Cell Science at a Glance 3157

APP at a glance of the APP gene was followed by the Presenilins are also sites of many FAD-
identification of missense mutations associated missense mutations which alter
Michael S. Wolfe1 and Suzanne Y. associated with familial, early-onset AD the ␥-secretase cleavage event to skew
Guénette2 (FAD). These mutations are found in and production towards A␤42. Together, these
1
Center for Neurologic Diseases, Brigham and around the A␤ region of APP, and affect findings strongly supported the hypothesis
Women’s Hospital and Harvard Medical School, the production or aggregation properties that this peptide is indeed a pathogenic
Boston, MA, USA
2
Genetics and Aging Research Unit, MassGeneral of A␤. Those APP mutations near the entity for AD. Besides presenilin, which is
Institute for Neurodegenerative Disease, C-terminal region of the A␤ sequence an unusual intramembranous aspartyl
Charlestown, MA, USA specifically lead to increased proportions protease (Xia and Wolfe, 2003), other
E-mails: mwolfe@[Link];
guenette@[Link]
of the highly aggregation-prone 42- members of the ␥-secretase complex
residue form of A␤ (A␤42). Although include the membrane proteins nicastrin,
Journal of Cell Science 120, 3157-3161 two other APP-like proteins – APLP1 and APH1, and PEN2; this protease complex
Published by The Company of Biologists 2007
doi:10.1242/jcs.03481 APLP2 – are known, the A␤ regions are cuts within the transmembrane domain of
not well conserved, and no FAD APP and determines the length of A␤
mutations have been identified in these peptides. The pepsin-like aspartyl protease
The characteristic cerebral plaques of genes. ␤-secretase sheds the ectodomain of APP,
Alzheimer disease (AD) are primarily releasing the soluble protein sAPP-␤.
composed of an aggregation-prone 39-43- Production of A␤ involves sequential Alternative shedding by metalloproteases
residue peptide called amyloid ␤ (A␤), proteolysis by ␤- and ␥-secretases, the called ␣-secretases (e.g. ADAM17) leads
which is a proteolytic product derived former being a membrane-tethered to proteolysis within the A␤ region and
from the amyloid ␤ precursor protein protease and the latter a membrane- produces a slightly longer soluble protein
(APP), a type I integral membrane protein embedded complex with presenilin as sAPP-␣. After ectodomain shedding, ␥-
(Hardy and Selkoe, 2002). The discovery the catalytic component (Haass, 2004). secretase cuts the remaining membrane-
Journal of Cell Science

APP at a Glance
Michael S. Wolfe and Suzanne Y. Guénette

IDE APP
neprilysin Collagen/laminin
Amyloid APLPs fibronectin N
plaque Signal
F-Spondin

peptide

Aβ APP
Presenilin

sAPP-β
Pen-2 γ Nicastrin

BACE1 C99 Aph

BACE2 Kunitz
protease
KPI inhibitor
-T-

AICD
Ca2+ Cdk5 domain
P

GSK3β
-Y-

JNK1
IDE
P

Shc
Src/Abl Grb2
ER PAK3
Secretase
cleavage
sites

Go Transmembrane
region
Cytoxicity
MAPK APP-BP1
Caspase
Signaling? Other effects NOGO-6/reelin/SorLA
cleavage

Golgi
Cell Cycle
C
Endosome ApoER2
γ
Dab1

Other APP-
interacting
sAPP-α proteins
p3 AICD X11
Lysosome LICD LRP JIP-1, JIP-2
γ
FE65

γ C83
FE65
Tip FE65
PAT1, PAT1a
Kinesin 1
IDE 60 ARH
PKC
APP Numb Pin1/FKB12
FE65
γ
NOTCH
Tip NICD
60 NICD
ADAM10
ADAM17 (TACE) Nucleus ? Hes-1 Numb

Abbreviations: Aβ, amyloid β peptide; AICD, APP intracellular domain; APLP, APP-like protein; APP, amyloid precursor protein; ARH, autosomal recessive hypercholasteremia protein; APP-BP1, APP-binding protein 1;
sAPP-α, α-secretase-derived secreted APP; sAPP-β, β-secretase-derived secreted APP; BACE, β-site APP-cleaving enzyme or β-secretase; C83, 83-residue APP C-terminal fragment; C99, 99-residue APP C-terminal fragment; © Journal of Cell Science 2007 (120, pp. 3157-3161)
IDE, insulin-degrading enzyme; JIP, JNK-interacting protein; LICD, LRP intracellular domain; LRP, low-density lipoprotein-receptor-related protein; NICD, notch intracellular domain; TACE, tumor necrosis factor-α converting enzyme.

(See poster insert)

bound stub to release the APP intracellular knockout or APP-APLP1-APLP2 triple APP as a putative receptor
domain (AICD) as well as either A␤ (via knockout result in loss of viability. APP- The idea that APP functions as a receptor
the ␤-secretase pathway) or the N- APLP2 double knockout mice have a was bolstered by the discovery that
terminally truncated peptide p3 (via the ␣- neuromuscular junction defect (Wang et the Notch receptor signals through
secretase pathway). A␤ in turn can be al., 2005), whereas the triple knockout has proteolytic processing that is remarkably
degraded by proteases such as the insulin- neuronal ectopias resembling type II similar to that of APP (Annaert and De
degrading enzyme (IDE) (Farris et al., lissencephaly (Herms et al., 2004). These Strooper, 1999; Selkoe and Kopan, 2003).
2003) and neprilysin (Iwata et al., 2001). findings demonstrated the importance of Notch is essential for many differentiation
the APP family in development, and events during development and
Despite advances in our understanding suggest functional redundancy consistent adulthood. Signaling is initiated by
of the role of APP processing in AD, the with a role in neuronal cell adhesion and interaction with cognate ligands, which
normal physiological function of this migration. Interestingly, knocking out triggers shedding of the Notch
protein has proven more difficult to Fe65, an intracellular APP-interacting ectodomain by ADAM10 and ADAM17.
elucidate (De Strooper and Annaert, protein, in worms (Zambrano et al., 2002) These metalloproteases also shed the
2000). Initial reports speculated that the or the combined FE65-FE65L1 knockout ectodomain of APP through the ␣-
protein is a cell-surface receptor (Kang in mice (Guénette et al., 2006) results in secretase pathway (Buxbaum et al., 1998;
et al., 1987). The discovery of interacting phenotypes strikingly similar to those Lammich et al., 1999). Interestingly, the
proteins, genetic studies in animals, and seen when APP genes are knocked out. ADAM17-mediated shedding of APP can
gene expression profiling have since led This suggests that these proteins are be stimulated by phorbol esters and other
to the identification of putative pathways functionally as well as physically means of activating protein kinase C
for the APP family associated with connected (see below). (Buxbaum et al., 1993).
cellular and developmental changes.
APP-transgenic animals provide further The membrane-associated stub of Notch
clues to potential physiological roles. that remains is then cut by ␥-secretase
Journal of Cell Science

Knockouts, knockdowns and Overexpression of APP family members (De Strooper et al., 1999), releasing an
transgenics in Drosophila affects development of the intracellular domain that translocates to
Clues to physiological functions of the peripheral nervous system, and genetic the nucleus and interacts with certain
APP family mentioned above come analyses indicate Notch gain-of-function transcription factors to control gene
from knockout phenotypes in different phenotypes may be due to interaction of expression and cell fate. Thus, the
organisms. Loss of one copy of the APP APP with Numb, a negative regulator of thinking was that APP may likewise
orthologue APL-1 in Caenorhabditis Notch signaling (Merdes et al., 2004). have extracellular ligands and that the
elegans leads to pharyngeal pumping Other reports suggest that APP and intracellular domain (AICD) might
defects (Zambrano et al., 2002), while Notch interact directly through their translocate to the nucleus (Cupers et
loss of both copies leads to larval transmembrane domains (Chen et al., al., 2001) and interact with factors
lethality (Hornsten et al., 2007; 2006; Fassa et al., 2005; Oh et al., 2005). regulating the expression of certain
Zambrano et al., 2002). This lethality can Transgenic APP flies also show genes. Alternatively, APP proteolysis
be rescued by pan-neuronal expression increased axonal arborization, which may be a mechanism for turning off
of the apl-1 ectodomain, which indicates critically depends on the cytosolic normal APP functions. In this regard, the
that APP plays a non-cell-autonomous domain and its interaction with Abl proteases are simply degradative, a
role in development (Horsten et al., kinase (Leyssen et al., 2005). concept that is especially true for ␥-
2007). In Drosophila, deletion of the secretase, which cleaves many type I
single APP-like gene (Appl) results in Brain injury induces APP expression, integral membrane proteins and has even
only subtle behavioral defects that can be which suggests that APP plays a repair been likened to a proteasome of the
rescued by wild-type but not mutant role in this context. The correlation of AD membrane (Kopan and Ilagan, 2004).
APPL or APP (Luo et al., 1992), but a with head trauma may reflect an increase
later study suggested that deletion and in APP expression, with A␤ generation The search for APP ligands has not been
mutation affects kinesin-mediated being an unfortunate epiphenomenon. especially fruitful. F-spondin, a secreted
axonal transport and neuronal viability APP-transgenic mice have been generated neuronal protein purportedly involved in
(Gunawardena and Goldstein, 2001). in the hope of reproducing the A␤- cell-cell interactions, was identified by
containing plaques of AD and testing affinity isolation, and coexpression of this
In mice, single knockouts of APP gene therapeutic candidates. A recent report protein prevents shedding of the APP
family members are viable. However, shows that pathological, physiological ectodomain by ␤-secretase and reduces
APP knockout mice display several and behavioral deficits in APP-transgenic A␤ production (Ho and Sudhof, 2004).
phenotypes, which include impairment mice are not seen in those with a mutation However, it is unclear whether soluble F-
in spatial learning and long-term at a caspase-cleavage site in the spondin added to cultures has the same
potentiation (LTP). These deficits can be intracellular domain (Galvan et al., 2006) effect, or whether the F-spondin–APP
rescued by a knock-in allele of sAPP-␣, and yet still produce A␤ and amyloid interaction occurs when the two proteins
indicating that the ectodomain of APP is deposits. This suggests a role for the APP are expressed in different cells. Reelin, an
sufficient for APP function in the adult intracellular domain and possibly for the extracellular matrix protein essential for
brain (Ring et al., 2007). By contrast, the caspase-released cytosolic tail in the cortical development that shares
APP-APLP2 and APLP1-APLP2 double pathogenesis of AD. homology with F-spondin, was shown to
 Journal of Cell Science 120 (18) 3159

increase binding of the reelin signaling are known to play a role in vesicular or JIP-2 binds to phosphorylated and
mediator Dab1 to APP (Hoe et al., protein trafficking: X11 (Mint1) and unphosphorylated APP equally well
2006b). Furthermore, fewer reelin- X11L (Mint2) involved in vesicle (Muresan and Muresan, 2005). A Glu
expressing pyramidal neurons are exocytosis; Jun N-terminal-kinase- substitution at Thr668, mimicking
observed in the entorhinal cortex of APP- interacting protein 1 (JIP-1), a scaffold phosphorylation, destabilizes the Fe65-
transgenic mice and AD brains (Chin protein that binds kinesin light chain 1 APP interaction (Ando et al., 2001),
et al., 2007). The Nogo-66 receptor, and coordinates transport of whereas Tyr682 phosphorylation
implicated in axonal sprouting in the adult phosphorylated APP into neurites; facilitates binding of Shc and Grb2 to
CNS, has also been reported to interact kinesin 1; Pat1a, a microtubule- APP (Russo et al., 2005).
with the APP ectodomain and inhibit A␤ interacting protein that plays a role in
production (Park et al., 2006). LRP and anterograde transport of APP and A recent study shows binding of the APP
SORL1 (SorLA, LR11) also bind to the APLPs; and autosomal recessive tail to hARD1, an acetylase subunit, but
APP ectodomain and influence A␤ hypercholesteremia (ARH) protein, an modification of the APP tail by this
production (Andersen et al., 2005; Bu et adaptor protein involved in the acetylase has not been examined
al., 2006). Indirect triggering of ␤- and ␥- internalization of LDL receptors (Kamal (Asaumi et al., 2005). In addition, prolyl
secretase cleavage of APP has been et al., 2000; King et al., 2004; Kuan et isomerases, Pin1 and FKBP12, bind to
reported for platelet-derived growth factor al., 2006; Muresan and Muresan, 2005; the APP C-terminus. Pin1 binds Thr668
and certain cytokines (Gianni et al., 2003; Zheng et al., 1998; Noviello et al., 2003). phosphorylated APP and accelerates its
Liao et al., 2004), and as mentioned isomerization (Pastorino et al., 2006).
above, activation of protein kinase C leads APP-binding proteins are also involved There are numerous reports addressing
to APP proteolysis through the ␣- in brain development: the Fe65 proteins the impact of APP-binding proteins on
secretase pathway (Buxbaum et al., transmit an APP-dependent signal APP proteolysis and A␤ generation
1993). important for neuronal positioning in the (Russo et al., 2005). In the case of Fe65
developing cortex; mDab1 plays a key and Dab1, the effects are cell type
Journal of Cell Science

sAPP released from the membrane may role in reelin signaling in the developing dependent, possibly owing to the
serve as a signaling molecule. Evidence cortex; and Numb is a scaffold protein existing complement of competing
suggests that the shed ectodomain plays important for Notch signaling (Guénette cellular APP-binding proteins in each
a role in the growth of fibroblasts in et al., 2006; Hoe et al., 2006b; Roncarati cell type (Hoe et al., 2006a; Hoe et al.,
culture (Park et al., 2006). sAPP was et al., 2002). Other APP-tail-binding 2006b; Parisiadou and Efthimiopoulos,
found to be neuroprotective for primary proteins are implicated in regulating cell 2007). In addition, tripartite complexes
neurons in culture, preventing elevations cycle progression; these include Go, involving APP-binding proteins, APP
in intracellular Ca2+ levels caused by PAK3, APP-BP1 (Chen et al., 2007; and other molecules, such as alcadein-
glucose deprivation and raising the Chen et al., 2003; Giambarella et al., X11L-APP and LRP-Fe65-APP, have
excitotoxic threshold of glutamate 1997; McPhie et al., 2003). In the case been shown to influence A␤ generation
(Mattson et al., 1993), as well as of Go and PAK3, this has been associated (Araki et al., 2004; Yoon et al., 2005).
mediating axonal and dendritic growth with FAD-linked APP mutations.
(Perez et al., 1997). Interaction of the APP tail with Shc and The APP-interacting protein that has
Grb2 is thought to lead to signaling generated the most interest is Fe65,
APP may also serve as an adhesion through the Ras-Raf-MAPK pathway, because a ternary complex consisting
molecule: it binds to extracellular matrix and APP-Shc-Grb2 complexes have of Fe65, APP and the histone
proteins such as heparin and collagen been reported to be increased in AD acetyltransferase Tip60 has been shown to
(Beher et al., 1996; Multhaup, 1994). patients (Russo et al., 2005). activate transcription (Baek et al., 2002;
Homo- and heterodimerization between Cao and Sudhof, 2001; Cao and Sudhof,
the APP family members in adjacent The APP C-terminus is a substrate for 2004). Most of the evidence supporting a
cells has also been suggested to promote several enzymes. Proteolysis by the ␥- role for an APP-Fe65-Tip60 complex in
intercellular adhesion (Soba et al., 2005). secretase complex occurs within the 99- transcriptional activation comes from
Such a mechanism would be analogous residue C-terminal tail of APP, and studies using an artificial reporter system
to that of known cell adhesion molecules binding to presenilins by this APP stub in cells overexpressing APP or AICD.
such as cadherins and nectins. APP and has been demonstrated. Phosphorylation Although AICD is rapidly degraded by
Fe65 have been reported to influence cell of the intracellular tail is mediated by IDE (Edbauer et al., 2002), it can be
motility, and several regulators of actin several kinases. These include the detected in primary neurons during
dynamics were recently found to be Ser/Thr kinases JNK, CDK5, GSK-3␤, differentiation in culture (Kimberly et al.,
regulated by AICD (Guénette et al., which phosphorylate Thr668, and the 2005). Nuclear translocation of Fe65 is
2006; Muller et al., 2007; Sabo et al., non-receptor tyrosine kinases Abl and required for transactivation, and ␥-
2001; Sabo et al., 2003). Src, and nerve growth factor tyrosine- secretase-mediated cleavage of APP can
kinase receptor A (TrkA), which facilitate this event. However, one
phosphorylate Tyr682 (Russo et al., report shows APP-Fe65-Tip60 signaling
Intracellular interactors 2005). Phosphorylation has been shown occurring independently of ␥-secretase
Numerous proteins that interact with the to regulate which proteins bind to the cleavage (Hass and Yankner, 2005).
intracellular tail of APP have been APP tail. JNK phosphorylation leads to Moreover, Fe65-GAL4 expression alone
identified. These include proteins that preferential binding to JIP-1, whereas was recently shown to mediate
 3160 Journal of Cell Science 120 (18)

transcriptional activation of the reporter, memory (Ring et. al. 2007; Ma et al. through complex formation between the estrogen receptor
and Fe65. Mol. Cell. Biol. 27, 1321-1333.
which could be partly blocked by 2007). Beher, D., Hesse, L., Masters, C. L. and Multhaup, G.
knocking down APP or overexpressing (1996). Regulation of amyloid protein precursor (APP)
Tip60 (Yang et al., 2006). binding to collagen and mapping of the binding sites on
APP and collagen type I. J. Biol. Chem. 271, 1613-1620.
Conclusions Bu, G., Cam, J. and Zerbinatti, C. (2006). LRP in
Intracellular and extracellular factors Our understanding of the normal amyloid-beta production and metabolism. Ann. N. Y. Acad.
Sci. 1086, 35-53.
that regulate Fe65-APP-dependent functions of APP remains limited. This Buxbaum, J. D., Koo, E. H. and Greengard, P. (1993)
transactivation have also been identified. integral membrane protein is reminiscent Protein phosphorylation inhibits production of Alzheimer
14-3-3␥ can bind both APP and Fe65 of a receptor and is processed in a manner amyloid beta/A4 peptide. Proc. Natl. Acad. Sci. USA. 90,
9195-9198.
and facilitate transcriptional activation closely similar to the Notch family of Buxbaum, J. D., Liu, K. N., Luo, Y., Slack, J. L.,
(Sumioka et al., 2005). 17-␤ estradiol receptors. Certain factors can indirectly Stocking, K. L., Peschon, J. J., Johnson, R. S., Castner,
was reported to repress transcriptional trigger APP proteolysis; however, no B. J., Cerretti, D. P. and Black, R. A. (1998). Evidence
that tumor necrosis factor ␣ converting enzyme is involved
activation through sequestration of Fe65 extracellular ligand for APP has been in regulated ␣-secretase cleavage of the Alzheimer’s
away from the Cd82 (KAI-1) promoter identified, and no downstream target amyloid protein precursor. J. Biol. Chem. 273, 27765-
through increased binding of estrogen 27767.
genes have been confirmed. Some Cao, X. and Sudhof, T. C. (2001). A transcriptionally
receptor ␣ and Fe65 (Bao et al., 2007). proteins that interact with the ectodomain active complex of APP with Fe65 and histone
Candidate AICD-target genes have been portion of APP can inhibit proteolysis, acetyltransferase Tip60. Science 293, 115-120.
suggested (e.g. tetraspanin CD82, APP, Cao, X. and Sudhof, T. C. (2004). Dissection of APP-
whereas the identities of others suggest dependent transcriptional transactivation. J. Biol. Chem.
GSK3␤ and neprilysin), although one APP functions as an adhesion molecule. 279, 24601-24611.
report provides evidence that the Dimerization within the APP family may Chen, C. D., Oh, S. Y., Hinman, J. D. and Abraham, C.
expression of none of these is ␥-secretase mediate an adhesion role, whereas
R. (2006). Visualization of APP dimerization and APP-
Notch2 heterodimerization in living cells using bimolecular
dependent and that Fe65 has a weak interaction with the Notch pathway may fluorescence complementation. J. Neurochem. 97, 30-43.
stimulating effect on various promoters modulate Notch signaling. Evidence for
Chen, Y., Liu, W., McPhie, D. L., Hassinger, L. and
Neve, R. L. (2003). APP-BP1 mediates APP-induced
(Hebert et al., 2006). Several novel AICD- an APP signaling function comes from apoptosis and DNA synthesis and is increased in
Journal of Cell Science

regulated candidate genes have been studies with Fe65 and Tip60 and with Alzheimer’s disease brain. J. Cell Biol. 163, 27-33.
identified as regulators of actin dynamics; Chen, Y., Bodles, A. M., McPhie, D. L., Neve, R. L.,
proteins that play a role in established Mrak, R. E. and Griffin, W. S. (2007). APP-BP1 inhibits
however, a direct association of Fe65 or signal transduction pathways. Kinases Abeta42 levels by interacting with Presenilin-1. Mol.
AICD with their promoters remains to be may play a key role in regulating the Neurodegener. 2, 3.
demonstrated (Muller et al., 2007). Thus, Chin, J., Massaro, C. M., Palop, J. J., Thwin, M. T., Yu,
stability of APP, its interaction with G. Q., Bien-Ly, N., Bender, A. and Mucke, L. (2007).
although the APP-Fe65 interaction is intracellular partners and downstream Reelin depletion in the entorhinal cortex of human amyloid
probably physiological, the identity of signaling events. Much work needs to be
precursor protein transgenic mice and humans with
Alzheimer’s disease. J. Neurosci. 27, 2727-2733.
downstream effectors remains unclear. In done to close the large gaps in our Cupers, P., Orlans, I., Craessaerts, K., Annaert, W. and
a very recent study, the EGFR promoter De Strooper, B. (2001). The amyloid precursor protein
knowledge about APP biology.
was identified as a target for AICD and (APP)-cytoplasmic fragment generated by gamma-
secretase is rapidly degraded but distributes partially in a
FE65 in mouse brain and embryonic nuclear fraction of neurones in culture. J. Neurochem. 78,
fibroblasts. Binding of AICD and FE65 to 1168-1178.
References
the EGFR promoter represses EGFR Andersen, O. M., Reiche, J., Schmidt, V., Gotthardt, M.,
De Strooper, B. and Annaert, W. (2000). Proteolytic
processing and cell biological functions of the amyloid
transcription (Zhang et al., 2007). Spoelgen, R., Behlke, J., von Arnim, C. A., Breiderhoff, precursor protein. J. Cell Sci. 113, 1857-1870.
T., Jansen, P., Wu, X. et al. (2005). Neuronal sorting De Strooper, B., Annaert, W., Cupers, P., Saftig, P.,
protein-related receptor sorLA/LR11 regulates processing Craessaerts, K., Mumm, J. S., Schroeter, E. H.,
AICD has also been implicated in of the amyloid precursor protein. Proc. Natl. Acad. Sci. Schrijvers, V., Wolfe, M. S., Ray, W. J. et al. (1999). A
regulating phosphoinositide-mediated USA 102, 13461-13466. presenilin-1-dependent ␥-secretase-like protease mediates
Ca2+ signaling (Leissring et al., 2002). Ando, K., Iijima, K. I., Elliott, J. I., Kirino, Y. and
Suzuki, T. (2001). Phosphorylation-dependent regulation
release of Notch intracellular domain. Nature 398, 518-522.
Presenilin and ␥-secretase activity were of the interaction of amyloid precursor protein with Fe65
Edbauer, D., Willem, M., Lammich, S., Steiner, H. and
Haass, C. (2002). Insulin-degrading enzyme rapidly
crucial to this process, which involves affects the production of beta-amyloid. J. Biol. Chem. 276, removes the beta-amyloid precursor protein intracellular
release of endoplasmic reticulum Ca2+ 40353-40361.
Annaert, W. and De Strooper, B. (1999). Presenilins:
domain (AICD). J. Biol. Chem. 277, 13389-13393.
Farris, W., Mansourian, S., Chang, Y., Lindsley, L.,
stores. Cells lacking APP show deficits molecular switches between proteolysis and signal Eckman, E. A., Frosch, M. P., Eckman, C. B., Tanzi, R.
in Ca2+ signaling that can be rescued by transduction. Trends Neurosci. 22, 439-443. E., Selkoe, D. J. and Guénette, S. (2003). Insulin-
Araki, Y., Miyagi, N., Kato, N., Yoshida, T., Wada, S.,
constructs containing the AICD region, Nishimura, M., Komano, H., Yamamoto, T., De
degrading enzyme regulates the levels of insulin, amyloid
beta-protein, and the beta-amyloid precursor protein
including AICD alone, but not by Strooper, B., Yamamoto, K. et al. (2004). Coordinated intracellular domain in vivo. Proc. Natl. Acad. Sci. USA
constructs lacking this domain. The in metabolism of Alcadein and amyloid beta-protein 100, 4162-4167.
precursor regulates FE65-dependent gene transactivation.
vivo relevance of this cellular effect of J. Biol. Chem. 279, 24343-24354.
Fassa, A., Mehta, P. and Efthimiopoulos, S. (2005).
Notch 1 interacts with the amyloid precursor protein in a
APP is unknown. However, a recent Asaumi, M., Iijima, K., Sumioka, A., Iijima-Ando, K., Numb-independent manner. J. Neurosci. Res. 82, 214-224.
report showed that AICD is the only APP Kirino, Y., Nakaya, T. and Suzuki, T. (2005). Interaction Galvan, V., Gorostiza, O. F., Banwait, S., Ataie, M.,
of N-terminal acetyltransferase with the cytoplasmic Logvinova, A. V., Sitaraman, S., Carlson, E., Sagi, S. A.,
proteolytic product that correlates with domain of beta-amyloid precursor protein and its effect on Chevallier, N., Jin, K. et al. (2006). Reversal of
enhanced spatial memory in mice A beta secretion. J. Biochem. 137, 147-155. Alzheimer’s-like pathology and behavior in human APP
overproducing wild-type human APP. Baek, S. H., Ohgi, K. A., Rose, D. W., Koo, E. H., Glass, transgenic mice by mutation of Asp664. Proc. Natl. Acad.
C. K. and Rosenfeld, M. G. (2002). Exchange of N-CoR Sci. USA 103, 7130-7135.
The findings of Ring et. al. (2007) show corepressor and Tip60 coactivator complexes links gene Giambarella, U., Yamatsuji, T., Okamoto, T., Matsui, T.,
that sAPP-␣ is essential for spatial expression by NF-kappaB and beta-amyloid precursor Ikezu, T., Murayama, Y., Levine, M. A., Katz, A.,
learning and those of Ma et al. (2007) protein. Cell 110, 55-67. Gautam, N. and Nishimoto, I. (1997). G protein
Bao, J., Cao, C., Zhang, X., Jiang, F., Nicosia, S. V. and betagamma complex-mediated apoptosis by familial
suggest that AICD may, in the presence Bai, W. (2007). Suppression of beta-amyloid precursor Alzheimer’s disease mutant of APP. EMBO J. 16, 4897-
of the APP ectodomain, enhance spatial protein signaling into the nucleus by estrogens mediated 4907.
 Journal of Cell Science 120 (18) 3161

Gianni, D., Zambrano, N., Bimonte, M., Minopoli, G., (1999). Constitutive and regulated alpha-secretase cleavage Alzheimer’s disease enhances neuron viability and
Mercken, L., Talamo, F., Scaloni, A. and Russo, T. of Alzheimer’s amyloid precursor protein by a disintegrin modulates neuronal polarity. J. Neurosci. 17, 9407-9414.
(2003). Platelet-derived growth factor induces the beta- metalloprotease. Proc. Natl. Acad. Sci. USA 96, 3922-3927. Ring, S., Weyer, S. W., Kilian, S. B., Waldron, E.,
gamma-secretase-mediated cleavage of Alzheimer’s Leissring, M. A., Murphy, M. P., Mead, T. R., Akbari, Pietrzik, C. U., Filippov, M. A., Herms, J., Buchholz, C.,
amyloid precursor protein through a Src-Rac-dependent Y., Sugarman, M. C., Jannatipour, M., Anliker, B., Eckman, C. B., Korte, M., et al. (2007) The secreted beta-
pathway. J. Biol. Chem. 278, 9290-9297. Muller, U., Saftig, P., De Strooper, B. et al. (2002). A amyloid precursor protein ectodomain APPs alpha is
Guénette, S., Chang, Y., Hiesberger, T., Richardson, J. physiologic signaling role for the gamma-secretase-derived sufficient to rescue the anatomical, behavioral, and
A., Eckman, C. B., Eckman, E. A., Hammer, R. E. and intracellular fragment of APP. Proc. Natl. Acad. Sci. USA electrophysiological abnormalities of APP-deficient mice.
Herz, J. (2006). Essential roles for the FE65 amyloid 99, 4697-4702. J. Neurosci. 27, 7817-26.
precursor protein-interacting proteins in brain Leyssen, M., Ayaz, D., Hebert, S. S., Reeve, S., De Roncarati, R., Sestan, N., Scheinfeld, M. H., Berechid,
development. EMBO J. 25, 420-431. Strooper, B. and Hassan, B. A. (2005). Amyloid B. E., Lopez, P. A., Meucci, O., McGlade, J. C., Rakic,
Gunawardena, S. and Goldstein, L. S. (2001). Disruption precursor protein promotes post-developmental neurite P. and D’Adamio, L. (2002). The gamma-secretase-
of axonal transport and neuronal viability by amyloid arborization in the Drosophila brain. EMBO J. 24, 2944- generated intracellular domain of beta-amyloid precursor
precursor protein mutations in Drosophila. Neuron 32, 389- 2955. protein binds Numb and inhibits Notch signaling. Proc.
401. Liao, Y. F., Wang, B. J., Cheng, H. T., Kuo, L. H. and Natl. Acad. Sci. USA 99, 7102-7107.
Haass, C. (2004). Take five – BACE and the gamma- Wolfe, M. S. (2004). Tumor necrosis factor-{alpha}, Russo, C., Venezia, V., Repetto, E., Nizzari, M., Violani,
secretase quartet conduct Alzheimer’s amyloid beta- interleukin-1{beta}, and interferon-{gamma} stimulate E., Carlo, P. and Schettini, G. (2005). The amyloid
peptide generation. EMBO J. 23, 483-488. {gamma}-secretase-mediated cleavage of amyloid precursor protein and its network of interacting proteins:
Hardy, J. and Selkoe, D. J. (2002). The amyloid precursor protein through a JNK-dependent MAPK physiological and pathological implications. Brain Res.
hypothesis of Alzheimer’s disease: progress and problems pathway. J. Biol. Chem. 279, 49523-49532. Brain Res. Rev. 48, 257-264.
on the road to therapeutics. Science 297, 353-356. Luo, L., Tully, T. and White, K. (1992). Human amyloid Sabo, S. L., Ikin, A. F., Buxbaum, J. D. and Greengard,
Hass, M. R. and Yankner, B. A. (2005). A {gamma}- precursor protein ameliorates behavioral deficit of flies P. (2001). The Alzheimer amyloid precursor protein (APP)
secretase-independent mechanism of signal transduction by deleted for Appl gene. Neuron 9, 595-605. and FE65, an APP-binding protein, regulate cell
the amyloid precursor protein. J. Biol. Chem. 280, 36895- Ma, H., Lesne, S., Kotilinek, L., Steidl-Nichols, J. V., movement. J. Cell Biol. 153, 1403-1414.
36904. Sherman, M., Younkin, L., Younkin, S., Forster, C., Sabo, S. L., Ikin, A. F., Buxbaum, J. D. and Greengard,
Hebert, S. S., Serneels, L., Tolia, A., Craessaerts, K., Sergeant, N., Delacourte, A. et al. (2007). Involvement of P. (2003). The amyloid precursor protein and its regulatory
Derks, C., Filippov, M. A., Muller, U. and De Strooper, beta-site APP cleaving enzyme 1 (BACE1) in amyloid protein, FE65, in growth cones and synapses in vitro and
B. (2006). Regulated intramembrane proteolysis of precursor protein-mediated enhancement of memory and in vivo. J. Neurosci. 23, 5407-5415.
amyloid precursor protein and regulation of expression of activity-dependent synaptic plasticity. Proc. Natl. Acad. Selkoe, D. and Kopan, R. (2003). Notch and Presenilin:
putative target genes. EMBO Rep. 7, 739-745. Sci. USA 104, 8167-8172. regulated intramembrane proteolysis links development
Herms, J., Anliker, B., Heber, S., Ring, S., Fuhrmann, Mattson, M. P., Cheng, B., Culwell, A. R., Esch, F. S., and degeneration. Annu. Rev. Neurosci. 26, 565-597.
M., Kretzschmar, H., Sisodia, S. and Muller, U. (2004). Lieberburg, I. and Rydel, R. E. (1993). Evidence for Soba, P., Eggert, S., Wagner, K., Zentgraf, H., Siehl, K.,
Cortical dysplasia resembling human type 2 lissencephaly excitoprotective and intraneuronal calcium-regulating roles Kreger, S., Lower, A., Langer, A., Merdes, G., Paro, R.
Journal of Cell Science

in mice lacking all three APP family members. EMBO J. for secreted forms of the beta-amyloid precursor protein. et al. (2005). Homo- and heterodimerization of APP family
23, 4106-4115. Neuron 10, 243-254. members promotes intercellular adhesion. EMBO J. 24,
Ho, A. and Sudhof, T. C. (2004). Binding of F-spondin to McPhie, D. L., Coopersmith, R., Hines-Peralta, A., 3624-3634.
amyloid-{beta} precursor protein: a candidate amyloid- Chen, Y., Ivins, K. J., Manly, S. P., Kozlowski, M. R., Sumioka, A., Nagaishi, S., Yoshida, T., Lin, A., Miura,
{beta} precursor protein ligand that modulates amyloid- Neve, K. A. and Neve, R. L. (2003). DNA synthesis and M. and Suzuki, T. (2005). Role of 14-3-3gamma in FE65-
{beta} precursor protein cleavage. Proc. Natl. Acad. Sci. neuronal apoptosis caused by familial Alzheimer disease dependent gene transactivation mediated by the amyloid
USA 101, 2548-2553. mutants of the amyloid precursor protein are mediated by beta-protein precursor cytoplasmic fragment. J. Biol.
Hoe, H. S., Magill, L. A., Guénette, S., Fu, Z., Vicini, S. the p21 activated kinase PAK3. J. Neurosci. 23, 6914-6927. Chem. 280, 42364-42374.
and Rebeck, G. W. (2006a). FE65 interaction with the Merdes, G., Soba, P., Loewer, A., Bilic, M. V., Wang, P., Yang, G., Mosier, D. R., Chang, P., Zaidi, T.,
ApoE receptor ApoEr2. J. Biol. Chem. 281, 24521-24530. Beyreuther, K. and Paro, R. (2004). Interference of Gong, Y. D., Zhao, N. M., Dominguez, B., Lee, K. F.,
Hoe, H. S., Tran, T. S., Matsuoka, Y., Howell, B. W. and human and Drosophila APP and APP-like proteins with Gan, W. B. et al. (2005). Defective neuromuscular
Rebeck, G. W. (2006b). DAB1 and Reelin effects on PNS development in Drosophila. EMBO J. 23, 4082-4095. synapses in mice lacking amyloid precursor protein (APP)
amyloid precursor protein and ApoE receptor 2 trafficking Muller, T., Concannon, C. G., Ward, M. W., Walsh, C. and APP-Like protein 2. J. Neurosci. 25, 1219-1225.
and processing. J. Biol. Chem. 281, 35176-35185. M., Tirniceriu, A. L., Tribl, F., Kogel, D., Prehn, J. H. Xia, W. and Wolfe, M. S. (2003). Intramembrane
Hornsten, A., Lieberthal, J., Fadia, S., Malins, R., Ha, and Egensperger, R. (2007). Modulation of gene proteolysis by presenilin and presenilin-like proteases. J.
L., Xu, X., Daigle, I., Markowitz, M., O’Connor, G., expression and cytoskeletal dynamics by the amyloid Cell Sci. 116, 2839-2844.
Plasterk, R. et al. (2007). APL-1, a Caenorhabditis elegans precursor protein intracellular domain (AICD). Mol. Biol. Yang, Z., Cool, B. H., Martin, G. M. and Hu, Q. (2006).
protein related to the human beta-amyloid precursor Cell 18, 201-210. A dominant role for FE65 (APBB1) in nuclear signaling.
protein, is essential for viability. Proc. Natl. Acad. Sci. USA Multhaup, G. (1994). Identification and regulation of the J. Biol. Chem. 281, 4207-4214.
104, 1971-1976. high affinity binding site of the Alzheimer’s disease Yoon, I. S., Pietrzik, C. U., Kang, D. E. and Koo, E. H.
Iwata, N., Tsubuki, S., Takaki, Y., Shirotani, K., Lu, B., amyloid protein precursor (APP) to glycosaminoglycans. (2005). Sequences from the low density lipoprotein
Gerard, N. P., Gerard, C., Hama, E., Lee, H. J. and Biochimie 76, 304-311. receptor-related protein (LRP) cytoplasmic domain enhance
Saido, T. C. (2001). Metabolic regulation of brain abeta by Muresan, Z. and Muresan, V. (2005). Coordinated amyloid beta protein production via the beta-secretase
neprilysin. Science 292, 1550-1552. transport of phosphorylated amyloid-beta precursor protein pathway without altering amyloid precursor protein/LRP
Kamal, A., Stokin, G. B., Yang, Z., Xia, C. H. and and c-Jun NH2-terminal kinase-interacting protein-1. J. nuclear signaling. J. Biol. Chem. 280, 20140-20147.
Goldstein, L. S. (2000). Axonal transport of amyloid Cell Biol. 171, 615-625. Zambrano, N., Bimonte, M., Arbucci, S., Gianni, D.,
precursor protein is mediated by direct binding to the Noviello, C., Vito, P., Lopez, P., Abdallah, M. and Russo, T. and Bazzicalupo, P. (2002). feh-1 and apl-1, the
kinesin light chain subunit of kinesin-I. Neuron 28, 449-459. D’Adamio, L. (2003) Autosomal recessive Caenorhabditis elegans orthologues of mammalian Fe65
Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. hypercholesterolemia protein interacts with and regulates and beta-amyloid precursor protein genes, are involved in
M., Masters, C. L., Grzeschik, K. H., Multhaup, G., the cell surface level of Alzheimer's amyloid beta precursor the same pathway that controls nematode pharyngeal
Beyreuther, K. and Muller-Hill, B. (1987). The precursor protein. J. Biol. Chem. 278, 31843-31847. pumping. J. Cell Sci. 115, 1411-1422.
of Alzheimer’s disease amyloid A4 protein resembles a Oh, S. Y., Ellenstein, A., Chen, C. D., Hinman, J. D., Zhang, Y. W., Wang, R., Liu, Q., Zhang, H., Liao, F. F.
cell-surface receptor. Nature 325, 733-736. Berg, E. A., Costello, C. E., Yamin, R., Neve, R. L. and and Xu, H. (2007) Presenilin/gamma-secretase-dependent
Kimberly, W. T., Zheng, J. B., Town, T., Flavell, R. A. Abraham, C. R. (2005). Amyloid precursor protein processing of beta-amyloid precursor protein regulates
and Selkoe, D. J. (2005). Physiological regulation of the interacts with notch receptors. J. Neurosci. Res. 82, 32-42. EGF receptor expression. Proc. Natl. Acad. Sci. USA. 104,
beta-amyloid precursor protein signaling domain by c-Jun Parisiadou, L. and Efthimiopoulos, S. (2007). 10613-10618.
N-terminal kinase JNK3 during neuronal differentiation. J. Expression of mDab1 promotes the stability and processing Zheng, P., Eastman, J., Vande Pol, S. and Pimplikar, S.
Neurosci. 25, 5533-5543. of amyloid precursor protein and this effect is counteracted W. (1998). PAT1, a microtubule-interacting protein,
King, G. D., Cherian, K. and Turner, R. S. (2004). by X11alpha. Neurobiol. Aging 28, 377-388. recognizes the basolateral sorting signal of amyloid
X11alpha impairs gamma- but not beta-cleavage of Park, J. H., Gimbel, D. A., GrandPre, T., Lee, J. K., precursor protein. Proc. Natl. Acad. Sci. USA 95, 14745-
amyloid precursor protein. J. Neurochem. 88, 971-982. Kim, J. E., Li, W., Lee, D. H. and Strittmatter, S. M. 14750.
Kopan, R. and Ilagan, M. X. (2004). Gamma-secretase: (2006). Alzheimer precursor protein interaction with the
proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 5, Nogo-66 receptor reduces amyloid-beta plaque deposition.
499-504. J. Neurosci. 26, 1386-1395.
Kuan, Y. H., Gruebl, T., Soba, P., Eggert, S., Nesic, I., Pastorino, L., Sun, A., Lu, P. J., Zhou, X. Z., Balastik, Cell Science at a Glance on the Web
Back, S., Kirsch, J., Beyreuther, K. and Kins, S. (2006). M., Finn, G., Wulf, G., Lim, J., Li, S. H., Li, X. et al. Electronic copies of the poster insert are
PAT1a modulates intracellular transport and processing of (2006). The prolyl isomerase Pin1 regulates amyloid available in the online version of this article
amyloid precursor protein (APP), APLP1, and APLP2. J. precursor protein processing and amyloid-beta production. at [Link]. The JPEG images can
Biol. Chem. 281, 40114-40123. Nature 440, 528-534. be downloaded for printing or used as
Lammich, S., Kojro, E., Postina, R., Gilbert, S., Pfeiffer, Perez, R. G., Zheng, H., Van der Ploeg, L. H. and Koo, slides.
R., Jasionowski, M., Haass, C. and Fahrenholz, F. E. H. (1997). The beta-amyloid precursor protein of