{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T06:27:54Z","timestamp":1773210474867,"version":"3.50.1"},"reference-count":102,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T00:00:00Z","timestamp":1525305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Passive immunotherapy has emerged as a very promising approach for the treatment of Alzheimer\u2019s disease and other neurodegenerative disorders, which are characterized by the misfolding and deposition of amyloid peptides. On the basis of the amyloid hypothesis, the majority of antibodies in clinical development are directed against amyloid \u03b2 (A\u03b2), the primary amyloid component in extracellular plaques. This review focuses on the current status of A\u03b2 antibodies in clinical development, including their characteristics and challenges that came up in clinical trials with these new biological entities (NBEs). Emphasis is placed on the current view of common side effects observed with passive immunotherapy, so-called amyloid-related imaging abnormalities (ARIAs), and potential ways to overcome this issue. Among these new ideas, a special focus is placed on molecules that are directed against post-translationally modified variants of the A\u03b2 peptide, an emerging approach for development of new antibody molecules.<\/jats:p>","DOI":"10.3390\/molecules23051068","type":"journal-article","created":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T03:20:27Z","timestamp":1525317627000},"page":"1068","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Passive A\u03b2 Immunotherapy: Current Achievements and Future Perspectives"],"prefix":"10.3390","volume":"23","author":[{"given":"Stephan","family":"Schilling","sequence":"first","affiliation":[{"name":"Fraunhofer Institute for Cell Therapy and Immunology, Department for Drug Design and Target Validation, 06120 Halle (Saale), Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens-Ulrich","family":"Rahfeld","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Cell Therapy and Immunology, Department for Drug Design and Target Validation, 06120 Halle (Saale), Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inge","family":"Lues","sequence":"additional","affiliation":[{"name":"Probiodrug AG, 06120 Halle (Saale), Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia A.","family":"Lemere","sequence":"additional","affiliation":[{"name":"Ann Romney Center for Neurologic Diseases, Brigham and Womens\u2019s Hospital, Harvard Medical School, Boston, MA 02116, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jalz.2012.11.007","article-title":"The global prevalence of dementia: A systematic review and metaanalysis","volume":"9","author":"Prince","year":"2013","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13195-016-0188-8","article-title":"Recent global trends in the prevalence and incidence of dementia, and survival with dementia","volume":"8","author":"Prince","year":"2016","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"b75","DOI":"10.1136\/bmj.b75","article-title":"Dementia","volume":"338","author":"Burns","year":"2009","journal-title":"BMJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"b158","DOI":"10.1136\/bmj.b158","article-title":"Alzheimer\u2019s disease","volume":"338","author":"Burns","year":"2009","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"511","DOI":"10.4140\/TCP.n.2017.511","article-title":"AChE Inhibitors and NMDA Receptor Antagonists in Advanced Alzheimer\u2019s Disease","volume":"32","author":"Ranola","year":"2017","journal-title":"Consult. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.trci.2017.05.002","article-title":"Alzheimer\u2019s disease drug development pipeline: 2017","volume":"3","author":"Cummings","year":"2017","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4103\/1673-5374.224362","article-title":"Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer\u2019s disease","volume":"13","author":"Onyango","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3109\/00207454.2015.1015722","article-title":"The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer\u2019s disease and mild-to-moderate Alzheimer\u2019s disease: A meta-analysis","volume":"126","author":"Cheng","year":"2016","journal-title":"Int. J. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.3892\/mmr.2014.2040","article-title":"Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer\u2019s disease","volume":"9","author":"Cai","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Timmers, M., Sinha, V., Darpo, B., Smith, B., Brown, R., Xue, H., Ferber, G., Streffer, J., Russu, A., and Tritsmans, L. (2018). Evaluating Potential QT Effects of JNJ-54861911, a BACE Inhibitor in Single- and Multiple-Ascending Dose Studies, and a Thorough QT Trial with Additional Retrospective Confirmation, Using Concentration-QTc Analysis. J. Clin. Pharmacol.","DOI":"10.1002\/jcph.1087"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S1474-4422(09)70299-6","article-title":"Hypothetical model of dynamic biomarkers of the Alzheimer\u2019s pathological cascade","volume":"9","author":"Jack","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1056\/NEJMra0909142","article-title":"Alzheimer\u2019s disease","volume":"362","author":"Querfurth","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease: Progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1474-4422(13)70044-9","article-title":"Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer\u2019s disease: A prospective cohort study","volume":"12","author":"Villemagne","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nm0197-67","article-title":"Mutant presenilins of Alzheimer\u2019s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice","volume":"3","author":"Citron","year":"1997","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"781","DOI":"10.3233\/JAD-151186","article-title":"Evidence For and Against a Pathogenic Role of Reduced gamma-Secretase Activity in Familial Alzheimer\u2019s Disease","volume":"52","author":"Jayne","year":"2016","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nature11283","article-title":"A mutation in APP protects against Alzheimer\u2019s disease and age-related cognitive decline","volume":"488","author":"Jonsson","year":"2012","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nrd3288","article-title":"Alzheimer\u2019s failure raises questions about disease-modifying strategies","volume":"9","author":"Extance","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/clpt.2010.165","article-title":"The development of new therapeutics for Alzheimer\u2019s disease","volume":"88","author":"Carter","year":"2010","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1152\/physrev.00023.2009","article-title":"Proteases and proteolysis in Alzheimer disease: A multifactorial view on the disease process","volume":"90","year":"2010","journal-title":"Physiol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/joim.12191","article-title":"Clinical trials and late-stage drug development for Alzheimer\u2019s disease: An appraisal from 1984 to 2014","volume":"275","author":"Schneider","year":"2014","journal-title":"J. Intern. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nrneurol.2013.223","article-title":"Alzheimer disease therapy\u2014Moving from amyloid-beta to tau","volume":"9","author":"Giacobini","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13195-016-0189-7","article-title":"Bapineuzumab for mild to moderate Alzheimer\u2019s disease in two global, randomized, phase 3 trials","volume":"8","author":"Vandenberghe","year":"2016","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1056\/NEJMoa1705971","article-title":"Trial of Solanezumab for Mild Dementia Due to Alzheimer\u2019s Disease","volume":"378","author":"Honig","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature19323","article-title":"The antibody aducanumab reduces Abeta plaques in Alzheimer\u2019s disease","volume":"537","author":"Sevigny","year":"2016","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1126\/science.aao2825","article-title":"Fibril structure of amyloid-beta(1-42) by cryo-electron microscopy","volume":"358","author":"Gremer","year":"2017","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"18325","DOI":"10.1074\/jbc.M117.801514","article-title":"Mechanisms of recognition of amyloid-beta (Abeta) monomer, oligomer, and fibril by homologous antibodies","volume":"292","author":"Zhao","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9649","DOI":"10.1038\/srep09649","article-title":"Molecular basis for mid-region amyloid-beta capture by leading Alzheimer\u2019s disease immunotherapies","volume":"5","author":"Crespi","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"39374","DOI":"10.1038\/srep39374","article-title":"Structure of Crenezumab Complex with Abeta Shows Loss of beta-Hairpin","volume":"6","author":"Ultsch","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Eggleton, P., Javed, M., Pulavar, D., and Sheldon, G. (2015). Immune Complexes, eLS.","DOI":"10.1002\/9780470015902.a0001118.pub2"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3389\/fimmu.2014.00520","article-title":"IgG subclasses and allotypes: From structure to effector functions","volume":"5","author":"Vidarsson","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"P609","DOI":"10.1016\/j.jalz.2016.06.1207","article-title":"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\u2019s Disease","volume":"12","author":"Blaettler","year":"2016","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.jval.2015.03.1787","article-title":"Quality of Life and Utility Measurement in a Large Clinical Trial Sample of Patients with Mild to Moderate Alzheimer\u2019s Disease: Determinants and Level of Changes Observed","volume":"18","author":"Lacey","year":"2015","journal-title":"Value Health"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13195-016-0177-y","article-title":"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\u2019s disease","volume":"8","author":"Delnomdedieu","year":"2016","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/WNF.0b013e318279bcfa","article-title":"Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease","volume":"36","author":"Burstein","year":"2013","journal-title":"Clin. Neuropharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1097\/WNF.0b013e31827db49b","article-title":"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","volume":"36","author":"Landen","year":"2013","journal-title":"Clin. Neuropharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jalz.2015.06.1893","article-title":"Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer\u2019s disease patients","volume":"12","author":"Siemers","year":"2016","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jalz.2016.07.005","article-title":"The DIAN-TU Next Generation Alzheimer\u2019s prevention trial: Adaptive design and disease progression model","volume":"13","author":"Bateman","year":"2017","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.neuron.2012.10.029","article-title":"A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer\u2019s disease mice","volume":"76","author":"Demattos","year":"2012","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"P352","DOI":"10.1016\/j.jalz.2016.06.665","article-title":"Safety, Pharmacokinetics [PK], and Florbetapir F-18 Positron Emission Tomography [PET] after Multiple Dose Administration of LY3002813, a \u00df-Amyloid Plaque-Specific Antibody, in Alzheimer\u2019s Disease [AD]","volume":"12","author":"Irizarry","year":"2016","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3233\/JAD-2011-110977","article-title":"Gantenerumab: A novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta","volume":"28","author":"Bohrmann","year":"2012","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9677","DOI":"10.1523\/JNEUROSCI.4742-11.2012","article-title":"An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta","volume":"32","author":"Adolfsson","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"575","DOI":"10.3233\/JAD-140741","article-title":"The murine version of BAN2401 (mAb158) selectively reduces amyloid-beta protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice","volume":"43","author":"Tucker","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13195-016-0181-2","article-title":"Safety and tolerability of BAN2401\u2014A clinical study in Alzheimer\u2019s disease with a protofibril selective Abeta antibody","volume":"8","author":"Logovinsky","year":"2016","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trci.2016.01.001","article-title":"Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer\u2019s disease","volume":"2","author":"Satlin","year":"2016","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12549","DOI":"10.1523\/JNEUROSCI.2080-16.2016","article-title":"Immunotherapy with Aducanumab Restores Calcium Homeostasis in Tg2576 Mice","volume":"36","author":"Kastanenka","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_48","first-page":"255","article-title":"Clinical Development of Aducanumab, an Anti-Abeta Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer\u2019s Disease","volume":"4","author":"Budd","year":"2017","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"P808","DOI":"10.1016\/j.jalz.2013.05.1678","article-title":"SAR228810: An antiprotofibrillar beta-amyloid antibody designed to reduce risk of amyloid-related imaging abnormalities [ARIA]","volume":"9","author":"Pradier","year":"2013","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.3233\/JAD-142988","article-title":"Development of Immunoassays for the Quantitative Assessment of Amyloid-beta in the Presence of Therapeutic Antibody: Application to Pre-Clinical Studies","volume":"46","author":"Bogstedt","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"29","DOI":"10.12703\/P6-29","article-title":"Advances in the management of macular degeneration","volume":"6","author":"Singer","year":"2014","journal-title":"F1000Prime Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/alzrt249","article-title":"Modulation of beta-amyloid by a single dose of GSK933776 in patients with mild Alzheimer\u2019s disease: A phase I study","volume":"6","author":"Leyhe","year":"2014","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"E279","DOI":"10.1073\/pnas.1100901108","article-title":"Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration","volume":"108","author":"Ding","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.jalz.2011.05.2351","article-title":"Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer\u2019s Association Research Roundtable Workgroup","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1474-4422(12)70015-7","article-title":"Amyloid-related imaging abnormalities in patients with Alzheimer\u2019s disease treated with bapineuzumab: A retrospective analysis","volume":"11","author":"Sperling","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"39941","DOI":"10.18632\/oncotarget.17990","article-title":"APOE genotype and Alzheimer\u2019s immunotherapy","volume":"8","author":"Pankiewicz","year":"2017","journal-title":"Oncotarget"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1111\/jnc.12202","article-title":"Alzheimer\u2019s Abeta42 and Abeta40 peptides form interlaced amyloid fibrils","volume":"126","author":"Gu","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1006\/abbi.1993.1112","article-title":"Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer\u2019s disease","volume":"301","author":"Miller","year":"1993","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"7013","DOI":"10.1074\/jbc.270.13.7013","article-title":"Amyloid beta protein (A beta) in Alzheimer\u2019s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42","volume":"270","author":"Gravina","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1021\/bc060349x","article-title":"Fusion antibody for Alzheimer\u2019s disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation","volume":"18","author":"Boado","year":"2007","journal-title":"Bioconjug. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1080\/14712598.2016.1230195","article-title":"Re-engineering therapeutic antibodies for Alzheimer\u2019s disease as blood-brain barrier penetrating bi-specific antibodies","volume":"16","author":"Pardridge","year":"2016","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"308","DOI":"10.7150\/thno.17155","article-title":"Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor","volume":"7","author":"Hultqvist","year":"2017","journal-title":"Theranostics"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.neuron.2013.10.061","article-title":"Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle","volume":"81","author":"Niewoehner","year":"2014","journal-title":"Neuron"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"84ra44","DOI":"10.1126\/scitranslmed.3002230","article-title":"Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target","volume":"3","author":"Yu","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"183ra57","DOI":"10.1126\/scitranslmed.3005338","article-title":"Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier","volume":"5","author":"Couch","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"261ra154","DOI":"10.1126\/scitranslmed.3009835","article-title":"Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates","volume":"6","author":"Yu","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/cpt.71","article-title":"Improving drug delivery to primary and metastatic brain tumors: Strategies to overcome the blood-brain barrier","volume":"97","author":"Parrish","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1001\/jamaneurol.2017.3129","article-title":"A Review of the Current Therapies, Challenges, and Future Directions of Transcranial Focused Ultrasound Technology: Advances in Diagnosis and Treatment","volume":"75","author":"Krishna","year":"2018","journal-title":"JAMA Neurol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Nisbet, R.M., and Gotz, J. (2018). Amyloid-beta and Tau in Alzheimer\u2019s Disease: Novel Pathomechanisms and Non-Pharmacological Treatment Strategies. J. Alzheimer\u2019s Dis.","DOI":"10.3233\/JAD-179907"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3389\/fnins.2018.00055","article-title":"Safety and Efficacy of Scanning Ultrasound Treatment of Aged APP23 Mice","volume":"12","author":"Leinenga","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"19235","DOI":"10.1074\/jbc.R116.746032","article-title":"A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis","volume":"291","author":"Andrew","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1021\/bi400377p","article-title":"Development and mechanism of gamma-secretase modulators for Alzheimer\u2019s disease","volume":"52","author":"Crump","year":"2013","journal-title":"Biochemistry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/alzrt258","article-title":"Truncated and modified amyloid-beta species","volume":"6","author":"Kummer","year":"2014","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/35014735","article-title":"Presenilin-1 mutations in Alzheimer\u2019s disease","volume":"405","author":"Russo","year":"2000","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"10810","DOI":"10.1021\/bi0508237","article-title":"Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques","volume":"44","author":"Miravalle","year":"2005","journal-title":"Biochemistry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1523\/JNEUROSCI.21-02-00372.2001","article-title":"Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer\u2019s disease","volume":"21","author":"Kawarabayashi","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nature11060","article-title":"Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-beta","volume":"485","author":"Nussbaum","year":"2012","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"38825","DOI":"10.1074\/jbc.R111.288308","article-title":"Pyroglutamate amyloid-beta (Abeta): A hatchet man in Alzheimer disease","volume":"286","author":"Jawhar","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1097\/00005072-199811000-00012","article-title":"Quantification of modified amyloid beta peptides in Alzheimer disease and Down syndrome brains","volume":"57","author":"Hosoda","year":"1998","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0014-5793(97)00564-4","article-title":"Heterogeneity of water-soluble amyloid beta-peptide in Alzheimer\u2019s disease and Down\u2019s syndrome brains","volume":"409","author":"Russo","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1006\/bbrc.1997.7083","article-title":"Isolation, chemical characterization, and quantitation of A beta 3-pyroglutamyl peptide from neuritic plaques and vascular amyloid deposits","volume":"237","author":"Kuo","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.neuroscience.2006.08.027","article-title":"High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain","volume":"143","author":"Guntert","year":"2006","journal-title":"Neuroscience"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1046\/j.1471-4159.2003.01818.x","article-title":"Truncated beta-amyloid peptide species in pre-clinical Alzheimer\u2019s disease as new targets for the vaccination approach","volume":"85","author":"Sergeant","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1093\/brain\/awt362","article-title":"Biochemical stages of amyloid-beta peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer\u2019s disease","volume":"137","author":"Rijal","year":"2014","journal-title":"Brain"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"385","DOI":"10.3233\/JAD-131535","article-title":"Glutaminyl cyclase in human cortex: Correlation with (pGlu)-amyloid-beta load and cognitive decline in Alzheimer\u2019s disease","volume":"39","author":"Morawski","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"12393","DOI":"10.1021\/bi0612667","article-title":"On the seeding and oligomerization of pGlu-amyloid peptides (in vitro)","volume":"45","author":"Schilling","year":"2006","journal-title":"Biochemistry"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"7072","DOI":"10.1021\/bi900818a","article-title":"Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides","volume":"48","author":"Schlenzig","year":"2009","journal-title":"Biochemistry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1111\/j.1471-4159.2012.07707.x","article-title":"N-Terminal pyroglutamate formation of Abeta38 and Abeta40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation","volume":"121","author":"Schlenzig","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/nm.1872","article-title":"Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer\u2019s disease-like pathology","volume":"14","author":"Schilling","year":"2008","journal-title":"Nat. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1124\/jpet.117.240614","article-title":"Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer\u2019s Disease-Studies on Relation to Effective Target Occupancy","volume":"362","author":"Hoffmann","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s13024-016-0115-2","article-title":"Immunotherapy targeting pyroglutamate-3 Abeta: Prospects and challenges","volume":"11","author":"Cynis","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1159\/000335913","article-title":"Passive immunization against pyroglutamate-3 amyloid-beta reduces plaque burden in Alzheimer-like transgenic mice: A pilot study","volume":"10","author":"Frost","year":"2012","journal-title":"Neurodegener. Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ajpath.2013.05.005","article-title":"Pyroglutamate-3 amyloid-beta deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models","volume":"183","author":"Frost","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3187","DOI":"10.1016\/j.neurobiolaging.2015.08.021","article-title":"An anti-pyroglutamate-3 Abeta vaccine reduces plaques and improves cognition in APPswe\/PS1DeltaE9 mice","volume":"36","author":"Frost","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"14537","DOI":"10.1523\/JNEUROSCI.2692-08.2008","article-title":"Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus","volume":"28","author":"Puzzo","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1002\/ana.22313","article-title":"Endogenous amyloid-beta is necessary for hippocampal synaptic plasticity and memory","volume":"69","author":"Puzzo","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"S111","DOI":"10.3233\/JAD-2012-129033","article-title":"Amyloid-beta peptide: Dr. Jekyll or Mr. Hyde?","volume":"33","author":"Puzzo","year":"2013","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Soscia, S.J., Kirby, J.E., Washicosky, K.J., Tucker, S.M., Ingelsson, M., Hyman, B., Burton, M.A., Goldstein, L.E., Duong, S., and Tanzi, R.E. (2010). The Alzheimer\u2019s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009505"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s00401-016-1546-0","article-title":"Phosphorylation of the amyloid beta-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity","volume":"131","author":"Kumar","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"803","DOI":"10.18632\/aging.100362","article-title":"Phosphorylation of amyloid beta (Abeta) peptides\u2014A trigger for formation of toxic aggregates in Alzheimer\u2019s disease","volume":"3","author":"Kumar","year":"2011","journal-title":"Aging"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1038\/emboj.2011.138","article-title":"Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer\u2019s disease","volume":"30","author":"Kumar","year":"2011","journal-title":"EMBO J."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.neuron.2011.07.001","article-title":"Nitration of tyrosine 10 critically enhances amyloid beta aggregation and plaque formation","volume":"71","author":"Kummer","year":"2011","journal-title":"Neuron"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/5\/1068\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:03:02Z","timestamp":1760194982000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/5\/1068"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,3]]},"references-count":102,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["molecules23051068"],"URL":"https:\/\/doi.org\/10.3390\/molecules23051068","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,3]]}}}