Alzheimer's disease and blood-brain barrier function-Why have anti-beta-amyloid therapies failed to prevent dementia progression?

Abstract

Proteopathies of the brain are defined by abnormal, disease-inducing protein deposition that leads to functional abrogation and death of neurons. Immunization trials targeting the removal of amyloid-beta plaques in Alzheimer's disease have so far failed to stop the progression of dementia, despite autopsy findings of reduced plaque load. Here, we summarize current knowledge of the relationship between AD pathology and blood-brain barrier function, and propose that the activation of the excretion function of the blood-brain barrier might help to achieve better results in trials targeting the dissolution of cerebral amyloid-beta aggregates. We further discuss a possible role of oligomers in limiting the efficacy of immunotherapy.

Figure 1

Aggregation of Aβ monomers to higher MW aggregates generates toxic oligomers. Protofibrils, fibrils, and lastly the β-amyloid plaques exhibit less specific toxicity per mol of aggregated monomers than do oligomeric assemblies. Toxic oligomers form stable intermediates such as dimeres, trimers, hexamers and dodecamers (12mers). Plaques can be degraded, e.g. by immunotherapy, to lower MW Aβ fragments that might exert toxic effects. However, oligomers and monomers can be degraded or excreted via the BBB. Here, ABC transporters play an important role. Inhibition of ABC transporter function leads to temporal accumulation of Aβ within the brain. Conversely, ABC transporter activation helps to reduce the amount of monomers and toxic intermediates that can result from plaque-degrading approaches. Accordingly, we propose that, to be most effective, immunotherapy of AD patients must be accompanied by the activation of the brain's gateway – the BBB – to the peripheral sink – the blood – to sufficiently reduce toxic oligomers of Aβ.