Alzheimer’s Disease
189
AD has been universally replicated, the rel-
ative signifcance oF these associations is
still in question.
3
Molecular and Cellular Mechanisms
Underlying Alzheimer’s Disease
3.1
β
-amyloid Precursor Protein
β
-Amyloid precursor protein (APP) is a
large, type I transmembrane protein that is
expressed in almost all cell types except ery-
throcytes. It consists oF a large extracellular
N-terminal region, a transmembrane do-
main, and a short intracellular C-terminal
tail. The A
β
-peptide sequence begins close
to the membrane on the extracellular part
oF APP and ends within the membrane-
spanning domain. At least fve diFFerent
mRNAs arise as a result oF alternative
splicing oF the primary transcript oF the
APP gene: APP770, 751, 714, 695, and
563. Transcript APP695 lacks the Kunitz-
type protease inhibitor (KPI) domain and
is the major Form expressed in neurons,
whereas APP751, which contains the KPI
domain, is the major transcript in non-
neuronal cell types. The APP transcripts
appear to be developmentally regulated,
and all cell types so Far tested contain at
least one oF the transcripts.
In addition to diFFerential RNA splicing,
APP undergoes posttranslational modif-
cation, including phosphorylation, N- and
O-linked glycosylation, sulFation and pro-
teolytic processing. It is not clear how these
diFFerent events modiFy APP metabolism
or Function. A detailed knowledge oF post-
translational events is undoubtedly crucial
to understanding amyloid plaque Forma-
tion and to
elucidating the biological
Functions oF APP and A
β
.
The normal Function oF APP is still
unclear, but it has been implicated in
neuroprotective action. APP is a member
oF a multigene Family that contains at least
two other homologs known as amyloid
precursor-like protein 1 and 2 (APLP1
and APLP2). Both APP
/
and APLP2
/
m
icearev
iab
lewh
i
leAPP/APLP2doub
le
knockout mice are early postnatal lethal
suggesting that APP and APLPs may share
important physiological Functions and the
APLPs may compensate For the Function
oF APP.
3.2
Production of A
β
–Proteolytic Processing of
APP
It is clear that A
β
production does occur
in normal cells, suggesting that excessive
A
β
production in AD is due to enhanced
or altered processing oF APP by normal
pathways that generate A
β
, rather than by
an abnormal route specifc to Alzheimer’s
cells. APP undergoes a series oF proteolytic
processing events (±ig. 4) by several diFFer-
ent proteases called secretases. It is frst
cleaved by either
α
-o
r
β
-secretase. Two
disintegrin metalloproteases, ADAM 10
and TACE (TN±-
α
converting enzyme), are
involved in
α
-cleavage oF APP. This cleav-
age produces a large soluble N-terminal
Fragment (NT±), APPs
α
and an 83-amino
acid membrane-bound C-terminal Frag-
ment, C83 (CT±
α
). Alternatively, cleavage
by the
β
-secretase results in an N-terminal
Fragment APPs
β
and a 99-amino acid
membrane-bound Fragment, C99 (CT±
β
).
The
β
-secretase has recently been identi-
fed as a transmembrane aspartyl protease
called BACE1, For
β
-site APP-cleaving en-
zyme. Both C83 and C99 are substrates
For
γ
-secretase, a mysterious enzyme that
carries out an unusual proteolysis in the
middle oF the transmembrane domain oF
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