Lipopolysaccharide Induced Opening of the Blood Brain Barrier on Aging 5XFAD Mouse Model

Article type: Research Article

Authors: Barton, Shawn M.^{a; b} | Janve, Vaibhav A.^{a; b; c} | McClure, Richard^{a; b} | Anderson, Adam^{a; b; c} | Matsubara, Joanne A.^h | Gore, John C.^{a; b; c; d; e; f} | Pham, Wellington^{a; b; c; d; e; f; g; *}

Affiliations: [a] Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN, USA | [b] Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA | [c] Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA | [d] Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA | [e] Vanderbilt Ingram Cancer Center, Nashville, TN, USA | [f] Vanderbilt Institute of Chemical Biology, Nashville, TN, USA | [g] Vanderbilt Institute of Nanoscale Science and Engineering, Nashville, TN, USA | [h] Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC, Canada

Correspondence: [*] Correspondence to: Wellington Pham, PhD, Associate Professor of Radiology and Radiological Sciences, Associate Professor of Biomedical Engineering, Institute of Imaging Science, Vanderbilt University School of Medicine, 1161, 21st Avenue South, Nashville, TN 37232-2310, USA. Tel.: +1 615 936 7621; E-mail: wellington.pham@vanderbilt.edu.

Abstract: The development of neurotherapeutics for many neurodegenerative diseases has largely been hindered by limited pharmacologic penetration across the blood-brain barrier (BBB). Previous attempts to target and clear amyloid-β (Aβ) plaques, a key mediator of neurodegenerative changes in Alzheimer’s disease (AD), have had limited clinical success due to low bioavailability in the brain because of the BBB. Here, we test the effects of inducing an inflammatory response to disrupt the BBB in the 5XFAD transgenic mouse model of AD. Lipopolysaccharide (LPS), a bacterial endotoxin recognized by the innate immune system, was injected at varying doses. 24 hours later, mice were injected with either thioflavin S, a fluorescent Aβ-binding small molecule or 30 nm superparamagnetic iron oxide (SPIO) nanoparticles, both of which are unable to penetrate the BBB under normal physiologic conditions. Our results showed that when pretreated with 3.0 mg/kg LPS, thioflavin S can be found in the brain bound to Aβ plaques in aged 5XFAD transgenic mice. Following the same LPS pretreatment, SPIO nanoparticles could also be found in the brain. However, when done on wild type or young 5XFAD mice, limited SPIO was detected. Our results suggest that the BBB in aged 5XFAD mouse model is susceptible to increased permeability mediated by LPS, allowing for improved delivery of the small molecule thioflavin S to target Aβ plaques and SPIO nanoparticles, which are significantly larger than antibodies used in clinical trials for immunotherapy of AD. Although this approach demonstrated efficacy for improved delivery to the brain, LPS treatment resulted in significant weight loss even at low doses, resulting from the induced inflammatory response. These findings suggest inducing inflammation can improve delivery of small and large materials to the brain for improved therapeutic or diagnostic efficacy. However, this approach must be balanced with the risks of systemic inflammation.

Keywords: Alzheimer’s disease, blood-brain barrier, drug delivery, iron oxide nanoparticles, lipopolysaccharide

DOI: 10.3233/JAD-180755

Journal: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 503-513, 2019