Exploitation of the magneto-mechanical effect in the treatment of neurodegenerative diseases

The mechanisms and pathogenesis of many neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease are not completely understood. However, it is hypothesized that clearance of amyloid beta (Ab) aggregates in AD-patient can result in cognitive improvement and reverse the progression of disease. The Ab aggregates should be disrupted into insoluble fragments and not to soluble Ab peptide oligomers. Recently, soluble Ab peptide oligomers rather than insoluble fragments have been implicated in disease pathology. New methods for Ab disruption have been proposed based on nanotechnology as the answer to the presented challenges in the last decade. Heating of magnetic nanoparticles in the presence of radio frequency alternating magnetic field (RF-AMF, >100 kHz) has been suggested as a means to disaggregate Ab deposits. However, the approaches based on local heating of Ab aggregates with the nanoparticles demonstrate important drawbacks, since mainly soluble, and presumably toxic, Ab oligomers are generated during the Ab disruption process. This is still an unsolved challenge and the scientific arena is urgently seeking for possibly nanotech-based solutions to reduce the size of Ab aggregates in a controlled manner, and preferentially via remote and mechanical breaking up Ab aggregates into fragments. In this project we propose an entirely new concept for the disruption of Ab deposits based on the transformation of low frequency AMF (LF-AMF; up to 1kHz) energy into mechanical energy, mediated by anisotropic magnetic nanoparticles. When an anisotropic particle is placed in a magnetic field (B), it tends to align with a direction of the magnetic field vector. This causes rotation of the anisotropic particles in the direction of the field, which results in transfer of the induced force (magnetic torque tm) onto its surroundings. Three different types of anisotropic magnetic particles will be developed and tested, i.e., nanochains, configurable nanochains with sharp edges (i.e., nanoblades), and nanoplatelets. The particles cover various shapes and sizes, and vary in basic magnetic properties. The smallest nanoplatelets (50 nm wide and 3 nm thick) show hard-magnetic properties with high anisotropy. In contrast, larger nanochains and nanoblades (300 and 900 nm) display superparamagnetic properties. They mainly differ in the shape: the nanochains have round, smooth edges and the nanoblades have sharp edges. A remotely triggered mechanical torque of anisotropic magnetic particles selectively attached to Ab fibrils, which will be promoted by particles active targeting using Phe-Phe motif, will be studied to mechanically break up self-assembled Ab aggregates. The aggregates will disintegrate preferentially into fragments and not to toxic soluble Ab peptide oligomers because our approach fully exclude any local heating. The hope is that the mechanically broken protofibril-like fragments will expose new surfaces that can be easily recognized by immune-defence cells such as M2 microglia and thus naturally eliminated from the brain tissue. This mechanical disruption of the Ab aggregates could lead to a cure, not only for Alzheimer’s disease, but also other diseases linked to aberrantly folded peptides or proteins forming insoluble plaques. Moreover, the magneto-mechanical effect could also be beneficially applied for treating other diseases in the future, e.g., magneto-mechanical eradication of cancer cells or thrombus in blood vessels. Magnetic anisotropic particles can also be used for their magnetic targeting and simultaneous diagnostics as MRI contrast agent which is, in combination with therapy, agent for theranostics. The planned research will also be very important for understanding the nanoparticles’ interactions with the bio-relevant systems, which is the key issue in nanotechnology.