Comparison of pharmacological modulation of APP metabolism in primary chicken telencephalic neurons and in a human neuroglioma cell line.
Sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases and the formation of Aβ peptides are pivotal for Alzheimer's disease. Therefore, a large number of drugs has been developed targeting APP metabolism. However, many pharmacological compounds have been identified in vitro in immortalized APP overexpressing cell lines rather than in primary neurons. Here, we compared the effect of already characterized secretase inhibitors and modulators on Aβ formation in primary chicken telencephalic neurons and in a human neuroglioma cell line (H4) ectopically expressing human APP with the Swedish double mutation. Primary chicken neurons replicated the effects of a β-secretase inhibitor (β-secretase inhibitor IV), two γ-secretase inhibitors (DAPM, DAPT), two non-steroidal-anti-inflammatory drugs (sulindac sulfide, CW), and of the calpain inhibitor calpeptin. With the exception of the two γ-secretase inhibitors, all tested compounds were more efficacious in primary chicken telencephalic neurons than in the immortalized H4 cell line. Moreover, H4 cells failed to reproduce the effect of calpeptin. Hence, primary chicken telencephalic neurons represent a suitable cell culture model for testing drugs interfering with APP processing and are overall more sensitive to pharmacological interference than immortalized H4 cells ectopically expressing mutant human APP.
Czvitkovich
Stefan
S
JSW Lifesciences GmbH, Parkring 12, 8074, Grambach, Austria.
Duller
Stephan
S
Mathiesen
Else
E
Lorenzoni
Klaus
K
Imbimbo
Bruno P
BP
Hutter-Paier
Birgit
B
Windisch
Manfred
M
Wronski
Robert
R
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002645:Chickens; D017077:Culture Media, Conditioned / Q000737:chemistry; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D023421:Models, Animal; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017077:Culture Media, Conditioned; D053829:Amyloid Precursor Protein Secretases; D002154:Calpain; D016282:Aspartic Acid Endopeptidases