Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes

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.

Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein

“…This reveals accumulation of APP-CTFs in the brains of APP E693Q mice with age, in addition to the previous demonstration of accumulation of oAβ 17, 41 . No fibrillar amyloid deposits were observed in the brains of APP E693Q mice up to 24 months of age (Fig 1E).…”

“…Both cholinergic and GABAergic cell loss in the brain of these transgenic mice, in the absence of parenchymal and vascular β amyloid deposition, implies a role for intracellular accumulation of APP-CTFs/oAβ in neuronal degeneration and subsequent impaired spatial learning and memory, novel object recognition, and increased anxiety in APP E693Q transgenic mice 17, 39–41 .…”

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

“…The topic of amyloidogenesis has been the subject of many scientific endeavors and a great variety of papers have been published, approaching the problem from all possible angles: diagnostics [63][64][65][66], therapeutic [67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] and structural/molecular [82][83][84][85]. Our publication does not, however, discuss amyloidogenesis as such, but rather the molecular processes which lead to the formation of fibrillary aggregates commonly referred to as amyloids.…”

Alzheimer’s disease: experimental models and reality

“…The APP E693Δ-Tg model expresses the Osaka (APP E693Δ ) mutation, which results in a unique phenotype of significantly increased expression of Aβ oligomers, synaptic impairment and cognitive impairments from 8 months of age, but no plaque or tau pathology formation [159]. This allows the opportunity to examine the pathological effects of Aβ oligomers and/or the effect of therapeutics specifically on Aβ oligomers, which are thought to be the most toxic Aβ species[79]. The major benefit of these two mouse models is that they replicate specific pathological features of AD more robustly than other models.…”