Effective anti-Alzheimer A? therapy involves depletion of specific A? oligomer subtypes.

ABSTRACT:

Background

Recent studies have implicated specific assembly subtypes of ?-amyloid (A?) peptide, specifically soluble oligomers (soA?) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble A? 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 A? assemblies including soA?. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-A? 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 A? conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soA? levels using standard anti-soA? antibodies.

Results

We provide evidence that NU4-type soA? (NU4-soA?) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble A? plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soA? and A11-soA? but not OC-type fibrillar A? oligomers.

Conclusions

We propose that targeting of specific soA? assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-A? antibody drugs.

SUBMITTER: Knight EM 

PROVIDER: S-EPMC4864617 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature