Processing of APP Directory UMM :Data Elmu:jurnal:B:Brain Research:Vol886.Issue1-2.Nov2000:
R .L. Neve et al. Brain Research 886 2000 54 –66
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[118]. Cells expressing FAD mutants of APP and the transmission [28]. There has been some question of
presenilins are reported to secrete increased amounts of whether C100 exerts its neurotoxic effects from the inside
Ab , suggesting a link of this variant of Ab to AD
or the outside of the cell [23,117]. Our data of the past 6
1 – 42
pathogenesis. Consequently, a leading hypothesis for the years suggest strongly that C100 kills from inside the cell;
etiology of AD is that increased Ab is a shared
this is supported by the observation that C100 is not
1 – 42
molecular correlate of FAD mutations, and that it repre- secreted, even when it carries a signal peptide [19,14,66].
sents a gain of deleterious function that can cause FAD Although at least one group has reported neurotoxicity due
[38] and may be an essential early event in AD [118]. to the addition of C100 to the culture medium [50], we
While this ‘amyloid hypothesis’ is attractive, molecular believe that that type of neurotoxicity is mechanistically
mechanisms other than those mediated by extracellular Ab different from the neurodegeneration that we observe upon
could also lead to AD neurodegeneration. expression of C100 within primary neurons.
These mechanisms are likely to be linked in some way The findings that APP interacts with the signaling
to the b-amyloid protein precursor APP, the source of molecule G , that FAD mutants of APP can cause G -
o o
Ab. One of the most compelling pieces of evidence that mediated apoptosis in neuronal cells, and that these same
links AD neurodegeneration to APP and or its Ab-con- FAD mutants of APP cause the intracellular accumulation
taining derivatives is the early finding that the APP gene is of C100, suggested to us the following working hypoth-
on chromosome 21: virtually all individuals trisomic for esis: In the brain a portion of APP is present as an integral
this chromosome show AD-like neuropathology by the age plasma membrane protein that mediates the transduction of
of 40. Additionally, it has been discovered that specific extracellular signals into the cell via its C-terminal tail, and
mutations in APP cause some forms of familial FAD. abnormal accumulation of its Ab-containing C-terminal
These data have raised the possibility that AD may result tail in the neuron causes progressive dysfunction of APP
from an alteration in the normal function of APP [74,76], signaling in AD, resulting in apoptosis. This hypothesis has
and have refocused attention on the delineation of the been supported by the finding that the intracellular C-
function that APP subserves in the brain. It has been terminal tail of APP interacts with the cell cycle protein
shown [47,83] that in the brain a percentage of APP is APP-BP1 [10,9], and with members of the Fe65 family of
present on the cell surface, and it is proposed [76,83] that adaptor proteins reviewed in Ref. [89]. Additional sup-
this cell surface APP mediates the transduction of extracel- port for this hypothesis emerged with the recent report [60]
lular signals into the cell via its C-terminal tail. that the C31 peptide of APP, which is derived from C100
Nishimoto and his colleagues [75] showed that APP and within which are contained the binding sites for the
binds to the brain-specific signal transducing G protein G ; above proteins, is elevated in AD brain and is a potent
o
independent confirmation of this finding has subsequently inducer of apoptosis.
been published [4,5]. It was then discovered [113] that V642 ‘London’ FAD mutants of APP induce neuronal
DNA fragmentation, a feature of apoptosis, in a neuronal