Effect of anti-amyloid β antibody on Aβ trafficking at the blood-brain barrier
2021-12
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Effect of anti-amyloid β antibody on Aβ trafficking at the blood-brain barrier
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2021-12
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Alzheimer’s disease (AD) is broadly recognized as a global public health priority, which has been characterized by the atrophy of the brain and the impairment of memory. The abnormal accumulation of amyloid-beta (Aβ) peptides in the brain have been identified as a major contributor to AD. Thus, the use of monoclonal antibodies (mAbs) to alter Aβ trafficking kinetics at the blood-brain barrier (BBB) represents a promising therapeutic strategy. While anti-Aβ antibodies have been shown to bind and clear Aβ deposits from the brain, the effects of anti-Aβ antibodies on Aβ trafficking in the blood-to-brain direction remain unclear. Plasma Aβ levels are shown to correlate with AD risk, and the overall amount of Aβ in the periphery is estimated to be ~10 fold greater than the amount in the brain. Therefore, Aβ trafficking in the blood-to-brain direction cannot be ignored. We proposed that anti-Aβ mAbs are not required to enter the brain to elicit their therapeutic actions, and mAbs in the circulatory system would be sufficiently effective to change the Aβ trafficking at the BBB. To clarify the effects of anti-Aβ antibodies on Aβ trafficking in both the blood-to-brain and brain-to-blood directions, we conducted a series of Aβ uptake/ transport assays with BBB cell monolayers following exposure to IgG4.1, a well-characterized anti-Aβ mAb. In a wild-type mice model, brain uptake of 125I labeled Aβ40 tended to increase in the presence of systemically injected IgG4.1. In studies examining the endothelial cell uptake of Aβ in vitro, IgG4.1 significantly prevented both Aβ40 and Aβ42 cellular uptake through the formation of immune complexes. Moreover, Aβ42 has a higher magnitude of cellular uptake and is more susceptible to IgG4.1 than that of Aβ40. Overall, our in vitro studies support the premise that IgG4.1 affects Aβ trafficking kinetics (especially Aβ42) without entering into the brain.
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University of Minnesota M.S. thesis. 2021. Major: Pharmaceutics. Advisors: Karunya Kandimalla, Timothy Wiedmann. 1 computer file (PDF); 78 pages.
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Li, Chenxu. (2021). Effect of anti-amyloid β antibody on Aβ trafficking at the blood-brain barrier. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/226632.
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