Multiple Alzheimer’s disease (AD) clinical trials target pathogenic amyloid-β (Aβ) species using therapeutic anti-Aβ antibodies. However, failures from recent clinical trials investigating passive anti-Aβ antibody immunization demonstrate a continued gap in our understanding of AD pathogenesis. Hence, there is an immediate need to develop new safe therapeutic approaches that can be applicable at an early stage of the disease. We developed superparamagnetic iron oxide nanoparticles (SPIONs) conjugated with anti-Aβ antibodies, which bind to Aβ peptides and aggregated Aβ species in vitro and in vivo. We hypothesized that acute and rapid removal of pathogenic Aβ species using our antibody-conjugated magnetic nanoparticles can block Aβ-driven pathogenic cascades, including Aβ-driven tau pathology in human neurons. To test this hypothesis, we applied our conjugated SPIONs in our 3D human neural cell culture model of AD, followed by rapid removal of SPION-Aβ complex by an external magnet force in real-time. We detected a 25% reduction in soluble and insoluble Aβ species including Thioflavin-S (ThioS) positive Aβ. We also showed that our targeted SPIONs could efficiently remove ThioS positive Aβ aggregates from 5XFAD AD mouse brain slices and frozen AD patient brain sections. More importantly, we found a 16% reduction in pathogenic phosphorylated-tau species after acute removal of Aβ species in our 3D human neural cell model. Our results demonstrate the therapeutic potential of SPION-assisted immunotherapy to acutely reduce both Aβ accumulation and tau pathology without chronic exposure to anti-Aβ antibodies that leads to amyloid-related imaging abnormality (ARIA) side effects. We next explored the in vivo application of conjugated SPIONs in a transgenic AD mouse model. We found that remote alternating magnetic field treatment at lower frequencies enhanced antibody delivery across the blood-brain barrier. We also observed increased microglial activation without inducing neuroinflammation using this methodology. Taken together, this work demonstrates proof of concept for applying nanomedicine and neurostimulation as a tool to remotely modulate AD pathology and improve cerebral AD drug bioavailability. / 2025-01-23T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/45504 |
| Date | 23 January 2023 |
| Creators | Ning, Shen |
| Contributors | Ho, Angela, Tanzi, Rudolph E. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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