Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

doi:10.1073/pnas.0904866106

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

Departments of ^aNeurology and Neurological Sciences and
^dMedicine, Stanford University School of Medicine, Stanford, CA 94305;
^bDepartment of Chemical Engineering, Stanford University, Stanford, CA 94305-5025;
^cInstitute of Social and Preventive Medicine, Biostatistics Unit, University of Zurich, CH-8001 Zurich, Switzerland;
^eGeriatric Research Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304;
^fDepartment of Neurology, Alzheimer's Disease Center, and Institute on Aging, University of Pennsylvania, Philadelphia, PA 19104;
^gDepartment of Neurology, Washington University, St. Louis, MO 63110;
^hDepartment of Neurosciences, University of California at San Diego, La Jolla, CA 92093;
ⁱDepartment of Internal Medicine and Allergology, Wroclaw Medical University, 50-417 Wroclaw, Poland;
^jLayton Aging and Alzheimer's Disease Center, Oregon Health Sciences University, Portland, OR 97201;
^kBrigham and Women's Hospital and Center for Neurologic Diseases, Harvard Medical School, Boston, MA 02115;
^lDepartment of Psychiatry, Wroclaw Medical University, 51-622 Wroclaw, Poland;
^mAlzheimer's Disease Research Center, University of Washington, Seattle, WA 98108;
ⁿVeterans Affairs Puget Sound Health Care System, Seattle, WA 98108; and
^oDepartments of Pathology and Psychiatry, New York University Langone Medical Center, New York, NY 10016

Abstract

A number of distinct β-amyloid (Aβ) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Aβ-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Aβ and amyloidogenic non-Aβ species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21–89 years. Antibody reactivity was most prominent against oligomeric assemblies of Aβ and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Aβ1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Aβ, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Aβ toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Aβ the monkeys developed high titers not only against Aβ peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Aβ antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.

Footnotes

¹To whom correspondence should be addressed. E-mail: twc{at}stanford.edu
Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved May 28, 2009
Author contributions: M.B. and T.W.-C. designed research; M.B., C.E.O., H.T.J., Y.T.-U., M.C.L., J.R., H.Z., B.T., and J.A.G. performed research; J.R., W.H.R., C.M.C., A.M.F., D.R.G., D.M.H., M.J., J.A.K., C.A.L., J.L., G.L., E.R.P., J.F.Q., J.A.Y., and J.A.G. contributed new reagents/analytic tools; M.B., C.E.O., K.R., and J.A.G. analyzed data; and M.B. and T.W.-C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0904866106/DCSupplemental.