Friday, April 19, 2024
4/19/2024
ABSTRACT/PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive disturbances affecting over 5 million Americans. AD is hypothesized to be due to the accumulation of two pathogenic proteins in the brain. One is the accumulation of amyloid-ß (Aß) outside of cells and the second is the accumulation of hyperphosphorylated tau protein inside cells that eventually leads to aggregates called neurofibrillary tangles. The aggregation of amyloid prevents normal cell signaling pathways while neurofibrillary inhibit nutrient delivery to the neurons, both of which ultimately leads to neuronal death. Multiple AD previous clinical trials target pathogenic Aß species using therapeutic anti-Aß antibodies. However, previous failures in clinical trials demonstrate a gap in knowledge in our current understanding of the pathogenesis of AD and an immediate need for the development of new safe therapeutic approaches, which can be applicable at the very early stage of the disease. One major side effect in previous clinical trials is the chronic presence of high-titer anti-Aß antibodies in brains triggers inflammatory responses and other undesirable side effects, namely amyloid- related imaging abnormalities including microhemorrhages (ARIA-H) and edema (ARIA-E). Since recent results from the aducanumab clinical trial is showing immense promise, there is an urgent need for the development of a technology to reduce these side effects. To address this challenge, which may contribute to the failures of these previous current drug trials, we developed superparamagnetic iron oxide nanoparticles conjugated with anti-Aß antibodies that bind to Aß peptides and aggregated Aß species. These particles are paramagnetic, which allows them to be removed by an external magnetic field in vitro. To validate the efficacy and safety of anti-Aß antibody conjugated SPIONs, we will use both 3D human neural cell culture models of AD, which our lab developed previously, and transgenic AD mouse models. Combining these two technologies, we devised a methodology to rapidly remove Aß species using external magnetic force guided removal of anti-Aß antibody conjugated SPIONs in 3D cell culture of AD. The 3D cell culture model will be mostly used for testing efficacy and the impact of the anti-Aß antibody on Aß-driven tau pathology while transgenic AD mice will be used to assess the efficacy and potential toxicity in vivo. Aim 1 evaluates the use of a static magnet with SPIONs with to reduce Aß species in 3D culture model of AD and in an AD mouse model. The aim further investigates the downstream tau effects of Aß removal in the 3D culture model. Aim 2 will examine the potential of using an alternating magnetic field to deliver therapeutic antibodies conjugated to SPIONs across the blood-brain barrier in the AD 5XFAD mouse model. This second aim has tremendous impact on the feasibility of this technology as a new therapeutic avenue not only for AD, but to deliver large molecule drugs for a variety of neurological diseases. Ultimately, the results of this work will lead to the potential development of a new therapy for AD as well as a new method for formulating and applying current AD drugs and therapeutics.
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