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Raft disorganization leads to reduced plasmin activity in Alzheimer's disease brains

Maria Dolores Ledesma1, José Abad-Rodriguez, Cristian Galvan

  • 1Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (TO), Italy.

EMBO Reports
|November 18, 2003
PubMed

Insights

Reduced brain cholesterol disrupts membrane rafts, impairing plasminogen binding and activity in Alzheimer's disease (AD). This suggests raft alterations contribute to AD pathogenesis by affecting the plasmin system.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • Plasmin degrades amyloid peptides, but its levels are low in Alzheimer's disease (AD) brains.
  • The reason for reduced plasmin in AD brains is currently unknown.

Purpose of the Study:

  • To investigate the cause of reduced plasmin levels in Alzheimer's disease (AD) brains.
  • To explore the role of membrane cholesterol and raft microdomains in plasminogen binding and activity.

Main Methods:

  • Biochemical analysis of brain samples from AD patients and age-matched controls.
  • Investigating plasminogen and plasminogen-binding molecules.
  • Assessing membrane cholesterol levels and raft microdomain integrity.
  • Experiments using cultured hippocampal neurons to model cholesterol reduction.

Main Results:

  • Total brain plasminogen and binding molecules were normal, but plasminogen membrane binding was reduced in AD brains.
  • AD brains showed reduced membrane cholesterol and disorganized raft microdomains, affecting raft-enriched proteins.
  • Reduced membrane cholesterol in cultured neurons mimicked these effects, decreasing plasminogen binding and plasmin activity.

Conclusions:

  • Brain raft alterations, specifically cholesterol reduction, impair plasminogen membrane binding and activity in Alzheimer's disease (AD).
  • These findings suggest that disruptions in brain raft structure contribute to AD pathogenesis by compromising the plasmin system's efficiency.

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