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Altered function of factor I caused by amyloid beta: implication for pathogenesis of age-related macular degeneration

Jiying Wang1, Kyoko Ohno-Matsui, Takeshi Yoshida

  • 1Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan.

Journal of Immunology (Baltimore, Md. : 1950)
|June 21, 2008
PubMed

Insights

Amyloid beta (Abeta) in drusen activates the complement system in age-related macular degeneration (AMD) by blocking factor I, causing chronic inflammation. This links Abeta, inflammation, and complement activation in AMD pathogenesis.

Area of Science:

  • Ophthalmology
  • Immunology
  • Neuroscience

Background:

  • Age-related macular degeneration (AMD) pathogenesis involves local inflammation and complement activation.
  • Amyloid beta (Abeta) deposition in drusen is implicated in AMD.
  • Neprilysin gene-disrupted mice exhibit Abeta accumulation and AMD features.

Purpose of the Study:

  • To investigate the mechanisms by which Abeta triggers AMD development.
  • To elucidate the role of Abeta in complement activation within the context of AMD.

Main Methods:

  • Studied Abeta's interaction with complement factor I and factor H.
  • Assessed the effect of Abeta on the cleavage of C3b to iC3b.
  • Utilized eyes from neprilysin gene-disrupted mice and age-matched wild-type mice.

Main Results:

  • Abeta binds to complement factor I, inhibiting its ability to cleave C3b to iC3b.
  • Preincubation of factor I with Abeta and factor H abolished C3b cleavage.
  • Abeta did not affect factor H function.
  • Reduced iC3b production was observed in neprilysin gene-disrupted mouse eyes compared to wild-type.

Conclusions:

  • Abeta activates the complement system in drusen by inhibiting factor I function.
  • This leads to chronic, low-grade inflammation in subretinal tissues, contributing to AMD.
  • Establishes a link between inflammation, complement activation, Abeta deposition, and drusen in AMD.

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