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A megalin polymorphism associated with promoter activity and Alzheimer's disease risk

Teo Vargas1, Maria Jesus Bullido, Ana Martinez-Garcia

  • 1Neuroscience Laboratory, Research Center, Hospital 12 de Octubre, Madrid, Spain.

American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics
|January 7, 2010
PubMed

Insights

A specific gene variant in megalin may increase Alzheimer's disease (AD) risk by impairing amyloid beta-protein (Abeta) clearance. This finding highlights megalin's role in AD pathogenesis and suggests potential therapeutic targets.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Alzheimer's disease (AD) is characterized by elevated cerebral amyloid beta-protein (Abeta) levels.
  • Faulty Abeta clearance, rather than overproduction, is implicated in many AD cases.
  • Megalin is crucial for Abeta clearance and a candidate gene for AD association.

Purpose of the Study:

  • To investigate the association between the megalin gene and Alzheimer's disease risk.
  • To determine if megalin polymorphisms influence Abeta clearance and AD pathogenesis.

Main Methods:

  • Genetic analysis of the megalin gene in 2,183 subjects.
  • Analysis of the rs3755166 (G/A) polymorphism in the megalin promoter.
  • Luciferase reporter assay to assess transcriptional activity of the rs3755166 A variant.

Main Results:

  • The rs3755166 (G/A) polymorphism in the megalin promoter was associated with AD risk, independent of apolipoprotein E genotype.
  • The rs3755166 AA genotype was significantly more frequent in AD patients than in controls.
  • The rs3755166 A variant exhibited 20% less transcriptional activity than the G variant.

Conclusions:

  • The studied megalin polymorphism confers an increased risk for Alzheimer's disease.
  • This finding supports a significant biological role for megalin in the neurodegenerative processes underlying AD.
  • Megalin's function in Abeta clearance is critical for AD pathogenesis.

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