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Perturbations in calcium-mediated signal transduction in microglia from Alzheimer's disease patients

James G McLarnon1, Hyun B Choi, Lih-Fen Lue

  • 1Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. mclarnon@interchange.ubc.ca

Journal of Neuroscience Research
|June 11, 2005
PubMed

Insights

Alzheimer's disease (AD) microglia exhibit altered calcium signaling, with higher basal intracellular calcium and reduced responses to ATP and platelet-activating factor (PAF). These findings highlight dysregulated calcium homeostasis in AD pathogenesis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Immunology

Background:

  • Microglia play crucial roles in brain immunity and are implicated in Alzheimer's disease (AD) pathogenesis.
  • Calcium (Ca2+) signaling is fundamental to microglial function and immune responses.
  • Aberrant Ca2+ signaling in microglia may contribute to neuroinflammation and neuronal damage in AD.

Purpose of the Study:

  • To investigate Ca2+-dependent signal transduction pathways in microglia from AD patients compared to non-demented (ND) individuals.
  • To characterize differences in basal intracellular Ca2+ levels and responses to stimuli like adenosine triphosphate (ATP) and platelet-activating factor (PAF).
  • To examine the role of store-operated calcium channels (SOC) in AD microglia.

Main Methods:

  • Calcium-sensitive fluorescence microscopy was employed to measure intracellular Ca2+ ([Ca2+]i) dynamics.
  • Microglia were isolated from postmortem brain tissue of AD patients and ND individuals.
  • Stimulation with ATP and PAF was used to assess Ca2+ responses, including depletion of endoplasmic reticulum stores and SOC-mediated Ca2+ entry.

Main Results:

  • AD microglia displayed significantly higher basal [Ca2+]i (20% increase) compared to ND microglia.
  • Responses to ATP and the initial phase of PAF signaling, reflecting Ca2+ store depletion, were markedly reduced in AD microglia (63% and 59% decrease, respectively).
  • AD microglia showed diminished SOC-mediated Ca2+ entry induced by PAF (61% reduction) and prolonged ATP response time courses (60% increase).

Conclusions:

  • Microglia from AD patients exhibit significant abnormalities in Ca2+-mediated signal transduction.
  • These alterations include elevated basal Ca2+ levels and impaired responses to key signaling molecules.
  • The findings suggest dysregulated Ca2+ homeostasis in AD microglia, potentially contributing to disease progression.

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