Docteur de l'université Automatic Segmentation and Shape Analysis ...

4 Chapter 1 Introduction
.β.α .γ
.
.APP
.α-secretase .β-secretase
.APPsα .α-stub .APPsβ .β-stub
.γ-secretase
Figure 1.2: Generation of amyloid-β from the amyloid precursor protein
(APP). Adapted from Goedert and Spillantini (2006).
identified to be amyloid-β (Aβ), and the tangle is made of tau. The current amy-
loid cascade hypothesis suggests the disease is caused by excessive deposition of
Aβ which will be briefly summarized as follows (for an up-to-date review of the
current development in the pathogenesis and related issues of Alzheimer’s disease,
see Blennow et al., 2006; Goedert and Spillantini, 2006; Murphy and LeVine, 2010;
Ballard et al., 2011).
Amyloid-β is the secreted peptide of 40 or 42 amino acids from larger transmem-
brane amyloid precursor protein (APP), with the physiological function still un-
known. During the amyloidogenic cleavage, APP is processed by β- and γ-secretase
subsequently, releasing Aβ peptide. In the alternative pathway, APP is cleaved
by α-secretase within the Aβ domain first, which is therefore non-amyloidogenic.
The Aβ product is degraded and cleared in normal metabolism. Observing in the
familial Alzheimer’s disease that the mutations in the APP gene causes preference
of β-secretase, and that the mutations in presenilin genes associated with the sec-
retase enzymes increase the production of Aβ42, being more ready to aggregate to
plaque, the current amyloid cascade hypothesis suggests that synaptic dysfunction
and neuronal death are triggered by the Aβ deposition and oligomers aggregated
from Aβ. In sporadic AD, the ε4 allele of apolipoprotein E (APOE-ε4) associated
with the failure of Aβ clearance has been identified as the main genetic factor that
increases the risk of AD 3.8 times (Alzgene database, see Bertram et al., 2007).
.Aβ