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  3. PubMed:22122372

PubMed: 22122372

Title
Proteolytic processing of Alzheimer's β-amyloid precursor protein.
Journal
Journal of neurochemistry
Volume
120 Suppl 1
Issue
None
Pages
9-21
Date
2012-01-01
Authors
Ma Q | Xu H | Zhang H | Zhang YW

Evidence 5657d0d155
JSON

Abeta toxicity can lead to synaptic dysfunction, neuronal cell death, impaired learning/memory and abnormal behaviors in AD models in vitro and in vivo

a(CHEBI:"amyloid-beta") decreases bp(GO:"regulation of synapse structure or activity") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"amyloid-beta") increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

a(CHEBI:"amyloid-beta") decreases bp(GO:"learning or memory") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence a91f8477ea
JSON

Studies have demonstrated that Abeta overproduction leads to neurotoxicity, neuronal tangle formation, synaptic damage and eventually neuron loss in the pathologically affected brain regions (Selkoe 1998; Shankar and Walsh 2009)

a(CHEBI:"amyloid-beta") decreases bp(GO:"regulation of synapse structure or activity") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases bp(GO:"neurofibrillary tangle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence e4c2c49b07
JSON

gamma-Secretase further cleaves C99 to release AICD and the amyloidogenic Abeta peptide which aggregates and fibrillates to form amyloid plaques in the brain

a(CHEBI:"amyloid-beta") increases a(HBP:HBP00038) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(CHEBI:"amyloid-beta") increases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(HBP:HBP00018) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(HBP:HBP00038) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(FPLX:"Gamma_secretase") increases rxn(reactants(a(HBP:HBP00081)), products(a(HBP:HBP00071), a(MESH:"Amyloid beta-Peptides"))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence 314f4efc31
JSON

Although excessive Abeta causes neurotoxicity, some studies have shown that Abeta 40 protects neurons against Abeta 42- induced neuronal damage and is required for the viability of central neurons (Plant et al. 2003; Zou et al. 2003)

a(CHEBI:"amyloid-beta") increases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:APP, frag("672_711")) decreases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 77fb7001ef
JSON

The amyloid plaques associated with AD were first purified and found to consist of multimeric aggregates of Abeta polypeptide containing about 40 amino acid residues in the mid-1980s (Glenner and Wong 1984; Masters et al. 1985)

a(HBP:HBP00018) association a(MESH:"Amyloid beta-Peptides") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus

a(MESH:"Amyloid beta-Peptides") association a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence 73bf185ad2
JSON

Although there are only 17 amino acids difference between sAPP-beta and sAPP-alpha, sAPP-beta reportedly lacks most of the neuroprotective effects of sAPP-a (Furukawa et al. 1996a,b)

a(HBP:HBP00042) increases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence acccd27460
JSON

The levels of APP isoforms with a KPI domain seem to be elevated in patients with AD (Menendez- Gonzalez et al. 2005) and a splicing shift in neurons from APP695 to KPI-containing APP isoforms, along with increased Abeta generation, is observed when the NMDA receptor is activated (Bordji et al. 2010)

a(HBP:HBP00064) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(HBP:HBP00065) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(MESH:"Receptors, N-Methyl-D-Aspartate") increases a(HBP:HBP00064) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(MESH:"Receptors, N-Methyl-D-Aspartate") increases a(HBP:HBP00065) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

a(MESH:"Receptors, N-Methyl-D-Aspartate") decreases a(HBP:HBP00063) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00064) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00065) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence 95e09a0c7e
JSON

APP can also be cleaved by alpha-secretase to form a soluble or secreted APP ectodomain (sAPP-alpha) that has been shown to be mostly neuro-protective

a(HBP:HBP00067) decreases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:ADAM10) increases rxn(reactants(p(HGNC:APP)), products(a(HBP:HBP00067))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:ADAM10) increases sec(p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence bb98e4dd4a
JSON

The constitutively secreted sAPP-alpha has been found to be neuro-protective (Mattson et al. 1993; Furukawa et al. 1996a,b; Han et al. 2005; Ma et al. 2009)

sec(a(HBP:HBP00067)) decreases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence a88cb34ef0
JSON

sAPP-alpha is thought to promote neurite outgrowth and synaptogenesis as well as cell adhesion (Mattson 1997; Gakhar Koppole et al. 2008)

a(HBP:HBP00067) increases bp(GO:"cell adhesion") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(HBP:HBP00067) increases bp(MESH:"Neuronal Outgrowth") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(HBP:HBP00067) increases bp(GO:"synapse assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 605d44b86b
JSON

In vivo studies have also shown that sAPP-alpha promotes learning and memory in animal models (Meziane et al. 1998; Taylor et al. 2008)

a(HBP:HBP00067) increases bp(GO:learning) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(HBP:HBP00067) increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 13c3c35728
JSON

Caspase-cleavages of APP are thought to be harmful because both C31 and the Jcasp fragment generated were found to be cytotoxic (Lu et al. 2003a)

a(HBP:HBP00069) increases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(HBP:HBP00070) increases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 72ba7411be
JSON

However, C31, a short form of AICD generated by caspase cleavage, has been reported to directly activate caspase 3 in the tumor cell death process (Lu et al. 2000; Bertrand et al. 2001; Nishimura et al. 2002; Madeira et al. 2005)

a(HBP:HBP00069) increases act(p(HGNC:CASP3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence b19ba331fb
JSON

C31 also appears to induce a caspase-independent toxicity by selectively increasing Abeta42 (Dumanchin-Njock et al. 2001)

a(HBP:HBP00069) increases p(HGNC:APP, frag("672_713")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence eb58cc1a56
JSON

By binding to AICD, JIP mediates APP/AICD phosphorylation at Thr668, thus modulating APP trafficking, maturation and processing

a(HBP:HBP00073) association complex(p(HBP:HBP00071), p(HGNC:MAPK8IP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(p(HBP:HBP00071), p(HGNC:MAPK8IP1)) regulates p(HGNC:APP, pmod(Ph, Thr, 668)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(p(HBP:HBP00071), p(HGNC:MAPK8IP1)) association a(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence 7689f23dc2
JSON

The extracellular portion of APP contains E1 and E2 domains and a Kunitz protease inhibitor (KPI) domain that is missing in APP695 (Kang and Muller-Hill 1990; Rohan de Silva et al. 1997)

a(HBP:HBP00078) association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(HBP:HBP00079) association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:APP) association a(HBP:HBP00078) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:APP) association a(HBP:HBP00079) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence bf053b7a15
JSON

The E1 domain is reported to function as the major interaction interface for dimerization of cellular APP/APLPs (Soba et al. 2005)

a(HBP:HBP00078) increases complex(p(HGNC:APP), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(HBP:HBP00078) increases complex(p(HGNC:APLP1), p(HGNC:APLP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(HBP:HBP00078) increases complex(p(HGNC:APLP2), p(HGNC:APLP2)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence b97cb7d12c
JSON

Plaques consisting of beta-amyloid (Abeta) peptide (Selkoe 1998), neurofibrillary tangles consisting largely of hyperphosphorylated microtubule-associated tau protein (Buee et al. 2000; Gendron and Petrucelli 2009) and neuron loss in the hippocampus and cortex regions are the major pathological hallmarks of Alzheimer’s disease.

a(MESH:"Amyloid beta-Peptides") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

bp(GO:"neurofibrillary tangle assembly") association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

bp(GO:"neurofibrillary tangle assembly") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

bp(GO:"neuron death") association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus

p(HGNC:MAPT, pmod(Ph)) association bp(GO:"neurofibrillary tangle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Alzheimer Disease") association a(MESH:"Amyloid beta-Peptides") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Alzheimer Disease") association bp(GO:"neurofibrillary tangle assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Alzheimer Disease") association bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence f50517210a
JSON

AICD also contains three phosphorylation sites, including two threonine residues at 654 and 668 and a serine residue at 665. AICD has been found to be phosphorylated by PKC, calcium-calmodulin dependent-kinase II, GSK3-b, Cdk5 and c-Jun N-terminal kinase (JNK) at the Ser/Thr sites mentioned above

a(MESH:"JNK Mitogen-Activated Protein Kinases") increases p(HBP:HBP00071, pmod(Ph, Thr, 654)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(MESH:"JNK Mitogen-Activated Protein Kinases") increases p(HBP:HBP00071, pmod(Ph, Thr, 668)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(MESH:"JNK Mitogen-Activated Protein Kinases") increases p(HBP:HBP00071, pmod(Ph, Ser, 665)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:CAMK2A) increases p(HBP:HBP00071, pmod(Ph, Thr, 654)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:CAMK2A) increases p(HBP:HBP00071, pmod(Ph, Thr, 668)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:CAMK2A) increases p(HBP:HBP00071, pmod(Ph, Ser, 665)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:CDK5) increases p(HBP:HBP00071, pmod(Ph, Thr, 654)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:CDK5) increases p(HBP:HBP00071, pmod(Ph, Thr, 668)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:CDK5) increases p(HBP:HBP00071, pmod(Ph, Ser, 665)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:GSK3B) increases p(HBP:HBP00071, pmod(Ph, Thr, 654)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:GSK3B) increases p(HBP:HBP00071, pmod(Ph, Thr, 668)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:GSK3B) increases p(HBP:HBP00071, pmod(Ph, Ser, 665)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:PRKCA) increases p(HBP:HBP00071, pmod(Ph, Thr, 654)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:PRKCA) increases p(HBP:HBP00071, pmod(Ph, Thr, 668)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:PRKCA) increases p(HBP:HBP00071, pmod(Ph, Ser, 665)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 41b2055174
JSON

Because of its highly similar structure to Notch, APP has been proposed to function as a cell surface receptor (reviewed in Zheng and Koo 2011)

a(MESH:"Receptors, Cell Surface") association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Neurons

p(HGNC:APP) association a(MESH:"Receptors, Cell Surface") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Neurons

Evidence 1cc1240e95
JSON

In addition to cleavages involving secretases, APP can be cleaved by caspases independently at its C terminus (Asp664 of APP695), releasing a short tail containing the last 31 amino acids (C31) of APP and a fragment (Jcasp) from between the gamma- and caspase-cleavage sites (Lu et al. 2000)

a(MESH:Caspases) increases rxn(reactants(p(HGNC:APP)), products(a(HBP:HBP00069), a(HBP:HBP00070))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence f72ab181db
JSON

Such phosphorylation may affect APP processing or the binding of AICD-interacting proteins, thus affecting the function of AICD (Gandy et al. 1988; Suzuki et al. 1994; Iijima et al. 2000; Inomata et al. 2003)

bp(HBP:HBP00073) association p(HBP:HBP00071, pmod(Ph, Thr, 654)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

bp(HBP:HBP00073) association p(HBP:HBP00071, pmod(Ph, Thr, 668)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

bp(HBP:HBP00073) association p(HBP:HBP00071, pmod(Ph, Ser, 665)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

act(p(HBP:HBP00071)) association p(HBP:HBP00071, pmod(Ph, Ser, 665)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

act(p(HBP:HBP00071)) association p(HBP:HBP00071, pmod(Ph, Thr, 654)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

act(p(HBP:HBP00071)) association p(HBP:HBP00071, pmod(Ph, Thr, 668)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HBP:HBP00071, pmod(Ph, Ser, 665)) association bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HBP:HBP00071, pmod(Ph, Ser, 665)) association act(p(HBP:HBP00071)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HBP:HBP00071, pmod(Ph, Thr, 654)) association bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HBP:HBP00071, pmod(Ph, Thr, 654)) association act(p(HBP:HBP00071)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HBP:HBP00071, pmod(Ph, Thr, 668)) association bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HBP:HBP00071, pmod(Ph, Thr, 668)) association act(p(HBP:HBP00071)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence f2251f4247
JSON

Although alternative splicing of transcripts from the single APP gene results in several isoforms of the gene product, APP695, whose encoding cDNA lacks the gene sequence from exons 7 and 8, is preferentially expressed in neurons (Sandbrink et al. 1994)

bp(HBP:HBP00077) increases a(HBP:HBP00063) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 27621bbee8
JSON

APP751, lacking exon 8, and APP770, encoded with all 18 exons, are predominant variants elsewhere (Yoshikai et al. 1990)

bp(HBP:HBP00077) increases a(HBP:HBP00064) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 362c28ace5
JSON

The processing of APP to generate Abeta is executed by beta- and gamma-secretase and is highly regulated

complex(FPLX:"Gamma_secretase") increases rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta"))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HGNC:BACE1) increases rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta"))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence d3510c67a0
JSON

APP C83 is further cleaved by gamma-secretase to release a P3 peptide and the AICD, both of which are degraded rapidly

complex(FPLX:"Gamma_secretase") increases rxn(reactants(a(HBP:HBP00072)), products(a(HBP:HBP00071), a(HBP:HBP00080))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence 6f2fa02bdc
JSON

gamma-Secretase cleaves APP at multiple sites and in sequential steps to generate Abeta peptides of different lengths (Fig. 1). The majority of Abeta peptides produced are 40 amino acids long, however, peptides ranging from 38 to 43 amino acids are found in vivo

complex(FPLX:"Gamma_secretase") increases p(HGNC:APP, frag("1_38")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(FPLX:"Gamma_secretase") increases p(HGNC:APP, frag("1_43")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(FPLX:"Gamma_secretase") increases p(HGNC:APP, frag("672_711")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence 0c6d94707a
JSON

Accordingly, various AICDs (C50, C53, C57 and C59) can be generated during these multi-site cleavages executed by gamma-secretase. However, all of the endogenous AICD forms are rarely detected, probably because of their very rapid degradation (Lu et al. 2000; Passer et al. 2000; Sastre et al. 2001; Yu et al. 2001; Sato et al. 2003)

complex(FPLX:"Gamma_secretase") increases a(HBP:HBP00071) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence c5d87fce4b
JSON

Several studies have reported that certain ligands, including Abeta, F-spondin, Nogo- 66, netrin-1 and BRI2, bind to the extracellular domain of APP, resulting in modulated APP processing and sequential downstream signals (Lorenzo et al. 2000; Lu et al. 2003b; Ho and Sudhof 2004; Park et al. 2006; Lourenco et al. 2009; Matsuda et al. 2009; Zheng and Koo 2011)

complex(a(CHEBI:"amyloid-beta"), p(HGNC:APP)) regulates bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(p(HGNC:APP), p(HGNC:ITM2B)) regulates bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(p(HGNC:APP), p(HGNC:NTN1)) regulates bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(p(HGNC:APP), p(HGNC:RTN4R)) regulates bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(p(HGNC:APP), p(HGNC:SPON1)) regulates bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence edcbd4bde8
JSON

APP undergoes post-translational proteolysis/processing to generate the hydrophobic beta-amyloid (Abeta) peptides

p(HGNC:APP) increases a(MESH:"Amyloid beta-Peptides") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 411370ee1b
JSON

Cloning of the complementary DNA (cDNA) of Abeta revealed that Abeta is derived from a larger precursor protein (Tanzi et al. 1987)

p(HGNC:APP) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence 1af7ac8b8f
JSON

Nevertheless, APP is more widely accepted as a protein contributing to cell adhesion via its extracellular domain

p(HGNC:APP) increases bp(GO:"cell adhesion") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence a66a07588e
JSON

However, recent studies suggest that Cathepsin B can degrade Abeta into harmless fragments

p(HGNC:CTSB) increases deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 5341fe3f78
JSON

Furthermore, the E1 and E2 regions of APP were found to interact with themselves, in parallel or anti-parallel, forming homo- (with APP) or hetero-dimers (with APLPs) (Wang and Ha 2004; Soba et al. 2005; Dahms et al. 2010)

complex(a(HBP:HBP00078), a(HBP:HBP00079)) increases complex(p(HGNC:APLP1), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(a(HBP:HBP00078), a(HBP:HBP00079)) increases complex(p(HGNC:APLP2), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(a(HBP:HBP00078), a(HBP:HBP00079)) increases complex(p(HGNC:APP), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence a2e1a5ca3b
JSON

Many studies have documented that AICD is cytotoxic and that over-expressing different AICDs (C31, C57, C59) in Hela, H4, N2a or PC12 cell lines, as well as neuronal cell lines, induces cell death (Lu et al. 2000)

p(HBP:HBP00071) increases bp(GO:"cell death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 62573ab80f
JSON

For example, P53 expression, as well as p53-mediated apoptosis, can be enhanced by AICD (Alves da Costa et al. 2006; Ozaki et al. 2006)

p(HBP:HBP00071) increases p(HGNC:TP53) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

p(HBP:HBP00071) increases act(p(HGNC:TP53)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

act(p(HGNC:TP53)) increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence 1a2d243a6d
JSON

In addition, cellular Ca2+ homeostasis appears to be modulated by AICD (Hamid et al. 2007)

p(HBP:HBP00071) regulates bp(GO:"calcium ion homeostasis") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 936584bc8d
JSON

A recent study suggested that sAPP-beta can be cleaved to generate an N-terminal fragment that is a ligand for death receptor 6, activating caspase 6 which further stimulates axonal pruning and neuronal cell death (Nikolaev et al. 2009)

complex(p(HBP:HBP00042, frag("?")), p(HGNC:TNFRSF21)) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(p(HBP:HBP00042, frag("?")), p(HGNC:TNFRSF21)) increases bp(GO:"synapse pruning") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 3315767308
JSON

As an adaptor protein involved in protein sorting and trafficking, X11 has been suggested as affecting APP trafficking/metabolism by interacting with AICD, leading to reduced Abeta production

complex(p(HBP:HBP00071), p(HGNC:APBA1)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 46ca242120
JSON

Although Tip60 does not bind to AICD directly, an indirect interaction between AICD and Tip60 is mediated by Fe65. Upon forming this complex, AICD is stabilized and can be translocated into the nucleus to regulate expression of genes such as KAI1, Neprilysin, LRP1, p53, GSK-3b and EGF receptor (Baek et al. 2002; Kim et al. 2003; Cao and Sudhof 2004; Pardossi-Piquard et al. 2005; Alves da Costa et al. 2006; Liu et al. 2007; Zhang et al. 2007)

complex(p(HBP:HBP00071), p(HGNC:APBB1), p(HGNC:KAT5)) regulates p(HGNC:CD82) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(p(HBP:HBP00071), p(HGNC:APBB1), p(HGNC:KAT5)) regulates p(HGNC:MME) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(p(HBP:HBP00071), p(HGNC:APBB1), p(HGNC:KAT5)) regulates p(HGNC:TP53) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(p(HBP:HBP00071), p(HGNC:APBB1), p(HGNC:KAT5)) regulates p(HGNC:GSK3B) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(p(HBP:HBP00071), p(HGNC:APBB1), p(HGNC:KAT5)) regulates p(HGNC:EGFR) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

complex(p(HBP:HBP00071), p(HGNC:APBB1), p(HGNC:KAT5)) regulates p(HGNC:LRP1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence f1b0617928
JSON

Another transactivating complex consisting of AICD, Fe65 and Late SV40 Factor (LSF)/leader-binding protein-1 (LBP1)/transcription factor CP2 (TFCP2) has also been reported to induce the expression of GSK3-b (Kim et al. 2003)

complex(p(HBP:HBP00071), p(HGNC:APBB1), p(HGNC:TFCP2)) increases p(HGNC:GSK3B) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 8fbb83443c
JSON

APP-binding protein 1 reportedly interacts with AICD and activates the neddylation pathway (Chen 2004), further down-regulating the level of beta-catenin and potentially resulting in apoptosis

complex(p(HBP:HBP00071), p(HGNC:NAE1)) increases bp(GO:"protein neddylation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(p(HBP:HBP00071), p(HGNC:NAE1)) decreases p(HGNC:CTNNB1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(p(HBP:HBP00071), p(HGNC:NAE1)) increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence e6ad3ae307
JSON

However, APP/APLP2, APLP1/APLP2 double knockout or APP/APLP1/APLP2 triple knockout mice show early postnatal lethality

composite(p(MGI:Aplp1), p(MGI:Aplp2), p(MGI:App)) decreases path(MESH:"Perinatal Death") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 23a21efaed
JSON

As APP was found to be constitutively cleaved at the alpha-site to yield sAPP-alpha (Esch et al. 1990), three members of the a disintegrin and metalloproteinase (ADAMs), ADAM-10,ADAM-17 and ADAM-9 have been proposed as the alpha-secretase (Buxbaum et al. 1998; Koike et al. 1999;Lammich et al. 1999)

p(HGNC:ADAM10) increases rxn(reactants(p(HGNC:APP)), products(a(HBP:HBP00067))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:ADAM17) increases rxn(reactants(p(HGNC:APP)), products(a(HBP:HBP00067))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:ADAM9) increases rxn(reactants(p(HGNC:APP)), products(a(HBP:HBP00067))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence a856c3e2c1
JSON

alpha-cleavage, which cuts APP at the 17th amino acid inside the Abeta peptide sequence (Fig. 1), releases a large secreted extracellular domain (sAPP-alpha) and a membrane-associated C-terminal fragment consisting of 83 amino acids (C83)

p(HGNC:ADAM10) increases rxn(reactants(p(HGNC:APP)), products(a(HBP:HBP00067), a(HBP:HBP00072))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence cc8c9135be
JSON

Moderate neuronal over-expression of human ADAM10 increases sAPP-alpha production while reducing Abeta generation/ plaque formation in mice carrying the human APP V717I mutation, while expression of a catalytically-inactive form of the ADAM10 mutation increases the size and number of amyloid plaques in mouse brains (Postina et al. 2004)

p(HGNC:ADAM10) increases a(HBP:HBP00067) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:ADAM10) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:ADAM10) decreases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 5212701c9e
JSON

However, although sAPP-alpha generation is not affected in ADAM9/17 knock-down cell lines nor in mice carrying deficient ADAM9/17 genes (Weskamp et al. 2002; Kuhn et al. 2010), over-expression of ADAM9/17 does increase the level of sAPP-alpha under some conditions, suggesting that ADAM9 and ADAM17 are more likely involved in the regulated alpha-cleavage of APP rather than in constitutive alpha-cleavage

p(HGNC:ADAM17) increases a(HBP:HBP00067) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:ADAM9) increases a(HBP:HBP00067) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 598f62db22
JSON

Among the various Ab peptides generated by the multiplesite cleavages of secretases, Abeta 42 has proved to be more hydrophobic and amyloidogenic than others (Burdick et al. 1992)

p(HGNC:APP, frag("672_713")) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 100fe0bd4c
JSON

Studies also suggest that increased Abeta 42 levels probably provide the core for oligomerization, fibrillation and amyloid plaque generation (Jarrett et al. 1993; Iwatsubo et al. 1994)

p(HGNC:APP, frag("672_713")) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:APP, frag("672_713")) increases a(HBP:HBP00022) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:APP, frag("672_713")) increases a(HBP:HBP00038) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 6c604bfcb2
JSON

In the amyloidogenic pathway, APP is primarily processed by beta-secretase at the first residue or at the 11th residue (so called beta’ site) of the Abeta peptide sequence (Fig. 1), shedding sAPPbeta and generating a membrane associated C-terminal fragment consisting of 99 amino acids (C99) (Sarah and Robert 2007)

p(HGNC:BACE1) increases rxn(reactants(p(HGNC:APP)), products(a(HBP:HBP00042), a(HBP:HBP00081))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence b349242b15
JSON

Abeta generation is initiated by beta-cleavage at the ectodomain of APP, resulting in the generation of an sAPP-beta domain and the membrane associated APP C-terminal fragment C99. The putative beta-secretase, beta-site APP cleaving enzyme 1 (BACE1), was first identified and characterized in 1999 (Sinha et al. 1999; Vassar et al. 1999; Yan et al. 1999; Hussain et al. 2000; Lin et al. 2000).

p(HGNC:BACE1) increases rxn(reactants(p(HGNC:APP)), products(a(HBP:HBP00042), a(HBP:HBP00081))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 26a8552172
JSON

Knocking out the BACE1 gene prevents Abeta generation and completely abolishes Abeta pathology in mice expressing the Swedish mutation of human APP (Cai et al. 2001; Luo et al. 2001; Roberds et al. 2001; Ohno et al. 2004; Laird et al. 2005)

p(HGNC:BACE1) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence f3e01fe41d
JSON

Transgenic mice over-expressing PSs with FAD mutations show significantly increased Abeta42 levels, suggesting that PS mutations probably induce AD by producing more of the hydrophobic Abeta42 form (Duff et al. 1996; Qian et al. 1998)

p(HGNC:PSEN1, var("?")) increases p(HGNC:APP, frag("672_713")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

p(HGNC:PSEN2, var("?")) increases p(HGNC:APP, frag("672_713")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.