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Microvascular injury and blood-brain barrier leakage in Alzheimer's disease

B D Zipser1, C E Johanson, L Gonzalez

  • 1Department of Pathology (Neuropathology Division), Brown Medical School, Rhode Island Hospital, Providence, RI 02903, United States.

Neurobiology of Aging
|June 20, 2006
PubMed

Insights

In Alzheimer's disease (AD), thinning of the vascular basement membrane (VBM) allows plasma protein prothrombin to leak across the blood-brain barrier (BBB). This leakage is more pronounced in advanced AD and may be linked to APOE4 genotype.

Area of Science:

  • Neuroscience
  • Pathology
  • Biochemistry

Background:

  • Thinning and discontinuities in the vascular basement membrane (VBM) are implicated in blood-brain barrier (BBB) dysfunction in Alzheimer's disease (AD).
  • Plasma protein prothrombin leakage across the BBB is a potential indicator of VBM damage in AD.

Purpose of the Study:

  • To investigate the localization and quantification of prothrombin in the brain tissue of Alzheimer's disease patients.
  • To correlate prothrombin levels and localization with AD severity (Braak stage) and APOE genotype.
  • To explore the relationship between prothrombin leakage and endothelial cell changes.

Main Methods:

  • Prothrombin immunohistochemistry and enzyme-linked immunosorbent assays (ELISA) were performed on prefrontal cortex tissue from control and AD cases.
  • Factor VIII staining was used to assess endothelial cell morphology.
  • Statistical analyses, including ANOVA and Tukey's test, were employed to compare prothrombin levels across different Braak stages and APOE genotypes.

Main Results:

  • In severe AD (Braak stage V-VI), prothrombin was found within microvessel walls and surrounding neuropil.
  • Prothrombin levels in the prefrontal cortex significantly increased with Braak stage, indicating progressive leakage.
  • A trend suggested higher prothrombin levels in AD patients with at least one APOE4 allele, particularly the APOE4,4 genotype.

Conclusions:

  • Advanced Alzheimer's disease is characterized by the presence of plasma protein prothrombin within the microvasculature and surrounding brain tissue, signifying BBB leakage.
  • Prothrombin leakage appears to correlate with disease severity and may be influenced by APOE genotype, suggesting a potential role in AD pathogenesis.
  • Endothelial cell shrinkage, indicated by Factor VIII staining, may accompany prothrombin leakage in severe AD.

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