R .L. Neve et al. Brain Research 886 2000 54 –66
57
Fig. 1. Schematic depicting the structural and functional domains of the amyloid precursor protein.
defined in greatest detail is G . Nishimoto and colleagues respective roles of G , APP-BP1, Fe65 and X11, and
o o
657 676
have demonstrated that the His –Lys
domain of APP- UV-DDB in the normal function of APP, to test the
695 activates the heterotrimeric GTP-binding protein G in hypothesis that progressive dysfunction of these roles
o
a GTP S-inhibitable manner [75,52]. Their demonstration occurs in AD.
g
that an antibody to the extracellular domain of APP 22C11 that acts as a ligand mimetic [79] causes activa-
tion of G , argues that APP may be a G protein-coupled
4. Apoptosis in Alzheimer disease
o
receptor. As noted above, the ‘London’ mutation of APP, V642I, causes DNA fragmentation when expressed in a
The notion that a form of cell suicide called apoptosis neuronal cell line [113]. Notably, expression of V642I
participates in the neuropathology of AD was raised by Su
657 676
APP deleted for residues His –Lys
in these cells did et al. [100], when they reported evidence for DNA
not cause DNA fragmentation. Pertussis toxin PTX, an fragmentation in neurons in AD brain. Although other
inhibitor of G and G , blocked the DNA fragmentation groups have also detected this feature of apoptosis in AD
o i
caused by V642I, as did co-transfection of V642I APP and brain, many in the field have been skeptical of the idea that
a cDNA encoding a dominant negative mutant of Ga , but the neurons that die in AD undergo apoptosis, partly
o
not with a cDNA encoding a dominant negative mutant of because DNA fragmentation can also be caused by oxida-
Ga . Inhibition of Ab production from the V642I APP
tive damage [106] or by postmortem autolysis [98].
i 1 – 42
by mutating the g-secretase cleavage site did not have any However, a report from the laboratory of Mark Mattson
effect on the DNA fragmentation caused by V642I. [34] revived interest in the possibility that apoptosis is
These data suggest that G mediates the DNA frag-
operative in AD. These investigators found that levels of a
o
mentation caused by the V642 mutants of APP; and marker of apoptosis, Par-4 prostate apoptosis response-4
indeed, a subsequent paper from Nishimoto’s group re- protein, are increased 15–20-fold over control in vulner-
vealed that the DNA fragmentation was mediated by the able neurons in AD brain. They also showed that Par-4
bg complex of G [29]. Ab does not appear to play a expression is increased in cultured neurons undergoing
o
causative role in inducing DNA fragmentation in this apoptosis, and that inhibition of Par-4 expression in these
experimental paradigm. The data support the notion that neurons blocks apoptosis.
these mutants act by causing unregulated activation of G These findings provide the strongest evidence to date
o
and, by inference, of a cellular signaling pathway down- that neuronal death in AD may be due to apoptosis. And
stream of G . The report by Rohn et al. [87] that 22C11, a they are consistent with the increasing awareness in the
o
monoclonal antibody to APP that acts as a ligand mimetic field that at least one of the normal functions of APP is to
[79], induces neuronal apoptosis provides further support regulate apoptosis in the neuron. As noted above,
for this notion. The task before us is to determine the Nishimoto’s group showed that the ‘London’ mutation of
58 R
differentially affected. PS-1 is reported to be expressed primarily in CNS neurons in the brain, suggesting that this
protein may perform a neuron-specific function [20]. In fact, in AD, neurons that express PS-1 antigen are less
vulnerable to the disease than are neurons that do not express it [30], and inhibition of PS-1 expression results in
apoptosis [88], suggesting a protective role for this protein. Although the precise role of PSs in regulation of apoptosis
in the neuron is still unclear, the evidence that they do play a role in this pathway is strong. These data implicate both
APP and PSs in the control of apoptotic death in the brain, and it is not unreasonable to suppose that FAD mutations
in these genes may cause dysfunction in this pathway.
It has been noted [82] that since the apoptotic process proceeds to completion within 16–24 h, the extent of
apoptosis reported in AD brain would predict a complete loss of neurons within a very brief period of time. Clearly,
this does not happen in AD. Cotman has suggested [15] that the induction of compensatory responses to apoptosis
in the AD brain protects the neurons from terminal apoptosis, and that a dynamic competition between cell
death processes and compensatory responses exists in AD brain.
5. Cell cycle abnormalities in Alzheimer’s disease
