Autoantibodies to Redox-modified Oligomeric Aβ Are Attenuated in the Plasma of Alzheimer's Disease Patients

Bradley T. Hyman,Katya A. Tseitlin,Rudolph E Tanzi,Stephanie Soscia,Robert D. Moir,Michael C. Irizarry

doi:10.1074/jbc.m414176200

Bradley T. Hyman, Katya A. Tseitlin + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m414176200

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Abstract

Accumulation of Abeta protein in beta-amyloid deposits is a hallmark event in Alzheimer's disease (AD). Recent findings suggest anti-Abeta autoantibodies may have a role in AD pathology. However, a consensus has yet to emerge as to whether endogenous anti-Abeta autoantibodies are elevated, depressed, or unchanged in AD patients. Whereas experiments to date have used synthetic unmodified monomeric Abeta (Abetamon) to test autoimmunity, up to 40% of the Abeta pool inB AD brain consists of low molecular weight oligomeric cross-linked beta-amyloid protein species (CAPS). Recent studies also suggest that CAPS may be the primary neurotoxic agent in AD. In the present study, AD and nondemented control plasma were analyzed for immunoreactivity to CAPS and Abetamon. Plasma of both nondemented and AD patients were found to contain autoantibodies specific for soluble CAPS. Nondemented control and AD plasmas demonstrated similar immunoreactivity to Abetamon. In contrast, anti-CAPS antibodies in AD plasma were found to be significantly reduced compared with nondemented controls (p=0.018). Furthermore, age at onset for AD correlated significantly (p=0.041) with plasma immunoreactivity to CAPS. These data suggest that autoantibodies to CAPS are depleted in AD patients and raise the prospect that immunization with anti-CAPS antibodies might provide therapeutic benefit for AD.

Highlights

A convergence of histological, biochemical, and genetic evidence links the widespread neuronal loss characteristic of Alzheimer’s disease (AD)1 with deposits of ␤-amyloid that pervade the brains of AD patients
Whereas experiments to date have used synthetic unmodified monomeric A␤ (A␤mon) to test autoimmunity, up to 40% of the A␤ pool in AD brain consists of low molecular weight oligomeric cross-linked ␤-amyloid protein species (CAPS)
Wells were coated with either unmodified monomeric A␤ (A␤mon), redox-treated peptide containing cross-linked ␤-amyloid protein species (CAPS), or peptide assembled into noncovalent multimers by incubation with Zn(II)/histidine (A␤Zn)

Summary

Introduction

A convergence of histological, biochemical, and genetic evidence links the widespread neuronal loss characteristic of Alzheimer’s disease (AD) with deposits of ␤-amyloid that pervade the brains of AD patients. Initial studies suggested that anti-A␤ antibodies aid in the clearance of amyloid by crossing the blood-brain barrier and binding directly to plaques. Subsequent studies have suggested that antibodies [19] and other A␤ binding agents [20] may not need to cross the blood-brain barrier to be effective in inhibiting cerebral A␤ plaque formation. In this model, A␤ is bound and sequestered in the periphery and prevented from crossing back into the brain, promoting a net flux out of neurological tissue [19]. It is imperative to advance our understanding of the autoimmune response to A␤ and its derivatives with greater alacrity

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