Humanin Blocks the Aggregation of Amyloid-β Induced by Acetylcholinesterase, an Effect Abolished in the Presence of IGFBP-3.
Price. Deanna D; Dorandish. Sadaf S; Williams. Asana A; Iwaniec. Brandon B; Stephens. Alexis A; Marshall. Keyan K; Guthrie. Jeffrey J; Heyl. Deborah D; Evans. Hedeel Guy HG
Key Findings
- Humanin blocks amyloid‑beta aggregation caused by acetylcholinesterase in vitro
- IGFBP‑3 binds humanin and prevents it from interacting with amyloid‑beta
- When IGFBP‑3 is added, humanin can’t stop amyloid‑beta aggregation and toxic oligomers increase, reducing cell viability
Practical Outcomes
- Humanin could be a useful supplement for protecting brain health, but its benefits may be limited if IGFBP‑3 levels are high. Monitoring or managing IGFBP‑3 (through diet, lifestyle, or other interventions) might be needed to get the full protective effect of humanin. More research is required before specific dosing or protocols can be recommended.
Summary
The study shows that the humanin peptide can stop harmful clumping of amyloid‑beta (a protein linked to Alzheimer’s) that is made worse by the enzyme acetylcholinesterase, but this protective effect disappears when another protein, IGFBP‑3, is present. In cell experiments, adding IGFBP‑3 reduced humanin’s ability to bind amyloid‑beta and led to more toxic protein clumps and cell death.
Abstract
It is known that the humanin (HN) peptide binding to amyloid-β (Aβ) protects against its cytotoxic effects, while acetylcholinesterase (AChE) binding to Aβ increases its aggregation and cytotoxicity. HN is also known to bind the insulin-like growth factor binding protein-3 (IGFBP-3). Here, we examined the regulation of Aβ conformations by HN, AChE, and IGFBP-3 both <i>in vitro</i> and in the conditioned media from A549 and H1299 lung cancer cells. Our <i>in vitro</i> results showed the following: IGFBP-3 binds HN and blocks it from binding Aβ in the absence or presence of AChE; HN and AChE can simultaneously bind Aβ but not when in the presence of IGFBP-3; HN is unable to reduce the aggregation of Aβ in the presence of IGFBP-3; and HN abolishes the aggregation of Aβ induced by the addition of AChE in the absence of IGFBP-3. In the media, AChE and HN can simultaneously bind Aβ. While both AChE and HN are detected when using 6E10 Aβ antibodies, only AChE is detected when using the Aβ 17-24 antibody 4G8, the anti-oligomer A11, and the anti-amyloid fibril LOC antibodies. No signal was observed for IGFBP-3 with any of the anti-amyloid antibodies used. Exogenously added IGFBP-3 reduced the amount of HN found in a complex when using 6E10 antibodies and correlated with a concomitant increase in the amyloid oligomers. Immunodepletion of HN from the media of the A549 and H1299 cells increased the relative abundance of the oligomer vs the total amount of Aβ, the A11-positive prefibrillar oligomers, and to a lesser extent the LOC-positive fibrillar oligomers, and was also correlated with diminished cell viability and increased apoptosis.
Study Information
pubmed
2020
2020-05-20T00:00:00.000Z
10.1021/acs.biochem.0c00274
18
92