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, 4 (12), e8191

Apolipoprotein E-mimetics Inhibit Neurodegeneration and Restore Cognitive Functions in a Transgenic Drosophila Model of Alzheimer's Disease

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Apolipoprotein E-mimetics Inhibit Neurodegeneration and Restore Cognitive Functions in a Transgenic Drosophila Model of Alzheimer's Disease

Svetlana Sarantseva et al. PLoS One.

Abstract

Background: Mutations of the amyloid precursor protein gene (APP) are found in familial forms of Alzheimer's disease (AD) and some lead to the elevated production of amyloid-beta-protein (Abeta). While Abeta has been implicated in the causation of AD, the exact role played by Abeta and its APP precursor are still unclear.

Principal findings: In our study, Drosophila melanogaster transgenics were established as a model to analyze AD-like pathology caused by APP overexpression. We demonstrated that age related changes in the levels and pattern of synaptic proteins accompanied progressive neurodegeneration and impairment of cognitive functions in APP transgenic flies, but that these changes may be independent from the generation of Abeta. Using novel peptide mimetics of Apolipoprotein-E, COG112 or COG133 proved to be neuroprotective and significantly improved the learning and memory of APP transgenic flies.

Conclusions: The development of neurodegeneration and cognitive deficits was corrected by injections of COG112 or COG133, novel mimetics of apolipoprotein-E (apoE) with neuroprotective activities.

Conflict of interest statement

Competing Interests: All authors with the exception of M. P. Vitek declare no competing interests. Dr. Vitek is an employee of Duke University Medical Center and of Cognosci, Inc., in which he is the founder.

Figures

Figure 1
Figure 1. Human APP expression in the brain of transgenic Drosophila.
A) Western blot analysis of APP and Aβ: 22C11 (APP-N): Full size human APP was detected by monoclonal antibody 22C11 (APP N terminal-specific); 4G8 (IP): Aβ was immunoprecipitated using anti-Aβ monoclonal 4G8 antibody; elav;APP; and -elav;APP/BACE- genotypes of transgenic strains used for analysis. All blots were scanned and relative intensity of bands was quantified using Image J software. B) Aβ deposits in Drosophila brain: 4G8 (IH): Immunohistochemistry with 4G8 antibody; Arrows indicate areas for magnification. Bar, 50 µm (a, b); Bar, 10 µm (c, d).
Figure 2
Figure 2. Distribution of GFP–n-synaptobrevin in the Drosophila brain.
A) Optical sections of the brain obtained by confocal microscopy (four brightest sections for each genotype). The fluorescent signal was visualized at a wavelength of λ 488 nm. The scanning sections were 2 µm thick. Microphotographs show the brains of 30-day-old flies. B) Quantitation of relative intensities of GFP–n-synaptobrevin (n-syb-eGFP) in the brain section for transgenic flies with different genotypes: 1.-elav; 2- elav;ΔNAPP; 3- elav;ΔCAPP; 4-elav;APP; 5-elav;APPSw; 6-elav;APP/BACE; 7- elav; APPSw/BACE. The pixel intensity in the selected areas was estimated using Image J software and was normalized to the fluorescent signal of elav genotype. Relative intensities are shown as averages±SEM. p<0.05.
Figure 3
Figure 3. Age-dependent neurodegeneration in APP expressing transgenics.
Microphotographs of the brains of 30-day-old flies; Bar, 50 µm. A) Percentage of the area lost in the regions of the cell body and neuropil: The ratio of lost area was calculated by dividing the sum of the vacuole areas from all brain sections by the total area of the brain from all brain sections. We analyzed 6 brains for each genotype, 16–18 sections per brain. Percentage of the area lost is shown as averages±SEM. p<0.05. B) Neurodegeneration in APP flies at day 30. Paraffin slices were stained with hematoxylin and eosin and were examined under bright-field illumination using a Leica DM 2500 microscope at a magnification of 120X.
Figure 4
Figure 4. In vivo delivery of peptides into Drosophila brain.
Immunohistochemistry with antibody to biotin: Left panels - Bar, 50 µm; Right panels-Bar, 10 µm. a,b - Antp-COG133 (COG112) - RQIKIWFQNRRMKWKK LRVRLASHLRKLRKRLL. c,d- CF (fragment 142–153 of human growth factor U2AF)-SQMTRQARRLYV, control peptide, which does not cross BBB ; e,f – no peptides added.
Figure 5
Figure 5. ApoE-mimetics inhibit neurodegeneration in Drosophila brain.
A) Effect of peptides on percentage of the area lost in the regions of the cell body and neuropil: The ratio of lost area was calculated by dividing the sum of the vacuole areas from all brain sections by the total area of the brain from all brain sections. Percentage of the area lost is shown as averages±SEM. p<0.05 Asterisks indicate significant differences from control. B) Effect of peptides on neurodegeneration in APP transgenic flies. Paraffin slices were stained with hematoxylin and eosin and were examined under bright-field illumination using a Leica DM 2500 microscope at a magnification of 120X. Left panel- Bar, 50 µm; Right panels - Bar, 10 µm.
Figure 6
Figure 6. Effect of peptides on Aβ accumulation in Drosophila brain.
Immunohistochemistry with 4G8 antibody: A) Distribution of Aβ deposits in Drosophila brain, Bar, 50 µm. B) Effect of peptides on Aβ accumulation in Drosophila brain, Bar, 10 µm.

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