Genetics APP

1
Genetics - APP

• Neurodegenerative autosomal dominant.
• DS individuals carry an extra copy of the APP
  locus on chromosome 21.
• In presenile AD, gene loci on chromosome 1, 14,
  21.
• 14q chromosome link - 50 of presenile cases.
• The gene for the amyloid precursor protein (APP)
  close to the defect on chromosome 21.
• Amyloid plaques contain cleavage products
  (Abeta40, Abeta42) of the APP.

2
Mutations familial sporadic AD

• ApoE4 genotype - factor for developing AD,
  possibly affect Abeta deposition and
  neurofibrillary tangle formation.
• Mutations in 3 genes linked to rare familial,
  early onset forms of AD. These genes APP
  encoding, presenilin I (PSI), presenilin 2 (PS2).
• Increased production and accumulation of the
  toxic Abeta.
• Amyloid cascade hypothesis.

3
APP is a type I membrane protein.

• Contains large extracellular region.
• Transmembrane helix.
• A short cytoplasmic tail.
• N-terminal (half of APP) contains heparin-
  binding domain (N-APP),copper binding
  domain(CuBD), APP protease inhibitor domain
  (APPI).

4
N-APP APP may belong to a superfamily of
cysteine - rich growth factors with a putative
heparin - binding site.

• CuBD structure, homologous to copper chaperones.
• May regulate dimerization or proteolytic
  processing or act as a metallotransporter.
• Structure information on the Abeta peptides that
  originate by proteolytic processing of APP.
• Abeta binds Cu, Fe, Zn coordinated by histidines
  and a tyrosine.

5
The Swedish mutation!

• Toxic Abeta originates from regulated
  intramembrane proteolysis of APP by a complex of
  secretases.
• Several mutations in APP (eg. the Swedish
  mutation) cluster at the beta-secretase cleavage
  sites.
• Increased amounts of Abeta peptide and
  protofibril formation.