====== Amyloid Plaques ======

**Definition**:  
[[Amyloid]] [[plaque]]s 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.

===== 🧬 Composition =====
  * **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  

===== 🧠 Pathophysiology =====
  * 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**

===== 🧪 Diagnostic Relevance =====
  * 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  

===== 🔬 Types of Plaques =====
  * **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  

===== 💊 Therapeutic Targeting =====
  * **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  

===== ⚠️ Limitations and Controversies =====
  * 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  

===== 📚 References =====
  * [[https://www.ncbi.nlm.nih.gov/books/NBK470458/|NIH: Amyloid Plaques in Alzheimer's Disease]]  
  * [[https://www.alzforum.org|AlzForum]]  
  * [[https://pubchem.ncbi.nlm.nih.gov/compound/Amyloid-beta-peptide|PubChem: Amyloid-beta Peptide]]