Amyloid beta and its naturally occurring N-terminal variants are potent activators of human and mouse formyl peptide receptor 1

Formyl peptide receptors (FPRs) may contribute to inflam-mation in Alzheimer's disease through interactions with neuropathological Amyloid beta (AP) peptides. Previous studies reported activation of FPR2 by AP1-42, but further investigation of other FPRs and AP variants is needed. This study provides a comprehensive overview of the interactions of mouse and human FPRs with different physiologically relevant AP-peptides using transiently transfected cells in combination with calcium imaging. We observed that, in addition to hFPR2, all other hFPRs also responded to AP1-42, AP1-40, and the naturally occurring variants AP11-40 and AP17-40. Notably, AP11-40 and AP17-40 are very potent activators of mouse and human FPR1, acting at nanomolar concentrations. Buffer composition and aggregation state are extremely crucial factors that criti-cally affect the interaction of AP with different FPR subtypes. To investigate the physiological relevance of these findings, we examined the effects of AP11-40 and AP17-40 on the human glial cell line U87. Both peptides induced a strong calcium flux at concentrations that are very similar to those obtained in ex-periments for hFPR1 in HEK cells. Further immunocyto-chemistry, qPCR, and pharmacological experiments verified that these responses were primarily mediated through hFPR1. Chemotaxis experiments revealed that AP11-40 but not AP17-40 evoked cell migration, which argues for a functional selectivity of different AP peptides. Together, these findings provide the first evidence that not only hFPR2 but also hFPR1 and hFPR3 may contribute to neuroinflammation in Alzheimer's disease through an interaction with different AP variants.

Automated summary

This study provides a comprehensive overview of the interactions between FPRs and different AP peptides, revealing that FPR1, FPR2, and FPR3 may contribute to neuroinflammation in Alzheimer's disease through interaction with various AP variants.