Abstract
A local dyshomeostasis of zinc ions in the vicinity of amyloid aggregates has been proposed in Alzheimer’s disease (AD) due to the sequestration of zinc in senile plaques. While an increase in zinc levels may promote the aggregation of amyloid beta (Aβ), increased brain zinc might also be beneficial rescuing some pathological alterations caused by local zinc deficiency. For example, increased Aβ degradation by metalloproteinases, and a reduction in inflammation can be hypothesized. In addition, zinc may allow a stabilization of the number of synapses in AD brains. Thus, to evaluate whether altering zinc-levels within the brain is a promising new target for the prevention and treatment of AD, we employed novel zinc loaded nanoparticles able to deliver zinc into the brain across the blood-brain barrier. We performed in vivo studies using wild type (WT) and APP23 mice to assess plaque load, inflammatory status and synapse loss. Furthermore, we performed behavioral analyses. After chronically injecting these nanoparticles for 14 days, our results show a significant reduction in plaque size and effects on the pro-inflammatory cytokines IL-6 and IL-18. On behavioral level we could not detect negative effects of increased brain zinc levels in APP23 mice and treatment with g7-NP-Zn normalized the observed hyperlocomotion of APP23 mice. Therefore, we conclude that a targeted increase in brain zinc levels may have beneficial effects in AD.
Highlights
N diseases [5,6]
C Previously, we examined the ability of zinc-loaded polylactide-co-glycolide (PLGA) Ananoparticles (NPs), with a glycopeptide consisting of 7 amino acids (g7), to cross the blood-brain barrier (BBB)
The organic solvent was removed by stirring at room temperature (RT) for at least 3 h, and the aqueous solution was filtered through a syringe filter to remove water-insoluble polymer
Summary
N diseases [5,6]. zinc-deficiency causes alterations in brain function and cognition [7]. C A second measurement of the lysate of the right hemisphere of mice after chronic S administration and behavioral experiments using AAS did not show a significant increase in zinc concentration after treatment with g7-NP-Zn (Fig. S1A). Measuring plaque area and number, we obtained similar results as those seen using anti- Aβ antibody staining showing a significant decrease in plaque area, but not number of plaques, between saline injected APP23 controls and APP23 mice treated with g7-NP-Zn (Fig. 3A-B).
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