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Preparation of Oligomeric β-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices
Published on: July 14, 2010
ApoE mimetic peptide decreases Abeta production in vitro and in vivo
S Sakura Minami1, Antoinette Cordova, John R Cirrito
1Department of Neuroscience, Georgetown University, 3970 Reservoir Rd, NW, Washington, DC 20057, USA. map65@georgetown.edu.
Background:
Apolipoprotein E (apoE) is postulated to affect brain Abeta levels through multiple mechanisms--by altering amyloid precursor protein (APP) processing, Abeta degradation, and Abeta clearance. We previously showed that an apoE-derived peptide containing a double repeat of the receptor-binding region was similarly effective in increasing APP processing in vivo. Here, we further examined whether peptides containing tandem repeats of the apoE receptor-binding region (amino acids 141-149) affected APP trafficking, APP processing, and Abeta production.
Results:
We found that peptides containing a double or triple tandem repeat of the apoE receptor-binding region, LRKLRKRLL, increased cell surface APP and decreased Abeta levels in PS1-overexpressing PS70 cells and in primary neurons. This effect was potentiated by a sequential increase in the number of apoE receptor-binding domain repeats (trimer > dimer > monomer). We previously showed that the apoE dimer increased APP CTF in vivo; to determine whether the dimer also affected secreted APP or Abeta levels, we performed a single hippocampal injection of the apoE dimer in wild-type mice and analyzed its effect on APP processing. We found increased sAPPalpha and decreased Abeta levels at 24 hrs after treatment, suggesting that the apoE dimer may increase alpha-secretase cleavage.
Conclusions:
These data suggest that small peptides consisting of tandem repeats of the apoE receptor-binding region are sufficient to alter APP trafficking and processing. The potency of these peptides increased with increasing repeats of the receptor binding domain of apoE. In addition, in vivo administration of the apoE peptide (dimer) increased sAPPalpha and decreased Abeta levels in wild-type mice. Overall, these findings contribute to our understanding of the effects of apoE on APP processing and Abeta production both in vitro and in vivo.
Insights
Small peptides mimicking apolipoprotein E's receptor-binding region effectively altered amyloid precursor protein (APP) processing and reduced amyloid-beta (Abeta) levels in brain cells and mice.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Apolipoprotein E (apoE) influences brain amyloid-beta (Abeta) levels via amyloid precursor protein (APP) processing, degradation, and clearance.
- Previous studies showed apoE-derived peptides enhance APP processing in vivo.
Purpose of the Study:
- To investigate if peptides with tandem repeats of the apoE receptor-binding region affect APP trafficking, processing, and Abeta production.
- To determine the dose-dependent effect of these repeat peptides.
Main Methods:
- Utilized PS1-overexpressing PS70 cells and primary neurons to test peptide efficacy.
- Administered apoE dimer via hippocampal injection in wild-type mice.
- Analyzed APP processing, including secreted APPalpha (sAPPalpha) and Abeta levels.
Main Results:
- Peptides with double or triple repeats of the apoE receptor-binding region increased cell surface APP and decreased Abeta levels.
- Potency increased with more repeats (trimer > dimer > monomer).
- In vivo hippocampal injection of apoE dimer increased sAPPalpha and decreased Abeta levels in mice, suggesting enhanced alpha-secretase cleavage.
Conclusions:
- Tandem repeat peptides of the apoE receptor-binding region can modify APP trafficking and processing.
- Peptide potency correlates with the number of receptor-binding domain repeats.
- In vivo administration of apoE dimer impacts APP processing and Abeta levels, offering insights into apoE's role.
