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.2017 Aug 14;7(1):8009.
doi: 10.1038/s41598-017-08604-8.

Targeting Apolipoprotein E/Amyloid β Binding by Peptoid CPO_Aβ17-21 P Ameliorates Alzheimer's Disease Related Pathology and Cognitive Decline

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Targeting Apolipoprotein E/Amyloid β Binding by Peptoid CPO_Aβ17-21 P Ameliorates Alzheimer's Disease Related Pathology and Cognitive Decline

Shan Liu et al. Sci Rep..

Abstract

Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Studies have shown that apoE, apoE4 in particular, binds to amyloid-β (Aβ) peptides at residues 12-28 of Aβ and this binding modulates Aβ accumulation and disease progression. We have previously shown in several AD transgenic mice lines that blocking the apoE/Aβ interaction with Aβ12-28 P reduced Aβ and tau-related pathology, leading to cognitive improvements in treated AD mice. Recently, we have designed a small peptoid library derived from the Aβ12-28 P sequence to screen for new apoE/Aβ binding inhibitors with higher efficacy and safety. Peptoids are better drug candidates than peptides due to their inherently more favorable pharmacokinetic properties. One of the lead peptoid compounds, CPO_Aβ17-21 P, diminished the apoE/Aβ interaction and attenuated the apoE4 pro-fibrillogenic effects on Aβ aggregation in vitro as well as apoE4 potentiation of Aβ cytotoxicity. CPO_Aβ17-21 P reduced Aβ-related pathology coupled with cognitive improvements in an AD APP/PS1 transgenic mouse model. Our study suggests the non-toxic, non-fibrillogenic peptoid CPO_Aβ17-21 P has significant promise as a new AD therapeutic agent which targets the Aβ related apoE pathway, with improved efficacy and pharmacokinetic properties.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Molecular structure of peptoid CPO_Aβ17-21 P and its inhibitory effect on apoE4/Aβ 42 binding and reduction of apoE4 mediated Aβ40 and Aβ42 fibrillization. (a) Molecular structure of the peptoid CPO_Aβ17-21 P. (b) Surface Plasmon Resonance assay of apoE4/Aβ42 binding. Binding of lipidated apoE4 is shown by the green line with the black line representing the reference. (c) Surface Plasmon Resonance assay of CPO_Aβ17-21 P inhibition of apoE4/Aβ42 binding at a 2:1 (blue line, peptoid:apoE4) and 8:1 molar ratio (red line, peptoid:apoE4), with the black line below each colored line representing the corresponding reference. (d) Shown is the half-maximal inhibition (IC50) of lipidated apoE/Aβ binding by increasing concentrations of CPO_Aβ17-21 P derived from a one-site competition, nonlinear, regression equation of CPO_ Aβ17-21 P was 1.02 nM, calculated using GraphPad Prism 7.0 (Graphpad, San Diego, CA). (e) and (f) Thioflavin T Aβ aggregation assay, showing inhibition of apoE4 potentiated Aβ40 and Aβ42 fibril formation when incubated with CPO_Aβ17-21 P. Solid red line shows the Aβ40 (400 µM, in e) or Aβ42 (100 µM, in f) fibril formation increment when incubated with recombinant apoE4 at 100:1 molar ratio. Dashed red line shows reduction of fibril formation on Aβ40 (in (e) and Aβ42 (inf) when apoE4 was pre-incubated with peptoid CPO_Aβ17-21 P. Green line shows Aβ40 (ine) and Aβ42 (inf) alone, blue line indicates Aβ40 or Aβ42 incubated with peptoid, brown line indicates apoE4 alone and purple line shows peptoid CPO_Aβ17-21 P. Repeated measures analysis of variance followed by a Tukey post-hoc multiple comparison analysis showedp < 0.0001 for difference between group; Aβ40 + apoE4 + CPO_Aβ17-21 P versus Aβ40 + apoE4p = 0.0034; Aβ42 + apoE4 + CPO_Aβ17-21 P versus Aβ42 + apoE4p = 0.0011; no significant difference between Aβ40 + CPO_Aβ17-21 P and Aβ40 alone; no significant difference between Aβ42 + CPO_Aβ17-21 P and Aβ42 alone were found.
Figure 2
Figure 2
Cytotoxicity of peptoid CPO_ Aβ17-21 P on SK-N-SH human neuroblastoma cells and mouse N2a neuroblastoma cells and inhibition of Aβ42/apoE4 cytotoxicity by pre-incubation of apoE4 with CPO_Aβ17-21 P. (a) CellTiter-Blue® cytotoxicity assay showing no significant differences between vehicle and CPO_ Aβ17-21 P at 0.1, 1 and 10 µM. on human SK-N-SH neuroblastoma cells or on (b) mouse N2a neuroblastoma cells. (c) Toxicity effect of Aβ42 on human SK-N-SH neuroblastoma cells and potentiation of toxicity in presence of apoE4. CPO_ Aβ17-21 P peptoid reduces significantly the toxicity of Aβ42/apoE4 at 1 and 4 µM (**p < 0.01, *p < 0.05).
Figure 3
Figure 3
Cognitive testing and locomotor assessment of APP/PS1 mice treated with peptoid CPO_ Aβ17-21 P. (a) Rotarod and (b) Traverse beam locomotor tests showing no significant differences between vehicle group and mice treated with the peptoid (p > 0.05). (c) Open field locomotor test results showing no significant differences in distance traveled, resting time, maximum velocity and average speed between vehicle group and peptoid treated mice (p > 0.05, two-tailed unpairedt-test). (d) Radial arm maze. Number of errors plotted versus number of days. Significant differences between vehicle mice group and mice treated with the peptoid (**p < 0.01, by two-way ANOVA for treatment effect). (e) Object recognition test showing the average time spent with the familiar and novel objects. Significant differences in the time that treated mice spent with the novel object compared to the vehicle group (*p < 0.05, two-tailed pairedt-test). There was no significant difference between the time spent with the familiar and novel objects in the vehicle control group.
Figure 4
Figure 4
Reduction of soluble and insoluble Amyloid-β levels on APP/PS1 mice treated with peptoid CPO_ Aβ17-21 P. (a) Reduction of Aβ40 in the soluble fraction extracted with diethylamine (DEA) from APP/PS1 mice brain homogenates (***p < 0.001, two-tailed unpaired t-test). (b) Reduction of Aβ40 and Aβ42 levels in the insoluble fraction extracted with formic acid (FA) (***p < 0.001 and ****p < 0.0001 respectively, two-tailed unpaired t-test). (c) Reduction of Aβ oligomeric species measured by ELISA assay (*p < 0.05, two-tailed unpaired t-test). (d) Plasma cholesterol levels on APP/PS1 mice treated with peptoid CPO_ Aβ17-21 P (p > 0.05, two-tailed unpairedt-test). (e) Reduction of Aβ oligomeric species shown by western blot with anti-amyloid antibody 4G8 on APP/PS1 mice brain homogenates (*p < 0.05, two-tailed unpairedt-test).
Figure 5
Figure 5
Amyloid-β plaque burden on brains of APP/PS1 mice treated with peptoid CPO_ Aβ17-21 P or vehicle alone. (a) Treatment with CPO_ Aβ17-21 P decreased cortical and hippocampal burden in APP/PSI mice. Scale bars represent 100 μm. (b) There was a significant reduction observed in 6E10/4G8 immunoreactivity in both cortex and hippocampus in the CPO_ Aβ17-21 P treated mice versus vehicle treated mice,*p < 0.05, one-tailed unpairedt-test.
Figure 6
Figure 6
Levels of reactive astrocytes and microglia in brains from APP/PS1 mice treated with CPO_ Aβ17-21 P or vehicle. (a) Treatment with CPO_ Aβ17-21 P had no significant effect on cortical astrogliosis, but it was associated with decreased hippocampal astrogliosis in APP/PS1 mice, (b) as quantified by GFAP immunoreactivity. (c) Treatment with CPO_ Aβ17-21 P decreased cortical, but had no significant effect on hippocampal microgliosis in APP/PS1 mice, (d) as quantified by CD11b immunoreactivity, (e) CPO_ Aβ17-21 P treatment reduced microgliosis in the cortex, but had no significant effect on hippocampal microgliosis of APP/PS1 mice, (f) as quantified by Iba1 immunoreactivity, (Scale bars represent 100 μm.*p < 0.05, ***p < 0.001, one-tailed unpairedt-test).
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