Amyloid Plaques

Definition: Amyloid plaques are extracellular deposits primarily composed of aggregated amyloid-beta (Aβ) peptides, especially Aβ₁–₄₂, found in the brain parenchyma. They are one of the two pathological hallmarks of Alzheimer’s disease (AD), along with neurofibrillary tangles composed of hyperphosphorylated tau protein.

• Core: Aggregated Aβ₁–₄₂ peptides in β-sheet conformation
• Associated proteins:
  • Apolipoprotein E (ApoE)
  • Complement components
  • Alpha-synuclein
  • Metal ions (Zn²⁺, Cu²⁺, Fe³⁺)
• Surrounded by dystrophic neurites, activated microglia, and astrocytes

• Aβ peptides are generated from amyloid precursor protein (APP) via sequential cleavage by β-secretase and γ-secretase
• Aβ₁–₄₂ is more hydrophobic and prone to aggregation than Aβ₁–₄₀
• Aggregates initially form soluble oligomers → protofibrils → fibrils → mature plaques
• Soluble Aβ oligomers are believed to be the most neurotoxic form
• Lead to synaptic dysfunction, oxidative stress, neuroinflammation, and neuronal death

• Visualized in vivo using amyloid PET imaging (e.g., [¹⁸F]-Florbetapir, Pittsburgh Compound B)
• CSF biomarkers: ↓ Aβ₁–₄₂ levels reflect plaque accumulation
• Post-mortem analysis (e.g., Congo red, Thioflavin S staining) confirms diagnosis

• Diffuse plaques:
  • Loosely packed, amorphous
  • Seen in aging and early AD
  • Often non-neuritic and less toxic
• Neuritic (senile) plaques:
  • Dense core with dystrophic neurites
  • Strongly associated with neurodegeneration
  • Trigger glial activation and local inflammation

• Monoclonal antibodies (e.g., aducanumab, lecanemab) designed to bind aggregated Aβ and facilitate clearance
• Secretase inhibitors (β-/γ-secretase) aimed at reducing Aβ production
• Immunotherapy and vaccine strategies under investigation
• Debate continues regarding clinical benefit of amyloid removal

• Amyloid plaques can be present in cognitively normal individuals
• Plaque burden does not correlate perfectly with cognitive decline
• Current therapeutic strategies often fail to reverse or halt disease progression

• NIH: Amyloid Plaques in Alzheimer's Disease
• AlzForum
• PubChem: Amyloid-beta Peptide