Optimization of the Linker Length in the Dimer Model of E22P-A beta 40 Tethered at Position 38
ACS chemical neuroscience(2022)
摘要
Since amyloid beta (A beta) oligomers are more cytotoxic than fibrils, various dimer models have been synthesized. We focused on the C-terminal region that could form a hydrophobic core in the aggregation process and identified a toxic conformer-restricted dimer model (E22P,G38DAP-A beta 40 dimer) with an i,,i,- 2,6-diaminopimelic acid linker (n = 3) at position 38, which exhibited moderate cytotoxicity. We synthesized four additional linkers (n = 2, 4, 5, 7) to determine the most appropriate distance between the two A beta 40 monomers for a toxic dimer model. Each di-Fmoc-protected two-valent amino acid was synthesized from a corresponding dialdehyde or cycloalkene followed by ozonolysis, using a Horner-Wadsworth-Emmons reaction and asymmetric hydrogenation. Then, the corresponding A beta 40 dimer models with these linkers at position 38 were synthesized using the solid-phase Fmoc strategy. Their cytotoxicity toward SH-SYSY cells suggested that the shorter the linker length, the stronger the cytotoxicity. Particularly, the E22P,G38DAA-A beta 40 dimer (n = 2) formed protofibrillar aggregates and exhibited the highest cytotoxicity, equivalent to E22P-A beta 42, the most cytotoxic analogue of A beta 42. Ion mobility-mass spectrometry (IM-MS) measurement indicated that all dimer models except the E22P,G38DAA-A beta 40 dimer existed as stable oligomers (12-24-mer). NativePAGE analysis supported the IM-MS data, but larger oligomers (30-150-mer) were also detected after a 24 h incubation. Moreover, E22P,G38DAA-A beta 40, E22P,G38DAP-A beta 40, and E22P,G38DAZ-A beta 40 (n = 5) dimers suppressed long-term potentiation (LTP). Overall, the ability to form fibrils with cross beta-sheet structures was key to achieving cytotoxicity, and forming stable oligomers less than 150-mer did not correlate with cytotoxicity and LTP suppression.
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关键词
Alzheimer's disease, amyloid beta, dimer, oligomer, SH-SYSY cells, toxic conformation
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