Improving Vascular Functions by Bioreactive Nanoparticles for Treatment of Alzheimer’s Disease

Abstract

BackgroundDeveloping effective disease‐modifying treatment for Alzheimer’s disease (AD) remains a tremendous challenge due to its multifactorial nature involving multiple pathologic signaling pathways in addition to ineffective drug delivery through the blood‐brain barrier (BBB).1 With this in mind our group has developed multifunctional bioreactive nanoparticles (Ab‐TP‐MDNPs), consisting of anti‐amyloid β antibody (Ab) linked to brain‐penetrating terpolymer (TP) and manganese dioxide (MnO2) nanoparticles (MDNPs), that are shown to reduce oxidative stress in AD brains.2 Given the early occurrence of oxidative stress, hypoxia, and vascular dysfunction in AD brains,3,4 we investigated the therapeutic effects of Ab‐TP‐MDNPs on reducing neuroinflammation and vascular dysfunction in an AD mouse model.MethodA transgenic mouse model of AD (TgCRND8 species) and wildtype littermates (WT) were treated with intravenous (i.v.) injection of Ab‐TP‐MDNPs (twice/week, 100 µmol Mn/kg b.w.) or vehicle for 2‐weeks. Oxidative and inflammatory biomarkers were examined using immunohistochemistry and enzyme‐linked immunosorbent assay (ELISA). Vascular function before and after the treatment was studied via high resolution magnetic resonance imaging (MRI). Cerebral blood flow (CBF) was assessed using FAIR (flow‐sensitive alternating inversion recovery) technique. BBB permeability was measured via T1 mapping re‐acquisition prior to and following i.v. injection of gadolinium‐diethylenetriamine penta‐acetate (Gd‐DTPA) at 1.2 mmol/kgResultAb‐TP‐MDNPs treatment significantly decreased inflammatory cytokines and activation of microglia and astrocytes markers (reactive microglia: hippocampus by 69% and cortex by 59%, reactive astrocytes: hippocampus by 32% and cortex by 33%). In addition, Ab‐TP‐MDNPs treatment improved CBF (cortex by 19% and subcortex by 35%) and vessel leakage by 29% in the cortex of AD mouse brains.ConclusionAb‐TP‐MDNPs treatment reduced neuroinflammation and vascular dysfunction in an AD mouse model. These findings suggest a new multimodal strategy for AD treatment and encourage further development of such approach for complex neurologic diseases.Reference:1. Panza F, Lozupone M, Logroscino G, Imbimbo BP. Nature Reviews Neurology. 2019;15(2):73‐88.2. He C, Ahmed T, Abbasi AZ, et al. Nano Today. 2020;35:100965.3. Sweeney MD, Montagne A, Sagare AP, et al. Alzheimer’s & Dementia. 2019;15(1):158‐167.4. Nortley R, Korte N, Izquierdo P, et al. Science. 2019:eaav9518.