Calcium Homeostasis Dysregulation

Overview

Calcium ($Ca^{2+}$) is a critical signaling molecule in neurons, involved in synaptic plasticity, neurotransmitter release, and gene expression. Dysregulation of calcium levels is a common feature in many neurodegenerative diseases, particularly Alzheimer’s disease.

Biological Mechanism

  1. Calcium Entry: Under normal conditions, calcium levels are tightly regulated by channels (e.g., NMDA receptors, VDCCs) and pumps.
  2. Amyloid Influence: Amyloid-β (Aβ) peptides can disrupt these mechanisms by:
    • Creating pores in the cell membrane that allow unregulated calcium influx.
    • Sensitizing NMDA receptors.
    • Inducing the release of calcium from internal stores like the endoplasmic reticulum (ER).
  3. Downstream Toxicity: Elevated intracellular calcium ($[Ca^{2+}]_i$) activates:
    • Kinases: Such as GSK-3β, which hyperphosphorylate tau protein (see: Tau Tangles).
    • Proteases: Like calpains, which can damage the cytoskeleton and activate cell death pathways.
    • Mitochondrial Stress: Leading to oxidative stress and apoptosis.

Scientific Consensus

  • Established Fact: Elevated intracellular calcium is toxic to neurons and can trigger apoptosis.
  • Hypothesis: Calcium dysregulation is the primary link between Aβ and tau pathology.
  • Level of Consensus: Moderate; well-supported by in vitro and animal studies, but difficult to measure directly in the living human brain.