190
Alzheimer’s Disease
APP-FL
N
APPs
α
APPs
β
β
α
γ
γ
A
β
p3
TM
C
C83
C99
CTF
γ
cytoplasm
α
or
β
Extracellular
environment
Fig. 4
Proteolytic processing of APP. APP is initially cleaved by either
α
-or
β
-secretase to generate membrane-bound C-terminal fragments, C83 or C99,
which are subsequently cleaved by the
γ
-secretase (in the transmembrane
domain) to produce p3 or A
β
.
APP, resulting in the release and secre-
tion of the 4-kD A
β
from C99 and the
3-kD p3, a nonpathogenic peptide, from
C83.
γ
-secretase cleavage is promiscuous
and produces a spectrum of A
β
peptides
varying from 39 to 43 residues in length.
Over 90% of the A
β
in the brain is A
β
40
and the remaining 5 to 10% is the longer
species A
β
42/43.
The
C-terminal
product
of
the
γ
-
secretase cleavage is called CTF
γ
or AICD
(from APP Intracellular Domain). Inter-
estingly, CTF
γ
, puri±ed from brain tissue,
is not C59/57, which would be the pre-
dicted length of the C-terminal product
of A
β
cleavage. Instead, sequence analysis
reveals that it is C50/49, several amino
acids shorter. The mechanism that ac-
counts for such differential cleavages is
currently under investigation. Several re-
ports have suggested a role of CTF
γ
in
APP signaling to the nucleus. Indeed, it
was shown that CTF
γ
, when together with
Fe65 protein, translocates to the nucleus
and that this complex can activate tran-
scription of a reporter gene
in vitro
.
3.3
β
-secretase – BACE1
In late 1999, four groups almost simulta-
neously reported the discovery of BACE1,
a novel aspartyl protease that exhibited
all the known functional characteristics of
the
β
-secretase. BACE1 is a type I trans-
membrane protein with an open reading
frame of 501 amino acids. It is most closely
related to the pepsin family of aspartyl pro-
teases. BACE1 is expressed in most tissues
and cell types at modest levels, but shows
much higher expression levels in neurons.
Structurally, it contains an N-terminal 21
amino acid signal peptide, a propeptide
domain, a large lumenal domain fol-
lowed by a transmembrane domain, and
a short cytosolic C-terminal tail. BACE1
contains two aspartyl protease active site
motifs in the lumenal domain: DTGS
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