 dimers are distinct from those of the Aβ42 monomer. Biochemistry 2016; 55(44): 6150-61.
[] [PMID: 27750419]
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci USA 2017; 114(4): E476-85.
[] [PMID: 27930341]
Chen AC, Kim S, Shepardson N, Patel S, Hong S, Selkoe DJ. Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis. J Cell Biol 2015; 211(6): 1157-76.
[] [PMID: 26694839]
Masters CL, Selkoe DJ. Biochemistry of amyloid β-protein and amyloid deposits in Alzheimer disease. Cold Spring Harb Perspect Med 2012; 2(6)a006262
[] [PMID: 22675658]
Zhao J, Nussinov R, Ma B. Mechanisms of recognition of amyloid-β (Aβ) monomer, oligomer, and fibril by homologous antibodies. J Biol Chem 2017; 292(44): 18325-43.
[] [PMID: 28924036]
Cline EN, Bicca MA, Viola KL, Klein WL. The amyloid-β oligomer hypothesis: Beginning of the third decade. J Alzheimers Dis 2018; 64(s1): S567-610.
[] [PMID: 29843241]
Istrate AN, Kozin SA, Zhokhov SS, et al. Interplay of histidine residues of the Alzheimer’s disease Aβ peptide governs its Zn-induced oligomerization. Sci Rep 2016; 6: 21734.
[] [PMID: 26898943]
Silva KI, Saxena S. Zn(II) ions substantially perturb Cu(II) ion coordination in amyloid-β at physiological pH. J Phys Chem B 2013; 117(32): 9386-94.
[] [PMID: 23841511]
Cline EN, Bicca MA, Viola KL, Klein WL. The amyloid-β oligomer hypothesis: Beginning of the third decade. J Alzheimers Dis 2018; 64(s1): S567-610.
[] [PMID: 29843241]
Tu S, Okamoto S, Lipton SA, Xu H. Oligomeric Aβ-induced synaptic dysfunction in Alzheimer’s disease. Mol Neurodegener 2014; 9: 48.
[] [PMID: 25394486]
Green KN. Calcium in the initiation, progression and as an effector of Alzheimer’s disease pathology. J Cell Mol Med 2009; 13(9A): 2787-99.
[] [PMID: 19650832]
Penke B, Bogár F, Fülöp L. β-Amyloid and the pathomechanisms of Alzheimer’s disease: a comprehensive view. Molecules 2017; 22(10): 1692.
[] [PMID: 28994715]
Sengupta U, Nilson AN, Kayed R. The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 2016; 6: 42-9.
[] [PMID: 27211547]
Habib A, Sawmiller D, Tan J. Restoring soluble amyloid precursor protein α functions as a potential treatment for alzheimer’s disease. J Neurosci Res 2017; 95(4): 973-91.
[] [PMID: 27531392]
Wang H, Megill A, He K, Kirkwood A, Lee HK. Consequences of inhibiting amyloid precursor protein processing enzymes on synaptic function and plasticity. Neural plasticity 2012 2012.
Bandyopadhyay S, Rogers JT. Alzheimer’s disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis. Biochem Pharmacol 2014; 88(4): 486-94.
[] [PMID: 24513321]
Esch FS, Keim PS, Beattie EC, et al. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 1990; 248(4959): 1122-4.
[] [PMID: 2111583]
Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci USA 1999; 96(12): 6959-63.
[] [PMID: 10359821]
Zhang Z, Nadeau P, Song W, et al. Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nat Cell Biol 2000; 2(7): 463-5.
[] [PMID: 10878814]
Li Y, Zhou W, Tong Y, He G, Song W. Control of APP processing and Abeta generation level by BACE1 enzymatic activity and transcription. FASEB J 2006; 20(2): 285-92.
[] [PMID: 16449801]
Vassar R, Bennett BD, Babu-Khan S, et al. β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735-41.
Bennett BD, Denis P, Haniu M, et al. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s β -secretase. J Biol Chem 2000; 275(48): 37712-7.
[] [PMID: 10956649]
Hussain I, Powell D, Howlett DR, et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol Cell Neurosci 1999; 14(6): 419-27.
[] [PMID: 10656250]
Ghosh AK, Cárdenas EL, Osswald HL. The design, development, and evaluation of BACE1 inhibitors for the treatment of Alzheimer’s diseaseAlzheimer’s Disease II. Cham: Springer 2016; pp. 27-85.
Cole DC, Manas ES, Stock JR, et al. Acylguanidines as small-molecule β-secretase inhibitors. J Med Chem 2006; 49(21): 6158-61.
[] [PMID: 17034121]
Deng Y, Wang Z, Wang R, et al. Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis. Eur J Neurosci 2013; 37(12): 1962-9.
[] [PMID: 23773065]
Mullan M, Crawford F, Axelman K, et al. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Nat Genet 1992; 1(5): 345-7.
[] [PMID: 1302033]
Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Nature 1999; 402(6761): 533-7.
[] [PMID: 10591213]
Sun X, Wang Y, Qing H, et al. Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J 2005; 19(7): 739-49.
[] [PMID: 15857888]
Luo Y, Bolon B, Kahn S, et al. Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nat Neurosci 2001; 4(3): 231-2.
[] [PMID: 11224535]
Luo Y, Bolon B, Damore MA, et al. BACE1 (β-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol Dis 2003; 14(1): 81-8.
[] [PMID: 13678669]
Singer O, Marr RA, Rockenstein E, et al. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 2005; 8(10): 1343-9.
[] [PMID: 16136043]
Laird FM, Cai H, Savonenko AV, et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 2005; 25(50): 11693-709.
[] [PMID: 16354928]
Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. β-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 2002; 59(9): 1381-9.
[] [PMID: 12223024]
Li R, Lindholm K, Yang LB, et al. Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci USA 2004; 101(10): 3632-7.
[] [PMID: 14978286]
Yang LB, Lindholm K, Yan R, et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 2003; 9(1): 3-4.
[] [PMID: 12514700]
Tamagno E, Bardini P, Obbili A, et al. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 2002; 10(3): 279-88.
[] [PMID: 12270690]
Zhang X, Zhou K, Wang R, et al. Hypoxia-inducible factor 1α (HIF-1α)-mediated hypoxia increases BACE1 expression and β-amyloid generation. J Biol Chem 2007; 282(15): 10873-80.
[] [PMID: 17303576]
Wen Y, Onyewuchi O, Yang S, Liu R, Simpkins JW. Increased β-secretase activity and expression in rats following transient cerebral ischemia. Brain Res 2004; 1009(1-2): 1-8.
[] [PMID: 15120577]
Tesco G, Koh YH, Kang EL, et al. Depletion of GGA3 stabilizes BACE and enhances β-secretase activity. Neuron 2007; 54(5): 721-37.
[] [PMID: 17553422]
Blasko I, Beer R, Bigl M, et al. Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer’s disease β-secretase (BACE-1). J Neural Transm (Vienna) 2004; 111(4): 523-36.
[] [PMID: 15057522]
Kitazume S, Tachida Y, Oka R, Shirotani K, Saido TC, Hashimoto Y. Alzheimer’s β-secretase, β-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. Proc Natl Acad Sci USA 2001; 98(24): 13554-9.
[] [PMID: 11698669]
Lichtenthaler SF, Dominguez DI, Westmeyer GG, et al. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J Biol Chem 2003; 278(49): 48713-9.
[] [PMID: 14507929]
Eggert S, Paliga K, Soba P, et al. The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves α-, β-, γ-, and ϵ-like cleavages: modulation of APLP-1 processing by n-glycosylation. J Biol Chem 2004; 279(18): 18146-56.
[] [PMID: 14970212]
Pastorino L, Ikin AF, Lamprianou S, et al. BACE (β-secretase) modulates the processing of APLP2 in vivo. Mol Cell Neurosci 2004; 25(4): 642-9.
[] [PMID: 15080893]
von Arnim CA, Kinoshita A, Peltan ID, et al. The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate. J Biol Chem 2005; 280(18): 17777-85.
[] [PMID: 15749709]
Hu X, Hicks CW, He W, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 2006; 9(12): 1520-5.
[] [PMID: 17099708]
Hu X, He W, Diaconu C, et al. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J 2008; 22(8): 2970-80.
[] [PMID: 18413858]
Kim DY, Ingano LA, Carey BW, Pettingell WH, Kovacs DM. Presenilin/γ-secretase-mediated cleavage of the voltage-gated sodium channel β2-subunit regulates cell adhesion and migration. J Biol Chem 2005; 280(24): 23251-61.
[] [PMID: 15833746]
Wong HK, Sakurai T, Oyama F, et al. β Subunits of voltage-gated sodium channels are novel substrates of β-site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase. J Biol Chem 2005; 280(24): 23009-17.
[] [PMID: 15824102]
Fleck D, Voss M, Brankatschk B, et al. Proteolytic processing of neuregulin 1 type III by three intramembrane-cleaving proteases. J Biol Chem 2016; 291(1): 318-33.
[] [PMID: 26574544]
Felsenstein KM, Hunihan LW, Roberts SB. Altered cleavage and secretion of a recombinant β-APP bearing the Swedish familial Alzheimer’s disease mutation. Nat Genet 1994; 6(3): 251-5.
[] [PMID: 8012386]
Perez RG, Squazzo SL, Koo EH. Enhanced release of amyloid beta-protein from codon 670/671 “Swedish” mutant beta-amyloid precursor protein occurs in both secretory and endocytic pathways. J Biol Chem 1996; 271(15): 9100-7.
[] [PMID: 8621560]
Nilsberth C, Westlind-Danielsson A, Eckman CB, et al. The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci 2001; 4(9): 887-93.
[] [PMID: 11528419]
Stenh C, Nilsberth C, Hammarbäck J, Engvall B, Näslund J, Lannfelt L. The Arctic mutation interferes with processing of the amyloid precursor protein. Neuroreport 2002; 13(15): 1857-60.
[] [PMID: 12395079]
Sahlin C, Lord A, Magnusson K, et al. The Arctic Alzheimer mutation favors intracellular amyloid-β production by making amyloid precursor protein less available to α-secretase. J Neurochem 2007; 101(3): 854-62.
[] [PMID: 17448150]
Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991; 349(6311): 704-6.
[] [PMID: 1671712]
Eckman CB, Mehta ND, Crook R, et al. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A β 42(43). Hum Mol Genet 1997; 6(12): 2087-9.
[] [PMID: 9328472]
Van Nostrand WE, Melchor JP, Cho HS, Greenberg SM, Rebeck GW. Pathogenic effects of D23N Iowa mutant amyloid β -protein. J Biol Chem 2001; 276(35): 32860-6.
[] [PMID: 11441013]
Wisniewski T, Ghiso J, Frangione B. Peptides homologous to the amyloid protein of Alzheimer’s disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Commun 1991; 179(3): 1247-54.
[] [PMID: 1681804]
Willem M, Garratt AN, Novak B, et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 2006; 314(5799): 664-6.
[] [PMID: 16990514]
Kobayashi D, Zeller M, Cole T, et al. BACE1 gene deletion: impact on behavioral function in a model of Alzheimer’s disease. Neurobiol Aging 2008; 29(6): 861-73.
[] [PMID: 17331621]
Harrison SM, Harper AJ, Hawkins J, et al. BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci 2003; 24(3): 646-55.
[] [PMID: 14664815]
Hu X, He W, Luo X, Tsubota KE, Yan R. BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep 2013; 4(1): 40-9.
[] [PMID: 23831026]
Hu X, Zhou X, He W, et al. BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci 2010; 30(26): 8819-29.
[] [PMID: 20592204]
Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC. Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci USA 2008; 105(14): 5585-90.
[] [PMID: 18385378]
Cai J, Qi X, Kociok N, et al. β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol Med 2012; 4(9): 980-91.
[] [PMID: 22903875]
McCarthy JV, Twomey C, Wujek P. Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity. Cell Mol Life Sci 2009; 66(9): 1534-55.
[] [PMID: 19189053]
Marambaud P, Shioi J, Serban G, et al. A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 2002; 21(8): 1948-56.
[] [PMID: 11953314]
Ni CY, Murphy MP, Golde TE, Carpenter G. γ -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 2001; 294(5549): 2179-81.
[] [PMID: 11679632]
Wunderlich P, Glebov K, Kemmerling N, Tien NT, Neumann H, Walter J. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and γ-secretase-dependent intramembranous cleavage. J Biol Chem 2013; 288(46): 33027-36.
[] [PMID: 24078628]
Hata S, Taniguchi M, Piao Y, et al. Japanese Alzheimer’s Disease Neuroimaging Initiative. Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer’s disease subjects. Mol Neurodegener 2012; 7: 16.
[] [PMID: 22534039]
Lammich S, Okochi M, Takeda M, et al. Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J Biol Chem 2002; 277(47): 44754-9.
[] [PMID: 12223485]
Wang R, Tang P, Wang P, Boissy RE, Zheng H. Regulation of tyrosinase trafficking and processing by presenilins: partial loss of function by familial Alzheimer’s disease mutation. Proc Natl Acad Sci USA 2006; 103(2): 353-8.
[] [PMID: 16384915]
Guardia-Laguarta C, Pera M, Lleó A. gamma-Secretase as a therapeutic target in Alzheimer’s disease. Curr Drug Targets 2010; 11(4): 506-17.
[] [PMID: 20015011]
De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 1998; 391(6665): 387-90.
[] [PMID: 9450754]
Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 1999; 398(6727): 513-7.
[] [PMID: 10206644]
Yu G, Nishimura M, Arawaka S, et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000; 407(6800): 48-54.
[] [PMID: 10993067]
De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active γ-Secretase complex. Neuron 2003; 38(1): 9-12.
[] [PMID: 12691659]
Iwatsubo T. The γ-secretase complex: machinery for intramembrane proteolysis. Curr Opin Neurobiol 2004; 14(3): 379-83.
[] [PMID: 15194119]
De Strooper B, Annaert W. Novel research horizons for presenilins and γ-secretases in cell biology and disease. Annu Rev Cell Dev Biol 2010; 26: 235-60.
[] [PMID: 20604710]
Coen K, Flannagan RS, Baron S, et al. Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cells. J Cell Biol 2012; 198(1): 23-35.
[] [PMID: 22753898]
Bentahir M, Nyabi O, Verhamme J, et al. Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J Neurochem 2006; 96(3): 732-42.
[] [PMID: 16405513]
Lleó A, Berezovska O, Growdon JH, Hyman BT. Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am J Geriatr Psychiatry 2004; 12(2): 146-56.
[] [PMID: 15010344]
Lemere CA, Lopera F, Kosik KS, et al. The E280A presenilin 1 Alzheimer mutation produces increased A β 42 deposition and severe cerebellar pathology. Nat Med 1996; 2(10): 1146-50.
[] [PMID: 8837617]
Cai D, Leem JY, Greenfield JP, et al. Presenilin-1 regulates intracellular trafficking and cell surface delivery of β-amyloid precursor protein. J Biol Chem 2003; 278(5): 3446-54.
[] [PMID: 12435726]
Cheung KH, Shineman D, Müller M, et al. Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron 2008; 58(6): 871-83.
[] [PMID: 18579078]
Bezprozvanny I, Hiesinger PR. The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol Neurodegener 2013; 8: 23.
[] [PMID: 23829673]
Tu H, Nelson O, Bezprozvanny A, et al. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 2006; 126(5): 981-93.
[] [PMID: 16959576]
Mann DM, Pickering-Brown SM, Takeuchi A, Iwatsubo T. Members of the Familial Alzheimer’s Disease Pathology Study Group. Amyloid angiopathy and variability in amyloid β deposition is determined by mutation position in presenilin-1-linked Alzheimer’s disease. Am J Pathol 2001; 158(6): 2165-75.
[] [PMID: 11395394]
Walker ES, Martinez M, Brunkan AL, Goate A. Presenilin 2 familial Alzheimer’s disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem 2005; 92(2): 294-301.
[] [PMID: 15663477]
Sastre M, Steiner H, Fuchs K, et al. Presenilin-dependent γ-secretase processing of β-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2001; 2(9): 835-41.
[] [PMID: 11520861]
Zhao G, Mao G, Tan J, et al. Identification of a new presenilin-dependent ζ-cleavage site within the transmembrane domain of amyloid precursor protein. J Biol Chem 2004; 279(49): 50647-50.
[] [PMID: 15485850]
Zhao G, Tan J, Mao G, Cui MZ, Xu X. The same γ-secretase accounts for the multiple intramembrane cleavages of APP. J Neurochem 2007; 100(5): 1234-46.
[] [PMID: 17241131]
Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and β-amyloid precursor protein. Cell 2002; 110(1): 55-67.
[] [PMID: 12150997]
Kim HS, Kim EM, Lee JP, et al. C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3β expression. FASEB J 2003; 17(13): 1951-3.
[] [PMID: 12923068]
von Rotz RC, Kohli BM, Bosset J, et al. The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. J Cell Sci 2004; 117(Pt 19): 4435-48.
[] [PMID: 15331662]
Pardossi-Piquard R, Petit A, Kawarai T, et al. Presenilin-dependent transcriptional control of the Abeta-degrading enzyme neprilysin by intracellular domains of betaAPP and APLP. Neuron 2005; 46(4): 541-54.
[] [PMID: 15944124]
Liu Q, Zerbinatti CV, Zhang J, et al. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron 2007; 56(1): 66-78.
[] [PMID: 17920016]
Zhang YW, Wang R, Liu Q, Zhang H, Liao FF, Xu H. Presenilin/γ-secretase-dependent processing of β-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci USA 2007; 104(25): 10613-8.
[] [PMID: 17556541]
Kinoshita A, Whelan CM, Berezovska O, Hyman BT. The γ secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells. J Biol Chem 2002; 277(32): 28530-6.
[] [PMID: 12032152]
Giliberto L, Zhou D, Weldon R, et al. Evidence that the Amyloid beta Precursor Protein-intracellular domain lowers the stress threshold of neurons and has a “regulated” transcriptional role. Mol Neurodegener 2008; 3: 12.
[] [PMID: 18764939]
Schedin-Weiss S, Winblad B, Tjernberg LO. The role of protein glycosylation in Alzheimer disease. FEBS J 2014; 281(1): 46-62.
[] [PMID: 24279329]
Lu P, Bai XC, Ma D, et al. Three-dimensional structure of human γ-secretase. Nature 2014; 512(7513): 166-70.
[] [PMID: 25043039]
Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004; 279(13): 12876-82.
[] [PMID: 14709552]
Haapasalo A, Kovacs DM. The many substrates of presenilin/γ-secretase. J Alzheimers Dis 2011; 25(1): 3-28.
[] [PMID: 21335653]
Tamayev R, D’Adamio L. Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. Mol Neurodegener 2012; 7: 19.
[] [PMID: 22537414]
Wong GT, Manfra D, Poulet FM, et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004; 279(13): 12876-82.
[] [PMID: 14709552]
Doerfler P, Shearman MS, Perlmutter RM. Presenilin-dependent γ-secretase activity modulates thymocyte development. Proc Natl Acad Sci USA 2001; 98(16): 9312-7.
[] [PMID: 11470902]
He G, Luo W, Li P, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature 2010; 467(7311): 95-8.
[] [PMID: 20811458]
Satoh J, Tabunoki H, Ishida T, Saito Y, Arima K. Immunohistochemical characterization of γ-secretase activating protein expression in Alzheimer’s disease brains. Neuropathol Appl Neurobiol 2012; 38(2): 132-41.
[] [PMID: 21718343]
Chu J, Lauretti E, Craige CP, Praticò D. Pharmacological modulation of GSAP reduces amyloid-β levels and tau phosphorylation in a mouse model of Alzheimer’s disease with plaques and tangles. J Alzheimers Dis 2014; 41(3): 729-37.
[] [PMID: 24662099]
Chu J, Li JG, Joshi YB, et al. Gamma secretase-activating protein is a substrate for caspase-3: implications for Alzheimer’s disease. Biol Psychiatry 2015; 77(8): 720-8.
[] [PMID: 25052851]
Liu K, Solano I, Mann D, et al. Characterization of Abeta11-40/42 peptide deposition in Alzheimer’s disease and young Down’s syndrome brains: implication of N-terminally truncated Abeta species in the pathogenesis of Alzheimer’s disease. Acta Neuropathol 2006; 112(2): 163-74.
[] [PMID: 16865398]
Stephan A, Wermann M, von Bohlen A, et al. Mammalian glutaminyl cyclases and their isoenzymes have identical enzymatic characteristics. FEBS J 2009; 276(22): 6522-36.
[] [PMID: 19804409]
Cynis H, Rahfeld JU, Stephan A, et al. Isolation of an isoenzyme of human glutaminyl cyclase: retention in the Golgi complex suggests involvement in the protein maturation machinery. J Mol Biol 2008; 379(5): 966-80.
[] [PMID: 18486145]
Gunn AP, Masters CL, Cherny RA. Pyroglutamate-Aβ: role in the natural history of Alzheimer’s disease. Int J Biochem Cell Biol 2010; 42(12): 1915-8.
[] [PMID: 20833262]
Nussbaum JM, Schilling S, Cynis H, et al. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature 2012; 485(7400): 651-5.
[] [PMID: 22660329]
Russo C, Violani E, Salis S, et al. Pyroglutamate-modified amyloid β-peptides--AbetaN3(pE)--strongly affect cultured neuron and astrocyte survival. J Neurochem 2002; 82(6): 1480-9.
[] [PMID: 12354296]
Schlenzig D, Manhart S, Cinar Y, et al. Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry 2009; 48(29): 7072-8.
[] [PMID: 19518051]
Schilling S, Zeitschel U, Hoffmann T, et al. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer’s disease-like pathology. Nat Med 2008; 14(10): 1106-11.
[] [PMID: 18836460]
Becker A, Kohlmann S, Alexandru A, et al. Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration. BMC Neurosci 2013; 14: 108.
[] [PMID: 24083638]
Hartlage-Rübsamen M, Waniek A, Meissner J, et al. Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease. Acta Neuropathol 2015; 129(4): 565-83.
[] [PMID: 25666182]
Kiyota T, Yamamoto M, Xiong H, et al. CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction. PLoS One 2009; 4(7)e6197
[] [PMID: 19593388]
Cynis H, Hoffmann T, Friedrich D, et al. The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions. EMBO Mol Med 2011; 3(9): 545-58.
[] [PMID: 21774078]
Schilling S, Kohlmann S, Bäuscher C, et al. Glutaminyl cyclase knock-out mice exhibit slight hypothyroidism but no hypogonadism: implications for enzyme function and drug development. J Biol Chem 2011; 286(16): 14199-208.
[] [PMID: 21330373]
Becker A, Eichentopf R, Sedlmeier R, et al. IsoQC (QPCTL) knock-out mice suggest differential substrate conversion by glutaminyl cyclase isoenzymes. Biol Chem 2016; 397(1): 45-55.
[] [PMID: 26351917]
Huang KF, Liaw SS, Huang WL, et al. Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding. J Biol Chem 2011; 286(14): 12439-49.
[] [PMID: 21288892]
Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH. Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. Proc Natl Acad Sci USA 2005; 102(37): 13117-22.
[] [PMID: 16135565]
Neeper M, Schmidt AM, Brett J, et al. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 1992; 267(21): 14998-5004.
[PMID: 1378843]
Koch M, Chitayat S, Dattilo BM, et al. Structural basis for ligand recognition and activation of RAGE. Structure 2010; 18(10): 1342-52.
[] [PMID: 20947022]
Fritz G. RAGE: a single receptor fits multiple ligands. Trends Biochem Sci 2011; 36(12): 625-32.
[] [PMID: 22019011]
Semba RD, Gebauer SK, Baer DJ, et al. Dietary intake of advanced glycation end products did not affect endothelial function and inflammation in healthy adults in a randomized controlled trial. J Nutr 2014; 144(7): 1037-42.
[] [PMID: 24744309]
Bierhaus A, Humpert PM, Morcos M, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 2005; 83(11): 876-86.
[] [PMID: 16133426]
Opatrna S, Popperlova A, Kalousová M, Zima T. Low glucose degradation product peritoneal dialysis regimen is associated with lower plasma EN-RAGE and HMGB-1 proinflammatory ligands of receptor for advanced glycation end products. Ther Apher Dial 2014; 18(3): 309-16.
[] [PMID: 24965297]
Franko B, Brault J, Jouve T, et al. Differential impact of glucose levels and advanced glycation end-products on tubular cell viability and pro-inflammatory/profibrotic functions. Biochem Biophys Res Commun 2014; 451(4): 627-31.
[] [PMID: 25130465]
Tancharoen S, Tengrungsun T, Suddhasthira T, et al. Overexpression of receptor for advanced glycation end products and high-mobility group box 1 in human dental pulp inflammation. Mediators Inflamm 2014. 2014754069
[] [PMID: 25114379]
Di BB, Li HW, Li WP, Shen XH, Sun ZJ, Wu X. Pioglitazone inhibits high glucose-induced expression of receptor for advanced glycation end products in coronary artery smooth muscle cells. Mol Med Rep 2015; 11(4): 2601-7.
[] [PMID: 25523934]
Lv C, Wang L, Liu X, et al. Multi-faced neuroprotective effects of geniposide depending on the RAGE-mediated signaling in an Alzheimer mouse model. Neuropharmacology 2015; 89: 175-84.
[] [PMID: 25261783]
Yoon SS, Jo SA. Mechanisms of amyloid-β peptide clearance: potential therapeutic targets for Alzheimer’s disease. Biomol Ther (Seoul) 2012; 20(3): 245-55.
[] [PMID: 24130920]
Liu R, Wu CX, Zhou D, et al. Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis. BMC Med 2012; 10: 105.
[] [PMID: 22989295]
Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid β-peptide clearance through transport across the blood-brain barrier. Stroke 2004; 35(11)(Suppl. 1): 2628-31.
[] [PMID: 15459432]
Zlokovic BV, Yamada S, Holtzman D, Ghiso J, Frangione B. Clearance of amyloid β-peptide from brain: transport or metabolism? Nat Med 2000; 6: 718.
Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106(12): 1489-99.
[] [PMID: 11120756]
Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer’s Abeta peptide: the many roads to perdition. Neuron 2004; 43(5): 605-8.
[PMID: 15339642]
Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008; 57(2): 178-201.
[] [PMID: 18215617]
Deane R, Wu Z, Sagare A, et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 2004; 43(3): 333-44.
[] [PMID: 15294142]
Donahue JE, Flaherty SL, Johanson CE, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol 2006; 112(4): 405-15.
[] [PMID: 16865397]
Sirois CM, Jin T, Miller AL, et al. RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. J Exp Med 2013; 210(11): 2447-63.
[] [PMID: 24081950]
Bertheloot D, Naumovski AL, Langhoff P, et al. RAGE enhances TLR responses through binding and internalization of RNA. J Immunol 2016; 197(10): 4118-26.
[] [PMID: 27798148]
Park H, Adsit FG, Boyington JC. The 1.5 Å crystal structure of human receptor for advanced glycation endproducts (RAGE) ectodomains reveals unique features determining ligand binding. J Biol Chem 2010; 285(52): 40762-70.
[] [PMID: 20943659]
Herz J. The LDL receptor gene family: (un)expected signal transducers in the brain. Neuron 2001; 29(3): 571-81.
[] [PMID: 11301018]
Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 2001; 108(6): 779-84.
[] [PMID: 11560943]
Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106(12): 1489-99.
[] [PMID: 11120756]
Kanekiyo T, Liu CC, Shinohara M, Li J, Bu G. LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer’s amyloid-β. J Neurosci 2012; 32(46): 16458-65.
[] [PMID: 23152628]
Kanekiyo T, Cirrito JR, Liu CC, et al. Neuronal clearance of amyloid-β by endocytic receptor LRP1. J Neurosci 2013; 33(49): 19276-83.
[] [PMID: 24305823]
Zlokovic BV, Deane R, Sagare AP, Bell RD, Winkler EA. Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β-peptide elimination from the brain. J Neurochem 2010; 115(5): 1077-89.
[] [PMID: 20854368]
Geula C, Mesulam MM. Cholinesterases and the pathology of Alzheimer disease. Alzheimer Dis Assoc Disord 1995; 9(Suppl. 2): 23-8.
[] [PMID: 8534419]
Mesulam MM, Geula C. Butyrylcholinesterase reactivity differentiates the amyloid plaques of aging from those of dementia. Ann Neurol 1994; 36(5): 722-7.
[] [PMID: 7979218]
Alvarez A, Alarcón R, Opazo C, et al. Stable complexes involving acetylcholinesterase and amyloid-β peptide change the biochemical properties of the enzyme and increase the neurotoxicity of Alzheimer’s fibrils. J Neurosci 1998; 18(9): 3213-23.
[] [PMID: 9547230]
Alvarez A, Opazo C, Alarcón R, Garrido J, Inestrosa NC. Acetylcholinesterase promotes the aggregation of amyloid-β-peptide fragments by forming a complex with the growing fibrils. J Mol Biol 1997; 272(3): 348-61.
[] [PMID: 9325095]
Morgan C, Colombres M, Nuñez MT, Inestrosa NC. Structure and function of amyloid in Alzheimer’s disease. Prog Neurobiol 2004; 74(6): 323-49.
[] [PMID: 15649580]
Inestrosa NC, Alarcón R. Molecular interactions of acetylcholinesterase with senile plaques. J Physiol Paris 1998; 92(5-6): 341-4.
[] [PMID: 9789834]
Inestrosa NC, Alvarez A, Pérez CA, et al. Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 1996; 16(4): 881-91.
[] [PMID: 8608006]
Santulli G, Marks AR. Essential roles of intracellular calcium release channels in muscle, brain, metabolism, and aging. Curr Mol Pharmacol 2015; 8(2): 206-22.
[] [PMID: 25966694]
Giannini G, Conti A, Mammarella S, Scrobogna M, Sorrentino V. The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues. J Cell Biol 1995; 128(5): 893-904.
[] [PMID: 7876312]
Zalk R, Lehnart SE, Marks AR. Modulation of the ryanodine receptor and intracellular calcium. Annu Rev Biochem 2007; 76: 367-85.
[] [PMID: 17506640]
Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ. Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 2008; 59(2): 214-25.
[] [PMID: 18667150]
Cheung KH, Shineman D, Müller M, et al. Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron 2008; 58(6): 871-83.
[] [PMID: 18579078]
Querfurth HW, Jiang J, Geiger JD, Selkoe DJ. Caffeine stimulates amyloid β-peptide release from β-amyloid precursor protein-transfected HEK293 cells. J Neurochem 1997; 69(4): 1580-91.
[] [PMID: 9326287]
Popescu BO, Oprica M, Sajin M, et al. Dantrolene protects neurons against kainic acid induced apoptosis in vitro and in vivo. J Cell Mol Med 2002; 6(4): 555-69.
[] [PMID: 12611640]
Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron 2004; 44(1): 5-21.
[] [PMID: 15450156]
Ziviani E, Lippi G, Bano D, et al. Ryanodine receptor-2 upregulation and nicotine-mediated plasticity. EMBO J 2011; 30(1): 194-204.
[] [PMID: 21113126]
Furukawa H, Singh SK, Mancusso R, Gouaux E. Subunit arrangement and function in NMDA receptors. Nature 2005; 438(7065): 185-92.
[] [PMID: 16281028]
Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 1999; 51(1): 7-61.
[PMID: 10049997]
Liu Y, Zhang J. Recent development in NMDA receptors. Chin Med J (Engl) 2000; 113(10): 948-56.
[PMID: 11775847]
Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 2001; 11(3): 327-35.
[] [PMID: 11399431]
Paoletti P, Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol 2007; 7(1): 39-47.
[] [PMID: 17088105]
Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002; 5(5): 405-14.
[] [PMID: 11953750]
Sattler R, Xiong Z, Lu WY, MacDonald JF, Tymianski M. Distinct roles of synaptic and extrasynaptic NMDA receptors in excitotoxicity. J Neurosci 2000; 20(1): 22-33.
[] [PMID: 10627577]
Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic--ischemic brain damage. Ann Neurol 1986; 19(2): 105-11.
[] [PMID: 2421636]
Danysz W, Parsons CG. Alzheimer’s disease, β-amyloid, glutamate, NMDA receptors and memantine--searching for the connections. Br J Pharmacol 2012; 167(2): 324-52.
[] [PMID: 22646481]
Moore KJ, El Khoury J, Medeiros LA, et al. A CD36-initiated signaling cascade mediates inflammatory effects of β-amyloid. J Biol Chem 2002; 277(49): 47373-9.
[] [PMID: 12239221]
El Khoury JB, Moore KJ, Means TK, et al. CD36 mediates the innate host response to β-amyloid. J Exp Med 2003; 197(12): 1657-66.
[] [PMID: 12796468]
Coraci IS, Husemann J, Berman JW, et al. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to β-amyloid fibrils. Am J Pathol 2002; 160(1): 101-12.
[] [PMID: 11786404]
Stewart CR, Stuart LM, Wilkinson K, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010; 11(2): 155-61.
[] [PMID: 20037584]
Park L, Wang G, Zhou P, et al. Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β. Proc Natl Acad Sci USA 2011; 108(12): 5063-8.
[] [PMID: 21383152]
Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 2009; 89(1): 73-120.
[] [PMID: 19126755]
Taly A, Corringer PJ, Guedin D, Lestage P, Changeux JP. Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat Rev Drug Discov 2009; 8(9): 733-50.
[] [PMID: 19721446]
Thomsen MS, Hansen HH, Timmerman DB, Mikkelsen JD. Cognitive improvement by activation of α7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des 2010; 16(3): 323-43.
[] [PMID: 20109142]
Kadir A, Almkvist O, Wall A, Långström B, Nordberg A. PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer’s disease. Psychopharmacology (Berl) 2006; 188(4): 509-20.
[] [PMID: 16832659]
Bao F, Wicklund L, Lacor PN, Klein WL, Nordberg A, Marutle A. Different β-amyloid oligomer assemblies in Alzheimer brains correlate with age of disease onset and impaired cholinergic activity. Neurobiol Aging 2012; 33(4): 825.e1-825.e13.
[] [PMID: 21683475]
Buckingham SD, Jones AK, Brown LA, Sattelle DB. Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol Rev 2009; 61(1): 39-61.
[] [PMID: 19293145]
Ni R, Marutle A, Nordberg A. Modulation of α7 nicotinic acetylcholine receptor and fibrillar amyloid-β interactions in Alzheimer’s disease brain. J Alzheimers Dis 2013; 33(3): 841-51.
[] [PMID: 23042213]
Doody RS, Raman R, Farlow M, et al. Alzheimer’s disease cooperative study steering committee. Semagacestat study group. A phase 3 trial of semagacestat for treatment of alzheimer’s disease. N Engl J Med 2013; 369(4): 341-50.
[] [PMID: 23883379]
Crump CJ, Johnson DS, Li YM. Development and mechanism of γ-secretase modulators for Alzheimer’s disease. Biochemistry 2013; 52(19): 3197-216.
[] [PMID: 23614767]
Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414(6860): 212-6.
[] [PMID: 11700559]
Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA. Tarenflurbil Phase II Study investigators. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial. Lancet Neurol 2008; 7(6): 483-93.
[] [PMID: 18450517]
Green RC, Schneider LS, Amato DA, et al. Tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 2009; 302(23): 2557-64.
[] [PMID: 20009055]
Oehlrich D, Berthelot DJ, Gijsen HJ. γ-Secretase modulators as potential disease modifying anti-Alzheimer’s drugs. J Med Chem 2011; 54(3): 669-98.
[] [PMID: 21141968]
Pettersson M, Kauffman GW, am Ende CW, et al. Novel γ-secretase modulators: a review of patents from 2008 to 2010. Expert Opin Ther Pat 2011; 21(2): 205-26.
[] [PMID: 21231889]
Hoffmann T, Meyer A, Heiser U, et al. Glutaminyl cyclase inhibitor PQ912 improves cognition in mouse models of Alzheimer’s disease—studies on relation to effective target occupancy. J Pharmacol Exp Ther 2017; 362(1): 119-30.
[] [PMID: 28446518]
Bongarzone S, Savickas V, Luzi F, Gee AD. Targeting the receptor for advanced glycation endproducts (RAGE): a medicinal chemistry perspective. J of Med Chem 2017; 60: 7213-32.
Younan ND, Viles JH. A comparison of three fluorophores for the detection of amyloid fibers and prefibrillaroligomeric assemblies. ThT (thioflavin T); ANS (1-anilinonaphthalene-8-sulfonic acid); and bisANS (4, 4′-dianilino-1, 1′-binaphthyl-5, 5′-disulfonic acid). Biochemistry 2015; 54(28): 4297-306.
[] [PMID: 26087242]
Giorgetti S, Raimondi S, Pagano K, et al. Effect of tetracyclines on the dynamics of formation and destructuration of β2-microglobulin amyloid fibrils. J Biol Chem 2011; 286(3): 2121-31.
[] [PMID: 21068391]
Lendel C, Bolognesi B, Wahlström A, Dobson CM, Gräslund A. Detergent-like interaction of Congo red with the amyloid β peptide. Biochemistry 2010; 49(7): 1358-60.
[] [PMID: 20070125]
Merlini G, Ascari E, Amboldi N, et al. Interaction of the anthracycline 4′-iodo-4′-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis. Proc Natl Acad Sci USA 1995; 92(7): 2959-63.
[] [PMID: 7708755]
Bonanomi M, Natalello A, Visentin C, et al. Epigallocatechin-3-gallate and tetracycline differently affect ataxin-3 fibrillogenesis and reduce toxicity in spinocerebellar ataxia type 3 model. Hum Mol Genet 2014; 23(24): 6542-52.
[] [PMID: 25030034]
Funke SA, Willbold D. Peptides for therapy and diagnosis of Alzheimer’s disease. Curr Pharm Des 2012; 18(6): 755-67.
[] [PMID: 22236121]
McKoy AF, Chen J, Schupbach T, Hecht MH. A novel inhibitor of amyloid β (Aβ) peptide aggregation: from high throughput screening to efficacy in an animal model of Alzheimer disease. J Biol Chem 2012; 287(46): 38992-9000.
[] [PMID: 22992731]
Dodart JC, Bales KR, Gannon KS, et al. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 2002; 5(5): 452-7.
[] [PMID: 11941374]
DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A β antibody alters CNS and plasma A β clearance and decreases brain A β burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2001; 98(15): 8850-5.
[] [PMID: 11438712]
Bouter Y, Lopez Noguerola JS, Tucholla P, et al. Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models. Acta Neuropathol 2015; 130(5): 713-29.
[] [PMID: 26467270]
Siemers ER, Friedrich S, Dean RA, et al. Safety and changes in plasma and cerebrospinal fluid amyloid β after a single administration of an amyloid β monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol 2010; 33(2): 67-73.
[] [PMID: 20375655]
Farlow M, Arnold SE, van Dyck CH, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement 2012; 8(4): 261-71.
[] [PMID: 22672770]
Doody RS, Thomas RG, Farlow M, et al. Alzheimer’s disease cooperative study steering committee. Solanezumab study group. Phase 3 trials of solanezumab for mild-to-moderate alzheimer’s disease. N Engl J Med 2014; 370(4): 311-21.
[] [PMID: 24450890]
Sperling RA, Rentz DM, Johnson KA, et al. The A4 study: stopping AD before symptoms begin? Sci Transl Med 2014; 6(228) 228fs13
[] [PMID: 24648338]
Bohrmann B, Baumann K, Benz J, 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 2012; 28(1): 49-69.
[] [PMID: 21955818]
Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012; 69(2): 198-207.
[] [PMID: 21987394]
Ostrowitzki S, Lasser RA, Dorflinger E, et al. SCarlet RoAD Investigators. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 2017; 9(1): 95.
[] [PMID: 29221491]
Abi-Saab D, Andjelkovic M, Delmar P, Voyle N, Esau N, Lasser RA. The effect of 6 months’dosing on the rate of amyloid-related imaging abnormalities (aria) in the marguerite road study. Alzheimers Dement 2017; 13: 252-3.
Adolfsson O, Pihlgren M, Toni N, et al. An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci 2012; 32(28): 9677-89.
[] [PMID: 22787053]
Fuller JP, Stavenhagen JB, Christensen S, Kartberg F, Glennie MJ, Teeling JL. Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies. Acta Neuropathol 2015; 130(5): 699-711.
[] [PMID: 26433971]
Cummings JL, Cohen S, van Dyck CH, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 2018; 90(21): e1889-97.
[] [PMID: 29695589]
Salloway S, Honigberg LA, Cho W, et al. Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE). Alzheimers Res Ther 2018; 10(1): 96.
[] [PMID: 30231896]
Arndt JW, Qian F, Smith BA, et al. Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β. Sci Rep 2018; 8(1): 6412.
[] [PMID: 29686315]
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537(7618): 50-6.
[] [PMID: 27582220]
Kastanenka KV, Bussiere T, Shakerdge N, et al. Immunotherapy with aducanumab restores calcium homeostasis in Tg2576 mice. J Neurosci 2016; 36(50): 12549-58.
[] [PMID: 27810931]
Budd Haeberlein S, O’Gorman J, Chiao P, et al. Clinical development of aducanumab, an anti-aβ human monoclonal antibody being investigated for the treatment of early alzheimer’s disease. J Prev Alzheimers Dis 2017; 4(4): 255-63.
[PMID: 29181491]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy