56 R
can be detected intracellularly. C100-like amyloidogenic and colleagues have shown that b-secretase cleavage
fragments have been detected only intracellularly. products of APP are present in fetal and neonatal Down
It is important to note that APP processing is cell syndrome brain at twice normal levels [93] and personal
type-specific. LeBlanc and colleagues have reported that communication with Dr. Russo. We have hypothesized
human neurons secrete more 4 kDa than 3 kDa Ab, and that abnormal accumulation of the Ab-containing C-termi-
metabolize approximately 40 of newly-synthesized APP nal tail C100 of APP in neurons also occurs in Alzheimer
through the a-secretase pathway [53,55]. Moreover, disease.
human neurons produce five C-terminal fragments of APP in a pattern seen uniquely in human brain [21,53]. The two
largest C-terminal derivatives have the entire Ab sequence
3. APP as a signaling molecule
at or near their amino terminus [21], and most likely represent endogenous ‘C100’ fragments. Thus, C100 is a
The possibility that APP may act as a signaling receptor physiologically relevant fragment of APP in the human
was first proposed on the basis of its predicted amino acid brain. In contrast to human neurons, most APP-transfected
sequence, which suggested that APP was a type 1 intrinsic human or nonhuman cell lines produce more 3 kDa than 4
membrane protein consistent with the structure of a ‘cell kDa Ab and show a relatively nonamyloidogenic pattern
surface receptor.’ [49]. However, subsequent studies of the of C-terminal fragments [31,36,37,54].
function of APP concentrated largely on the secreted Analyses of b-amyloid Ab in genetically engineered
ectodomain, because of a lack of direct evidence that cell lines expressing FAD mutations in both APP and the
mature APP exists on the cell surface with intact intracel- presenilins PS have shown that all of the mutations cause
lular, transmembrane, and intracellular domains. Surface either increased overall secretion of Ab or secretion of the
APP was inferred to exist on a variety of cultured cells ‘long’ 42–43-amino acid form of Ab Ab
relative to [36,95,114], but some laboratories could not detect it
1 – 42
the shorter 40-amino acid form reviewed in Ref. [38]. [90,1]. Nevertheless some reports demonstrating in-
Increases in Ab have also been detected in transgenic
volvement of APP in neuronal development, synap-
1 – 42
mice expressing FAD mutations of both APP and PS togenesis, and synaptic plasticity [62,68,69,86,70,85] did
reviewed in Ref. [38]. Ab is the major component of
not restrict the observed function to secreted APP, raising
1 – 42
brain amyloid deposits in AD. Consequently, a leading the possibility that some aspects of synaptic plasticity are
hypothesis for the etiology of AD is that increased Ab mediated by cell-associated APP. Indeed, it has now been
1 – 42
is a shared molecular correlate of FAD mutations which demonstrated directly that a percentage of APP is found on
may also be operative in ‘sporadic’ AD. Increases in the cell surface in neurons [47,99,83]. Cell-surface APP
Ab have not been shown directly in human AD brain
possesses a neurite-promoting activity that is distinct from
1 – 42
homogenates, although it is clear that amyloid plaques that of the secreted APP [85], co-localizes with adhesion
contain a disproportionate amount of Ab . Furthermore,
plaque components [99,114], and participates in synaptic
1 – 42
analyses of levels of this peptide in the plasma and vesicle recycling [63], suggesting that a percentage of APP
cerebrospinal fluid CSF of AD patients have revealed no may function as a cell surface receptor, transducing signals
differences between AD patients and controls in the from the extracellular matrix to the interior of the cell.
plasma [43], and a reduction of Ab in the CSF of AD
The growth cone G protein G [75], the presumptive
1 – 42 o
patients relative to controls [67,43]. However, increased adaptor proteins Fe65 and X11 reviewed in Ref. [89],
release of Ab from fibroblasts of AD patients with
and APP-BP1 [10], a protein involved in cell cycle
1 – 42
presenilin mutations, as well as increased levels of regulation [9], have been reported to interact with the
Ab in their plasma, have been demonstrated [94].
C-terminus of APP Fig. 1, presumably to initiate intracel-
1 – 42
The b-secretase cleavage product of APP, C100, is lular signaling. While the functions of Fe65 and X11 are
increased in cell lines expressing the Swedish FAD not known, Fe65 has the characteristics of adaptor pro-
mutation of APP [12–14,8], but not in cell lines expressing teins, which are thought to link signal transduction events
the London V642 mutation of APP [102]. Because neurons emanating from plasma membrane receptors to intracellu-
process APP differently from cell lines, we expressed all lar molecules, by forming complexes of these proteins.
known FAD mutants of APP in primary neurons in culture, Therefore, one could envision APP being part of a G
o
and showed that all caused increases in the intracellular protein-centered complex that transduces extracellular
levels of C100 [66]. We have not yet determined whether signals to the cytoplasm and the nucleus, with Fe65 linking
FAD mutants of PS cause the same alterations in C100 APP to downstream molecules in the pathway, thereby
levels. Although increases of C100 in FAD APP transgenic facilitating direct interactions between the components of
animal models have not been published, at least one such the complex. APP-BP1 could be one of those downstream
model, expressing the V642F mutation numbering accord- molecules. The binding of an additional candidate down-
ing to APP-695 of APP [26], shows a significant increase stream molecule, UV-damaged DNA-binding protein UV-
in C100 in brain homogenates Dale Schenk, Elan Corp; DDB, to APP has been described more recently [110].
personal communication. Furthermore, Russo, Gambetti The molecule whose interaction with APP has been
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
