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.