186
Alzheimer’s Disease
Exon 3
Exon 4
Exon 5
Exon 6
Exon 6
Exon 7
Exon 8
Exon 9
Exon 8
Exon 7
Exon 4
Exon 5
Exon 10
Exon 11
Exon 12
Exon 11
Fig. 3
FAD mutations in presenilin-1. Shown is a schematic representation
of human presenilin 1 protein. The protein is predicted to have eight
transmembrane domains. Arrow indicates the endocleavage site. Shaded
residues are those associated with FAD mutations.
processing of the presenilins is an impor-
tant aspect of the biochemistry of both PS1
and PS2 proteins, since it has been impli-
ca
tedintheforma
t
ionofthefunc
t
iona
l
ly
active complex (see Sect. 3). The most con-
sistent effect mediated by the presenilin
FAD mutations is increased production of
A
β
42. This has been con±rmed both in
transfected cells and in transgenic mice.
Although the mechanism by which FAD
mutations in
PS1
and
PS2
cause AD is not
fully understood, it is suggested that FAD
mutations may alter
γ
-secretase activity to-
ward cleavage of the more amyloidogenic
peptide of A
β
,A
β
42/43. Although point
mutations are distributed throughout the
PS1
gene, the majority of them are clus-
tered within the TM domains and large
hydrophilic loop between TM6 and TM7
(Fig. 3). The mean age of onset in all
PS1
families is about 45 years with a range of
28 to 62 years, suggesting that mutations
in
PS1
result in a more aggressive form of
FAD than APP mutations.
In contrast to
PS1
, only eight point
mutations have been identi±ed in
PS2
(http: // molgen-www.uia.ac.be / ADMuta-
tions). The ±rst
PS2
mutation to be iden-
ti±ed was the N141I mutation that is
responsible for disease in a large Volga
German kindred. Whether the preponder-
ance of
PS1
versus
PS2
mutations is due to
the differing genomic environment of the
two genes or the factors related to differing
biological functions of the two molecules,
remains unclear. Mutation analysis of the
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