Shear-induced amyloid formation of IDPs in the brain.

The IDP amyloid β-protein (Aβ) has been both the prime causative suspect and drug development target in the fight against Alzheimer's disease (AD). Unfortunately, all clinical trials against Aβ based on this assumption have failed. This review proposes that the Aβ IDP conformation ensembles in the research laboratory may be somewhat different than those of Aβ found within the human brain. It is argued that the multiple quiescent Aβ molecular conformations may be the incorrect drug targets. Instead there may be much more complex ensembles found in the flowing liquids within the brain. The highly flexible Aβ is quite sensitive to shear-induced aggregation. Different shear types and shear energies must be generated by Aβ-containing fluids flowing through different constricted brain spaces at different velocities. A model is proposed in which Aβ subjected to shear-induced aggregation produces toxic Aβ oligomers that are different from those produced in the laboratory. It is proposed that amyloid researchers seeking Alzheimer drug candidates should perform experiments under shear conditions that attempt to mimic those found in the brain. Because Aβ experiments in devices with narrow bore capillaries are rather limited, it is imperative that further experiments of this type be carried out using spinal tap needles and microliter syringes. It is believed that analytical errors may be generated by plating out of amyloids on the inner wall surfaces of these capillary devices. It is suggested that shear-induced aggregation due to flow in confined brain fluid flow pathways may be responsible for many related amyloid diseases and brain trauma events.