BCH3052 Lecture 12: Alzhaeimer's Disease
25 May 2018
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Lecture 12 – Alzheimer’s Disease
• AD is a protein misfolding disease
• Most common neurodegenerative disease
o Accounts for 60-80% of all dementias
o Affects 24 million people worldwide
o Late onset (65 years) and sporadic
• AD brains are decreased in size (cell death)
o Reduced glucose usage
o Contain dense senile plaques and neurofibrillary tangles
• AD disrupts healthy neurons, axons and dendrites – can’t communicate, carry
out metabolism and repair themselves
• Hallmarks include:
o Extracellular amyloid plaques (ß-amyloid plaque)
▪ Dense deposits of protein and cellular material that
accumulates outside and around nerve cells
▪ Amyloidogenic Aß peptides are produced through cleavage of
APP protein by ß and y-secretases, resulting in the production
of extracellular amyloid plaques
o Intracellular neurofibrillary tangles
▪ Twisted fibers of hyperphosphorylated tau that build up inside
the nerve cell
• Amyloid cascade
o Overproduction of APP→ Aß42 oligomerization on synapses →
progressive synaptic and neuritic injury → altered kinase activities
o Aß peptide are formed by proteolytic cleavage
▪ Aß(17-40) – non toxic
▪ Aß (1-40) – toxic
▪ Both are mostly unfolded structure
▪ Peptideis are bipolar
• ß-amyloid Cascade
o Is an amyloid precursor protein (APP) – precursor to amyloid plaque
o APP sticks through neuron membrane
o Enzymes cut the APP into fragments of protein, including ß-amyloid
o ß-amyloid fragments aggregate to form plaques
• Aß fibril formation
o Lag phase → elongation phase → plateau
o Oligomer is thought to be toxic species
o NMR used to study structure of Aß
o 4.7Å between ß-strands
o Forms 4 strands
• Aß Oligomers
o Form via interactions between their C terminal hydrophobic ends
AD drugs development
• Current drug discovery approaches have focused on
o Preventing Aß formation or improving ‘normal’ APP processing via
the inhibition of y-secretase and ß-secretase or activation of a-secretase
▪ Inhibitors that have been developed have caused side effects -
blindness
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