@article{65250e1cf4d6434fa253e5b36d8c861c,
title = "Effective anti-Alzheimer Ab therapy involves depletion of specific Ab oligomer subtypes",
abstract = "Background: Recent studies have implicated specific assembly subtypes of b-amyloid (Ab) peptide, specifically soluble oligomers (soAb) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Ab assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Ab assemblies including soAb. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Ab antibodies to the clinical bioactivity of IVIg has been lacking. Methods: Five-month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Ab conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAb levels using standard anti-soAb antibodies. Results: We provide evidence that NU4-type soAb (NU4-soAb) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Ab plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAb and A11-soAb but not OC-type fibrillar Ab oligomers. Conclusions: We propose that targeting of specific soAb assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Ab antibody drugs.",
author = "Knight, {Elysse M.} and Kim, {Soong Ho} and Kottwitz, {Jessica C.} and Asa Hatami and Ricardo Albay and Akinobu Suzuki and Alex Lublin and Alberini, {Cristina M.} and Klein, {William L.} and Paul Szabo and Relkin, {Norman R.} and Michelle Ehrlich and Glabe, {Charles G.} and Sam Gandy and Steele, {John W.}",
note = "Funding Information: J.W.S. is a cofounder, shareholder, and member of the board of directors and scientific advisory board of OrPhi Therapeutics Inc. (Carlsbad, CA). Within the past 5 years, S.G. has held research grants from Amicus Therapeutics. S.G. is also a member of the Data and Safety Monitoring Board for the Pfizer-Janssen Alzheimer{\textquoteright}s Immunotherapy Alliance. Funding Information: E. Knight, S.H. Kim, and J. Kottwitz report no disclosures. A. Hatami is an associate editor for Journal of Alzheimer{\textquoteright}s Disease, received research support from NIH, Cure Alzheimer{\textquoteright}s Fund. R. Albay and A. Suzuki report no disclosures. A. Lublin has been employed by Sanofi Genzyme, received research support from University of California, Riverside, holds stock or stock options in Geron and Ionis. C. Alberini is on the editorial board for Neural Plasticity, Neurobiology of Learning and Memory, was on the editorial board for Cell Science, is an associate editor for Frontiers in Neuroscience, received research support from NIH. W.L. Klein served on the scientific advisory board for Acumen Pharmaceuticals, received research support from NIH, Baxter-NU Alliance, NUCATS/Northwestern. P. Szabo reports no disclosures. N. Relkin served on the scientific advisory board for Anavex, Herbal Science Group, Eisai, was an associate editor for Neurology Alert, has patents pending for Multiplexed CSF markers for Alzheimer{\textquoteright}s disease, Diffusion tensor histogram analysis for diagnosis of hydrocephalus: an analytic method for identifying a DTI pattern associated with normal pressure hydrocephalus, Volumetric MRI for predicting response to IVIg treatment of Alzheimer{\textquoteright}s disease, Cytokine analysis for predicting response to IVIg treatment of Alzheimer{\textquoteright}s disease, Systems and methods for automating the retrieval of portioned search results, receives royalties from UpToDate, has consulted for Aisai, Forest, Hydrocephalus Association. M. Ehrlich is on the editorial board for ASN Neuro, received research support from NIH, NYSTEM. C. Glabe served on the editorial board for Journal of Molecular Neurodegeneration, has patents and pending patents for immunotherapy and immunodiagnostics for AD, consults relating to intellectual property, receives license fee and royalty payments for antibodies for research purposes only and patent issues, received research support from NIH, Cure Alzheimer{\textquoteright}s Fund, was involved in legal proceedings for Sidley LLP. S. Gandy is an associate editor for ADAD, Molecular Neurodegenera-tion, is a consulting editor for JCI, received research support from Avid/ Lilly, Constellation Wines. J. Steele is a scientific advisory board member for OrPhi Therapeutics Inc., was editor-in-chief and consulting editor for Journal of Postdoctoral Research, has a pending patent for Mitoprotection for treatment of lysosomal storage diseases, consulted for Amicus Therapeutics, received research support from CurePSP, DPD Deficiency Foundation, is a cofounder and on the board of directors for OrPhi Therapeutics Inc., holds stock or stock options in Amicus Therapeutics, GlaxoSmithKline. Go to Neurology.org/nn for full disclosure forms. Funding Information: This work was supported in part by a grant from Baxter Pharmaceuticals, Inc. J.W.S. is supported by NIH grant K12 GM068524. This work was additionally supported by NIH grants P50 AG05138 (to Mary Sano; S.G.), U01 AG046170 (S.G., M.E.), R34 AG049649 (S.G.), R01 NS075685 (S.G.), R01 MH065635 (C.M.A.), R21 AT005510 (S.G.), RF1 AG042965 (S.G.), VA MERIT Review Grant I01 RX000684 (S.G.), the Cure Alzheimer's Fund (S.G.), and gifts from the Louis B. Mayer Foundation, the Sarah and Gideon Gartner Trust, the Rudin Foundation, and the Werber Family Foundation (all to S.G.). Funding Information: This work was supported in part by a grant from Baxter Pharmaceuticals, Inc. J.W.S. is supported by NIH grant K12 GM068524. This work was additionally supported by NIH grants P50 AG05138 (to Mary Sano; S.G.), U01 AG046170 (S.G., M.E.), R34 AG049649 (S.G.), R01 NS075685 (S.G.), R01 MH065635 (C.M.A.), R21 AT005510 (S.G.), RF1 AG042965 (S.G.), VA MERIT Review Grant I01 RX000684 (S.G.), the Cure Alzheimer{\textquoteright}s Fund (S.G.), and gifts from the Louis B. Mayer Foundation, the Sarah and Gideon Gartner Trust, the Rudin Foundation, and the Werber Family Foundation (all to S.G.). Publisher Copyright: {\textcopyright} 2016 American Academy of Neurology.",
year = "2016",
month = jun,
day = "1",
doi = "10.1212/NXI.0000000000000237",
language = "English (US)",
volume = "3",
journal = "Neurology: Neuroimmunology and NeuroInflammation",
issn = "2332-7812",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "3",
}