Discuss the molecular basis underlying Alzheimers:

1
Discuss the molecular basis underlying
Alzheimers

• Presentation will show
• How secretases operate under normal parameters
• The different types of secretases
• Why secretases are linked with the pathogenesis
  of Alzheimers disease
• The types of aggregate formed as a result of
  secretase action

2
What are secretases?

• These are enzymes which break down the amyloid
  precursor protein.
• Major catabolic pathway involves alpha-secretase
• Second catabolic pathway involves beta and gamma
  secretases.
• The amyloid precursor protein is located in
  membranes in cells at the fore brain and
  hippocampus

3
What happens normally?

• The amyloid precursor protein is cleaved by the
  protease alpha-secretase at its 40-42 amino acid
  domain. (see domain)
• This prevents the formation of the beta-amyloid
  peptide 42 (or causes very little of its
  production)
• The reason for this is because it digests the
  protein from within the domain that gives rise to
  the peptide

4
Normal cleavage
PICTURES FROM THOMPSON THOMPSON GENETICS IN
MEDICINE (PAGE 236,FIGURE 12-24)
5
When mutations occur in APP

• When mutations occur there is a greater
  occurrence of the secondary catabolic pathways.
• The b-secretase and gamma secretase become more
  involved
• The beta-secretase at the N-terminus
• The gamma-secretase at the C-terminus

6
When mutations occur in APP

• These 2 cleavages generate a series of
  beta-amyloid proteins, 40-42 amino acids in
  length.
• One of these peptides which is formed is called
  beta-amyloid-42.
• This is the most neurotoxic of the proteins as it
  is considered to be fibrillogenic (plaque
  formation).
• It causes the production of plaques from
  aggregates which degenerate neurones causing
  Alzheimer's.

7
Abnormal cleavage
PICTURES FROM THOMPSON THOMPSON GENETICS IN
MEDICINE (PAGE 236,FIGURE 12-24)
8
Summary

• Several of the mutations in the amyloid precursor
  protein gene increase the production of
  beta-amyloid-42
• The overproduction of this peptide appears to be
  the central pathogenic event in the disease
• Down syndrome patients with 3 copies of the APP
  gene (chr.21), develop the neuropathology of AD
  by 40.

9
References

• Thompson Thompson Genetics in medicine Sixth
  ed. Published by Saunders 2004 pages 234-237.
• Web resource Ross CA and Poirer MA (2004)
  Protein aggregation and neurodegenerative
  disease Nature Med Supl 10-17
  (http//nature.com/cgi-taf/DynaPage.taf?file/nm/j
  ournal/v10/n7s/index.html)
• Web resource A.J Markham Membrane Protein
  secretases Alzheimer's disease
  (http//www.bmb.leeds.ac.uk/staff/ajt/project1.htm
  l)