Signaling Events in APP Processing and Amyloid Plaque Formation

Overview

• APP (Amyloid Precursor Protein): Processed differently in normal and Alzheimer's brains.
• Normal Processing: Involves alpha-secretase.
• Alzheimer's Processing: Involves beta-secretase.

Normal Brain Processing

Enzyme: Alpha-Secretase

• Cleaves APP into:
  • sAPP alpha: Secreted APP alpha
  • CTF83: 83 amino acid, membrane-bound, C-terminal fragment

Further Processing by Gamma-Secretase

• Gamma-Secretase Complex Components: PSEN1, Pen-2, APH-1, GSAP, NCT
• Cleaves CTF83 into:
  • AICD: APP Intracellular Domain, translocates to nucleus
  • sAPP alpha: Drives synaptic signaling, learning, memory, neuronal survival, emotional behaviors

Alzheimer's Brain Processing

Enzyme: Beta-Secretase

• Cleaves APP into:
  • sAPP beta: Secreted APP beta
  • CTF99: 99 amino acid, membrane-bound, C-terminal fragment

Further Processing by Gamma-Secretase

• Cleaves CTF99 into:
  • AICD: Translocates to nucleus affecting transcription of proteins, driving neuroprotective pathways
  • Abeta 40/42 Peptide: Leads to amyloid plaque formation and downstream Alzheimer's pathology

Abeta 40/42 Peptide Pathways

• Interaction with ApoE: Results in aggregation to form amyloid plaque
  • Detection: Immunohistochemistry staining using Abeta 42 specific antibodies (e.g., MOAB2)
• Interaction with Receptors: mGluR5, NMDAR, alpha-7 NACHR
• Effects:
  • Reactive oxygen species and oxidative damage
  • Blocked ion channels
  • Disrupted calcium ion homeostasis
  • Dysregulated glucose metabolism
  • Mitochondrial oxidative stress
  • Neuronal apoptosis
  • Dementia and memory loss