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Amyloid diseases - Coggle Diagram

- - - - Muscle weakness
      - Muscle twitching
      - Muscle cramping
      - Poor balance
      - Fatigue
      - Slurred speech
    - - More severe muscle weakness
      - Paralysis in some muscles
      - Difficulty in swallowing
      - Difficulty in eating/chewing
      - Breathing issues
      - Bouts of uncontrollable laughter or crying (aseudobulbar affect)
    - - Paralysis in most muscles
      - Extreamly limited mobility
      - Inability to speak
      - Inability to breath without assistance
      - Inability to eat without assistance
      - Inability to drink without assistance
  - - - TAR DNA-binding protein 43 kDa
      - Transcriptional repressor
      - Splicing regulator
      - Nuclear localisation
      - Involved in stress regulation (cytoplasmic role)
      - Forms inclusions in 97% of patients with ALS
      - Inclusions also found in significant subsets of patients with AD, Huntington and other neurodegenerative disorders
      - Inclusion formation
        
        Liquid-liquid phase separation (LLPS) AND amyloid formation
        
        C-terminal truncations common (releases c-terminal amyloidogenic segments; 25kDa, 35kDa
    - - Shared with FTLD (frontotemporal lobar dementia; although affecting different parts of the CNS/brain)
  - - - Riluzole
        
        Thought to inhibit synaptic glutamate release
      - Edarvone (2017)
        
        Free radical scavenger, oxidative stress reduction
    - - Avoid death due to respiratory failure
- - - - A30P
      - E46K
      - H50Q
      - G51D
      - A53T/E/V
  - - - Effective against muscle rigidity and slowed movement
      - Reduced effect over time
      - Carbidopa (L-dopa structural analog; reduces side effects)
    - - Side effects is a problem with most PD treatments
- - - - Disease begins in Medial Temporal Lobe
    - - Disease spreads to Lateral Temporal and Parietal lobes
    - - Disease spreads to Frontal lobe
    - - Disease spreads to Occipital lobe
  - - - Cleavage of (Amyloid prcursor protein) APP generates 37-42 residues long
        A\(\beta\) peptides
        
        90% A\(\beta\)(1-40)
        
        ~5% A\(\beta\)(1-42)
        
        More aggregation prone, disease-associated variant
      - Pathological mutations associated with early onset hereditary AD
      - Amyloid cascade hypothesis
        
        "Our hypothesis is that the deposition of amyloid \(\beta\) protein, the main component of the plaques, is the causative agent of Amzheimer's pathology and that the neurofibrillary tangles, cell loss, vascular damage, and dementia follow as a direct result of this deposition."
      - Inhereted AD - Amyloid-\(\beta\) mutations
        
        Trisomy21 (Down's syndrome)
        
        3 copies of the APP gene
        
        Mutations in enzymes processing APP into A\(\beta\)
        
        More aggregation prone A\(\beta\)(1-42)
        
        Aggregation-promotion A\(\beta\) variants
        
        Arctic: E22G
    - - Microtubule-associated protein
      - Stabilizes microtubule
        
        Important for the morphology and physiology of neurons
      - Six isoforms, varying in length and number of repeats
      - Acidic N-terminal domain
        Basic C-terminal domain
  - - - Support function of synapse, but do not prevent degeneration
    - - Antibody-based therapies directed to A\(\beta\)
      - Phase III clinical trials (aducanumab, Biogen)
      - BAN2401 (Bioarctic, Uppsala)