gms | German Medical Science

Alzheimer's disease (AD) is characterized by the deposition of the amyloid beta (Aβ) protein in the brain. Various forms of Ab aggregates have been described in the AD brains. Soluble Ab protein aggregates have been discussed as toxic agents. Dispersible Aβ aggregates in the brain parenchyma are different from soluble, membrane-associated, and plaque-associated solid aggregates. They are in mixture with the extra or intracellular fluid but can be separated from soluble proteins by ultracentrifugation. We have recently described a critical role of dispersible Ab aggregates for neurodegeneration in the brain of amyloid precursor protein (APP)-transgenic mouse models. To clarify the role of dispersible Aβ aggregates in the human brain we analyzed brain homogenates from symptomatic AD (demented individuals with AD related pathology), preclinical AD (preAD, non demented individuals with AD related pathology) and control (non demented individuals without AD pathology) cases.

Native forebrain homogenate was prepared and centrifuged at 14,000 xg. The supernatant containing the mixture of soluble and dispersible fractions was separated from the pellets. Subsequent ultracentrifugation of the supernatant separated the soluble, i.e., the supernatant after ultracentrifugation, from the dispersible fraction, i.e., the resuspended pellet. Western blot analysis exhibited higher levels of dispersible Aβ oligomers, protofibrils and fibrils precipitated with oligomer (A11) and protofibril/fibril (B10AP) specific antibodies in AD cases compared to controls and preAD cases. Similarly, immunohistochemical analysis revealed that in addition to Aβ positive plaques, B10AP- and A11-positive material was more frequently observed in AD than in preAD and control cases.

Thus, higher levels of denaturable, dispersible Ab oligomers, protofibrils and fibrils in AD cases compared with that in controls with and without Aβ-plaque pathology strongly suggest that the concentration of dispersible Ab aggregates is relevant for neurodegeneration and for passing the threshold of dementia symptoms. As such, dispersible Aβ oligomers, protofibrils and fibrils represent presumably toxic forms of Aβ relevant for AD.