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Knight EM, Kim SH, Kottwitz JC, Hatami A, Albay R, Suzuki A, Lublin A, Alberini CM, Klein WL, Szabo P, Relkin NR, Ehrlich M, Glabe CG, Gandy S, Steele JW. Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2016; 3:e237. [PMID: 27218118 PMCID: PMC4864617 DOI: 10.1212/nxi.0000000000000237] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 04/04/2016] [Indexed: 11/15/2022]
Abstract
BACKGROUND Recent studies have implicated specific assembly subtypes of β-amyloid (Aβ) peptide, specifically soluble oligomers (soAβ) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Aβ 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 Aβ assemblies including soAβ. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Aβ 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 Aβ conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAβ levels using standard anti-soAβ antibodies. RESULTS We provide evidence that NU4-type soAβ (NU4-soAβ) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Aβ plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAβ and A11-soAβ but not OC-type fibrillar Aβ oligomers. CONCLUSIONS We propose that targeting of specific soAβ assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Aβ antibody drugs.
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Affiliation(s)
- Elysse M Knight
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Soong Ho Kim
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Jessica C Kottwitz
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Asa Hatami
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Ricardo Albay
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Akinobu Suzuki
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Alex Lublin
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Cristina M Alberini
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - William L Klein
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Paul Szabo
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Norman R Relkin
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Michelle Ehrlich
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Charles G Glabe
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - Sam Gandy
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
| | - John W Steele
- Departments of Psychiatry (E.M.K., S.H.K., J.C.K., A.L., S.G., J.W.S.), Neurology (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), and Pediatrics (M.E.), and Alzheimer's Disease Research Center (E.M.K., S.H.K., J.C.K., A.L., M.E., S.G., J.W.S.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Molecular Biology and Biochemistry (A.H., R.A., C.G.G.), University of California at Irvine; King Fahd Medical Research Center (A.H., R.A., C.G.G.), KAU, Jeddah, Saudi Arabia; Department of Biochemistry (A.S.), Faculty of Medicine, Graduate School of Medicine & Pharmaceutical Sciences, University of Toyama, Japan; Center for Neural Science (C.M.A.), New York University, NY; Northwestern University (W.L.K.), Chicago, IL; Department of Neurology and Brain Mind Research Institute (P.S., N.R.R.), Weill Cornell Medical College, New York, NY; Biochemistry Department (C.G.G.), Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; James J. Peters VA Medical Center (S.G.), Bronx, NY; and Sanford Consortium for Regenerative Medicine (J.W.S.), University of California San Diego, La Jolla, CA
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