Summary: Amyloid Precursor Protein Processing And Alzheimer’S Disease

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• 1 History of Alzheimer's Disease

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• What was the first reported case of Alzheimer's Disease?

  The presence of two distinctive pathologies (neurofibrillary tangles and neuritic plaques) in the brain of a woman who had died from progressive behavioural and cognitive disorder.

• When was Alzheimer's Disease considered to be a true distinctive disease?

  When the presence of neuritic plaques where linked to the incidence of dementia.

• 2 RELATIONSHIP OF BRAIN Aβ ACCUMULATION TO DEMENTIA IN HUMAN PATHOLOGIC SPECIMENS

• Is the accumulation of amyloid beta caused by dying neurons?

  Not necessarily, it comes into the extracellular matrix after nerve injury, but does not correlate with the age-expected neural degradation in other neurodegenerative disease like Parkinson's disease and frontotemporal dementia.

• What can be generalised from the brain pathology of demented elderly?

  They may have mixed pathologies including
  

  • neuritic plaques
  • neurofibrillary tangles
  • Lewy bodies
  • atherosclerosis 

• 3 STRUCTURE AND FUNCTION OF APP

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• What is the function of APP?

  overexpression may benefit cell health and growth
  it may be important in embryonic neural migration
  it may benefit synaptic density

• What is the function of the amyloid beta peptide?

  It influences regulation of synaptic physiology (scaling and vesicle release)

• 4 AMYLOID PRECURSOR PROTEIN PROCESSING

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• In which cells is APP metabolised?

  In neurons

• What are the pathways that proteolyse APP?

  
  

  • ER --> Golgi --> synaptic terminal --> TGN --> cell surface --> proteolysed by a secretase and g secretase
  • ER --> Golgi --> synaptic terminal --> TGN --> cell surface --> internalized into endosome --> proteolysed by BACE1 and g secretase --> amyloid b secretion
  • ER --> Golgi --> synaptic terminal --> TGN --> cell surface --> internalized into endosome --> proteolysed by BACE1 and g secretase --> retromers to the TGN
  • ER --> Golgi --> synaptic terminal --> TGN --> endosomal compartment

• How can secretion of amyloid beta best be prevented?

  By preventing cell surface endocytosis.

• What kind of enzyme is BACE1?

  a transmembrane aspartic protease, involved in the pathogenic pathway of APP proteolysis.