Alzheimer’s Disease
193
Human APH-1 and PEN-2 can partially
rescue the
C. elegans
mutants, suggesting
functional conservation among eukary-
otes. The human genes must be present
together to rescue the phenotypes and
adding PS1 improves the rescue, indi-
cating that these proteins act in concert.
Consistent with the genetic studies, bio-
chemical studies showed that reduction
of APH-1 and PEN-2 expression in mam-
malian cells by RNA inhibition reduced
γ
-secretase activity.
While the exact functions of these co-
factors remain to be elucidated, the data
obtained so far suggest that all four pro-
teins, presenilins, nicastrin, APH-1, and
PEN-2, are necessary components of the
γ
-secretase. They appear to regulate one
another for protein stability, proper mat-
uration, and functional
γ
-secretase com-
plex formation. It is also very likely that
the least abundant component becomes
the cellular-limiting factor that controls
overall
γ
-secretase activity.
3.5
Neurofbrillary Tangles and Tau Protein
NeuroFbrillary tangles are intracellular de-
posits that consist of aggregates of a Fbrous
substance, the paired helical Flaments
(PH±). These Flaments are highly insol-
uble, even resistant to strong detergents
such as SDS and guanidine hydrochlo-
ride. A major component of PH± is tau,
a microtubule (MT)-associated phospho-
protein. Tau is abundantly expressed in
the brain. At least six isoforms of tau are
present in the brain, resulting from alter-
native mRNA splicing of a single gene on
chromosome 17q.
Unlike APP, whose functions are not
clear, tau has a biological role that is
reasonably well understood. One function
of tau is to promote microtubule assembly,
a process controlled by phosphorylation
of tau. In addition, it has been proposed
that
tau
has
a
speciFc
role
in
the
generation of axon morphology. Increased
phosphorylation of tau decreases its ability
to
promote
tubulin
polymerization
to
microtubules.
Tau in PH± is hyperphosphorylated, and
is insoluble under conditions in which
no
rma
ltauisso
lub
le
.I
tisbe
l
ievedtha
t
tangles are formed when tau becomes hy-
perphosphorylated and dissociates from
microtubules and spontaneously forms
insoluble PH±. Over 25 phosphorylation
sites have been identiFed in PH± tau
puriFed from AD brains. Most of the
phosphorylation sites are located in the
flanking region of the MT-binding do-
main. A variety of protein kinases, includ-
ing glycogen synthase kinase-3
β
(GSK3
β
),
cyclin-dependent kinase 5 (cdk5), mitogen-
activated protein kinase (MAPK) and pro-
tein kinase A, have been found to be
involved in hyperphosphorylation of tau.
This suggests that multiple phosphoryla-
tion cascades may be activated in N±T-
bearing neurons. However, it remains
unclear whether these cascades are acti-
vated independently or whether one or
more kinases are primarily responsible for
initiating the cascade
in vivo
.
In addition to their presence in AD,
Flamentous tau inclusions accompanied
by extensive gliosis and loss of neurons
are the neuropathological hallmarks of
other neurodegenerative diseases that are
sometimes
designated
as
tauopathies.
There has been considerable debate in
the AD literature concerning the primacy
of A
β
versus N±T in the pathogenesis
of AD. This was largely resolved by the
identiFcation of mutations in the tau gene
in families with frontotemporal dementia
with parkinsonism (±TDP-17). ±TDP-17 is
characterized clinically by the presence of
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