A cyclic peptide that binds p75NTR protects neurones from beta amyloid (1-40)-induced cell death

• Published in: Neuropathology and applied neurobiology 2007-10, Vol.33 (5), p.533-543
• Main Authors: Yaar, M., Zhai, S., Panova, I., Fine, R. E., Eisenhauer, P. B., Blusztajn, J. K., Lopez-Coviella, I., Gilchrest, B. A.
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; apoptosis; Biological and medical sciences; c-jun; Hematologic and hematopoietic diseases; Human viral diseases; Infectious diseases; JNK; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Neurology; neurotrophin receptor; NGF; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/j.1365-2990.2007.00844.x

The current study determined the ability of a p75NTR antagonistic cyclic peptide to rescue cells from beta amyloid (Aβ) (1–40)‐induced death. p75NTR‐, p140trkA‐NIH‐3T3 cells or E17 foetal rat cortical neurones were incubated with 125I‐NGF or 125I‐Aβ (1–40) and increasing concentrations of the cyclic peptide (CATDIKGAEC). Peptide ability to displace 125I‐NGF or 125I‐Aβ (1–40) binding was determined. Duplicate cultures were preincubated with CATDIKGAEC (250 nm) or diluent and then stimulated with Aβ (1–40). Peptide ability to displace Aβ (1–40) binding, interfere with Aβ (1–40)‐induced signalling and rescue cells from Aβ‐mediated toxicity was determined by immunoprecipitation and autoradiography, Northern blotting, JNK activation, MTT and trypan blue assays. The peptide inhibited NGF and Aβ (1–40) binding to p75NTR, but not to p140trkA. Aβ (1–40) induced c‐jun transcription (57.3% ± 0.07%) in diluent‐treated p75NTR‐cells, but not in cells preincubated with the cyclic peptide. Also, at 250 nm, the peptide reduced Aβ (1–40)‐induced phsophorylation of JNK by 71.8% ± 0.03% and protected neurones against Aβ‐induced toxicity as determined by: trypan blue exclusion assay (53% ± 11% trypan blue‐positive cells in diluent pretreated cultures vs. 28% ± 5% in cyclic peptide‐pretreated cultures); MTT assay (0.09 ±0.03 units in diluent‐pretreated cells vs. 0.12 ± 0.004 units in cyclic peptide‐pretreated cells); and visualization of representative microscopic fields. Our data suggest that a cyclic peptide homologous to amino acids 28–36 of NGF known to mediate binding to p75NTR can interfere with Aβ (1–40) signalling and rescue neurones from Aβ (1–40)‐induced toxicity.