Alzheimer’s Disease
185
TEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK
APP
TM
A
β
CTF
γ
N
L
R
G G
Q
K
N
TM
G
P
F
A ATL
IMVI
11
1
1
6
40 42
49
γ
-secretase
α
-secretase
A
β
40
β
-secretase
Fig. 2
FAD mutations in APP. Shown is a schematic representation of the APP
protein showing the regions coding for A
β
peptide and C-terminal intracellular
domain-CTF
γ
/AICD. The location of each FAD mutation is shown. Letters in bold
are FAD-mutation sites, letters in gray are FAD substitutions. Major sites of APP
processing,
α
-,
β
-, and
γ
-secretase sites, are also labeled. The amino acid
numbering below the letters is according to the A
β
sequence.
have mainly vascular A
β
in the absence of
neuroFbrillary pathology. Recent analysis
of pathogenic effect on A
β
levels of Arctic,
Italian, Dutch, and ±lemish APP muta-
tions revealed that all, except the ±lemish
mutation, cause a decrease in both A
β
40
and A
β
42. In contrast, the ±lemish muta-
tion increases both A
β
40 and A
β
42 levels.
2.1.2
Presenilin Mutations
The discovery that mutations within the
presenilin 1
(PS1)
gene located on chro-
mosome 14 (14q24.3) were responsible for
most ±AD cases opened up a whole new
area of research into the molecular mech-
anisms of the pathogenesis of AD. Shortly
after the discovery of
PS1
,DNAsequence
database searches led to the identiFcation
of a homologous gene named presenilin 2
(PS2)
, located on chromosome 1 (1q41.2).
Mutations in
PS2
also result in ±AD.
Pathogenic mutations in both of these
genes have been identiFed; overall, mu-
tations in
PS1,
PS2
,a
n
d
APP
genes
account for the majority of ±AD cases.
Although the proteins encoded by the
two presenilin genes are 63% homologous
at the amino acid level, intensive mu-
tation and epidemiological analysis have
revealed some interesting differences be-
tween the two proteins. The number of
mutations identiFed in
PS1
is far greater
than those in
PS2
. To date, more than 107
individual point mutations in
PS1
have
been
identiFed
(±ig. 3,
http://molgen-
www.uia.ac.be/ADMutations) and found
to be responsible for the majority of the
early onset ±AD. Most of these alter-
ations are missense mutations that result
in single amino acid changes in residues
that are conserved between the PS1 and
PS2 proteins. An intronic mutation (re-
ferred as
1
E9) results in the disruption
of a splice acceptor site leading to the
in-frame deletion of exon 9/10. This is
the only
PS1
-±AD mutation that results
in pathologically active protein that does
not undergo proteolysis. Endoproteolytic
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