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  3. PubMed:21214928

PubMed: 21214928

Title
APP processing in Alzheimer's disease.
Journal
Molecular brain
Volume
4
Issue
None
Pages
3
Date
2011-01-07
Authors
Xu H | Thompson R | Zhang YW | Zhang H

Evidence b9faa0f904
JSON

APP was found to colocalize with beta1 intergrins in neural cells [23]

p(HGNC:APP) association p(HGNC:ITGB1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:ITGB1) association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 9ca943f0e7
JSON

Extracellular neuritic plaques are deposits of differently sized small peptides called beta-amyloid (Abeta) that are derived via sequential proteolytic cleavages of the b-amyloid precursor protein (APP) [6]

a(CHEBI:"amyloid-beta") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 7d451de367
JSON

In Down Syndrome (DS) patients, the accumulation of intracellular Abeta precedes extracellular plaque formation [148] and the level of intraneuronal Ab decreases as the extracellular Abeta plaques accumulate [149]

a(CHEBI:"amyloid-beta") increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

Evidence a697fbfd9e
JSON

While Abeta is neurotoxic, studies suggest that sAPPalpha is neuroprotective, making the subcellular distribution of APP an important factor in neurodegeneration [42-44]

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence cf8e6fd5c5
JSON

Multiple lines of evidence demonstrate that overproduction of Abeta results in a neurodegenerative cascade leading to synaptic dysfunction, formation of intraneuronal fibrillary tangles and eventually neuron loss in affected areas of the brain [6,142]

a(CHEBI:"amyloid-beta") increases bp(HBP:HBP00027) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence e6a4d3d4bf
JSON

Although excessive Abeta causes synaptic dysfunction and synapse loss [142], low levels of Abeta increase hippocampal longterm potentiation and enhances memory, indicating a novel positive, modulatory role on neurotransmission and memory [158,159]

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") decreases a(MESH:Synapses) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association bp(MESH:"Synaptic Transmission") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") decreases bp(GO:"long-term synaptic potentiation") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

bp(MESH:"Synaptic Transmission") association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

Evidence e46d0cf6ee
JSON

Intraneuronal Abeta can also impair amygdala-dependent emotional responses by affecting the ERK/MAPK signaling pathway [153]

a(CHEBI:"amyloid-beta") association bp(GO:"MAPK cascade") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association bp(GO:"ERK1 and ERK2 cascade") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

bp(GO:"ERK1 and ERK2 cascade") association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

bp(GO:"MAPK cascade") association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

Evidence 17b8783a6d
JSON

Picomolar levels of Abeta can also rescue neuronal cell death induced by inhibition of Abeta generation (by exposure to inhibitors of beta- or gamma-scretases) [160], possibly through regulating the potassium ion channel expression, hence affecting neuronal excitability [161]

a(CHEBI:"amyloid-beta") association a(MESH:"Potassium Channels") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Hippocampus
MeSH
Down Syndrome

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Hippocampus
MeSH
Down Syndrome

a(MESH:"Potassium Channels") association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 2864a99bc6
JSON

APP interaction with mint proteins has been shown to affect APP processing by stabilizing cellular APP, altering both sAPPalpha and Abeta generation and secretion [166]

a(CHEBI:"amyloid-beta") association complex(p(HGNC:APBA1), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(CHEBI:"amyloid-beta")) association complex(p(HGNC:APBA1), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association complex(p(HGNC:APBA2), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(CHEBI:"amyloid-beta")) association complex(p(HGNC:APBA2), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"amyloid-beta") association complex(p(HGNC:APBA3), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(CHEBI:"amyloid-beta")) association complex(p(HGNC:APBA3), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(HBP:HBP00067) association complex(p(HGNC:APBA1), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(HBP:HBP00067)) association complex(p(HGNC:APBA1), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(HBP:HBP00067) association complex(p(HGNC:APBA2), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(HBP:HBP00067)) association complex(p(HGNC:APBA2), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(HBP:HBP00067) association complex(p(HGNC:APBA3), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(HBP:HBP00067)) association complex(p(HGNC:APBA3), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA1), p(HGNC:APP)) association a(HBP:HBP00067) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA1), p(HGNC:APP)) association sec(a(HBP:HBP00067)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA1), p(HGNC:APP)) association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA1), p(HGNC:APP)) association sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA2), p(HGNC:APP)) association a(HBP:HBP00067) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA2), p(HGNC:APP)) association sec(a(HBP:HBP00067)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA2), p(HGNC:APP)) association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA2), p(HGNC:APP)) association sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA3), p(HGNC:APP)) association a(HBP:HBP00067) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA3), p(HGNC:APP)) association sec(a(HBP:HBP00067)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA3), p(HGNC:APP)) association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA3), p(HGNC:APP)) association sec(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 5f6e11a2ed
JSON

Indeed, phorbol ester’s effect on sAPPalpha secretion and Abeta generation though activation of protein kinase C (PKC) has been known for a long time [201-203]

a(CHEBI:"amyloid-beta") association a(CHEBI:"phorbol ester") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"phorbol ester") association sec(a(HBP:HBP00067)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"phorbol ester") association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:"phorbol ester") increases act(p(HGNC:PRKCA)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

sec(a(HBP:HBP00067)) association a(CHEBI:"phorbol ester") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 2899cf17be
JSON

We have found that estrogen may reduce Abeta levels by stimulating the alpha-secretase pathway and thereby inhibit Abeta generation

a(CHEBI:estrogen) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 8c4895d783
JSON

Interestingly, the stimulation of sAPPalpha secretion by estrogen can be blocked by a PKC inhibitor, suggesting the involvement of a PKC-dependent pathway [200]

a(CHEBI:estrogen) increases sec(a(HBP:HBP00067)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

act(p(HGNC:PRKCA)) increases sec(a(HBP:HBP00067)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 307d08e4bc
JSON

However, a recent study blocking the conversion of testosterone to estrogen found an estrogen-independent improvement in cognitive function and lowering of plaque formation along with a decrease in BACE1 mRNA, protein level, and activity [211]. In addition, testosterone may also reduce the protein level of PS1 [196]

a(CHEBI:testosterone) decreases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
Medium
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:testosterone) decreases r(HGNC:BACE1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
Medium
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:testosterone) decreases p(HGNC:BACE1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
Medium
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:testosterone) decreases act(p(HGNC:BACE1)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
Medium
MeSH
Hippocampus
MeSH
Down Syndrome

a(CHEBI:testosterone) decreases p(HGNC:PSEN1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
Medium
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 54cbc9aea6
JSON

However, overexpression of APP betaCTF was found to be cytotoxic and cause neuronal degeneration, perhaps by perturbing APP signal transduction [96,97]

a(HBP:HBP00024) increases bp(HBP:HBP00027) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence c45210ce41
JSON

A recent report found that sAPPbeta can rescue gene expression of transthyretin and Klotho, which is decreased in APP/APLP2 deficient mice, but cannot rescue the lethality and neuromuscular synapse defects of these mice, suggesting a gene expression regulation function for sAPPbeta that is independent of developmental APP functions [95]

a(HBP:HBP00042) increases p(HGNC:TTR) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

a(HBP:HBP00042) increases p(HGNC:KL) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence 65d1b622bf
JSON

A dramatically reduced ADAM10 protein level in the platelets of sporadic AD patients was also found to correlate with the significantly decreased sAPPalpha levels found in their platlets and cerebrospinal fluid [55] and the reduced alpha-secretase activity in the temporal cortex homogenates of AD patients [56]

a(HBP:HBP00067) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Blood Platelets
MeSH
Cerebrospinal Fluid

p(HGNC:ADAM10) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Blood Platelets

act(p(HGNC:ADAM10)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:ADAM10) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Blood Platelets

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(HGNC:ADAM10)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Temporal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation a(HBP:HBP00067) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Blood Platelets
MeSH
Cerebrospinal Fluid

Evidence 4afbe80cd9
JSON

In contrast to Abeta, sAPPalpha has an important role in neuronal plasticity/survival and is protective against excitotoxicity [42,43]. sAPPalpha also regulates neural stem cell proliferation and is important for early CNS development [57,58]

a(HBP:HBP00067) association bp(GO:"regulation of neuronal synaptic plasticity") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Temporal Lobe

a(HBP:HBP00067) regulates bp(GO:"central nervous system formation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Temporal Lobe

a(HBP:HBP00067) decreases bp(HBP:HBP00068) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Temporal Lobe

a(HBP:HBP00067) regulates bp(GO:"stem cell proliferation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

bp(GO:"regulation of neuronal synaptic plasticity") association a(HBP:HBP00067) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Temporal Lobe

Evidence fade5e0e9d
JSON

We and others have also found that sAPPalpha can inhibit stress-induced CDK5 activation and participate in various neuroprotective reagent-mediated excitoprotection [44,59-61]

a(HBP:HBP00067) decreases bp(HBP:HBP00068) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

a(HBP:HBP00067) decreases act(p(HGNC:CDK5)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 38dbb76517
JSON

In a similar fashion, released AICD has been shown to possess transactivation activity and can regulate transcription of multiple genes including APP, GSK- 3b, KAI1, neprilysin, BACE1, p53, EGFR, and LRP1 [127-132]

act(a(HBP:HBP00071), ma(tscript)) regulates p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

act(a(HBP:HBP00071), ma(tscript)) regulates p(HGNC:GSK3B) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

act(a(HBP:HBP00071), ma(tscript)) regulates p(HGNC:CD82) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

act(a(HBP:HBP00071), ma(tscript)) regulates p(HGNC:MME) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

act(a(HBP:HBP00071), ma(tscript)) regulates p(HGNC:BACE1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

act(a(HBP:HBP00071), ma(tscript)) regulates p(HGNC:EGFR) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

act(a(HBP:HBP00071), ma(tscript)) regulates p(HGNC:LRP1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

Evidence 3801fbba74
JSON

In addition, free AICD can induce apoptosis and may play a role in sensitizing neurons to toxic stimuli [133,134]

a(HBP:HBP00071) increases bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence 5f8bdafe8a
JSON

Abeta is generated from b-amyloid precursor protein (APP) through sequential cleavages first by beta-secretase and then by gamma-secretase complex

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

Appears in Networks:
Annotations
Confidence
Medium

a(MESH:"Amyloid Precursor Protein Secretases") increases rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta"))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

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 ee04e4104c
JSON

There are reports showing that the protein and mRNA levels of KPI-containing APP isoforms are elevated in AD brain and associated with increased Ab deposition [9]; and prolonged activation of extrasynaptic NMDA receptor in neurons can shift APP expression from APP695 to KPI-containing APP isoforms, accompanied with increased production of Ab [10]

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

Appears in Networks:
Annotations
Confidence
Medium

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

Appears in Networks:
Annotations
Confidence
Medium

a(MESH:"Receptors, N-Methyl-D-Aspartate") increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HBP:HBP00064) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

p(HBP:HBP00065) increases path(MESH:"Plaque, Amyloid") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

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

Appears in Networks:
Annotations
Confidence
Medium

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

Appears in Networks:
Annotations
Confidence
Medium

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

Appears in Networks:
Annotations
Confidence
Medium

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

Appears in Networks:
Annotations
Confidence
Medium

Evidence 00deea5f70
JSON

Cleavage of APP by caspases may also contribute to AD pathologies

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

Appears in Networks:
Annotations
Confidence
Medium

a(MESH:Caspases) increases path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence e99a852f87
JSON

It is also possible that APP betaCTF’s cytotoxic effect is actually mediated by the end products of gamma- and/or caspase-cleavage including APP intracellular domain (AICD), C31 and Jcasp which are cytotoxic (see below)

a(MESH:Caspases) increases rxn(reactants(p(HBP:HBP00071)), products(a(HBP:HBP00069), a(HBP:HBP00070))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Neurons

Evidence c60d7bc29f
JSON

In addition to secretases, caspases (predominantly caspase- 3) can directly cleave APP at position Asp664 (based on the APP695 sequence) within the cytoplasmic tail during apoptosis to release a fragment containing the last 31 amino acids of APP (called C31)

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence 1d73e8878a
JSON

Additional gamma-cleavage further generates the fragment (called Jcasp) containing the region between gamma- and caspase-cleavage sites

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence 7071280569
JSON

APP undergoes rapid anterograde transport in neurons

bp(GO:"anterograde axonal protein transport") association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

p(HGNC:APP) association bp(GO:"anterograde axonal protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 24bcd948a2
JSON

A role for APP has been suggested in neurite outgrowth and synaptogenesis, neuronal protein trafficking along the axon, transmembrane signal transduction, cell adhesion, calcium metabolism, etc, all requiring additional in vivo evidence (reviewed in [19])

bp(GO:"calcium ion homeostasis") association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

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

Appears in Networks:
Annotations
Confidence
High

bp(GO:"protein transport") association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Axons
MeSH
Neurons

bp(GO:"signal transduction") association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

bp(GO:"synapse assembly") association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

bp(MESH:"Neuronal Outgrowth") association p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:APP) association bp(MESH:"Neuronal Outgrowth") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:APP) association bp(GO:"synapse assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:APP) association bp(GO:"signal transduction") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

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

Appears in Networks:
Annotations
Confidence
High

p(HGNC:APP) association bp(GO:"calcium ion homeostasis") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:APP) association bp(GO:"protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Axons
MeSH
Neurons

Evidence 63acc9dea1
JSON

Moreover, internalization of APP from the cell surface for endosomal/lysosomal degradation can be mediated by clathrin

bp(GO:"clathrin-dependent endocytosis") increases deg(p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 75cb7334a3
JSON

Although sAPPbeta only differs from sAPPalpha by lacking the Abeta1-16 region at its carboxyl-terminus, sAPPbeta was reported to function as a death receptor 6 ligand and mediate axonal pruning and neuronal cell death [94]

bp(GO:"neuron death") association complex(a(HBP:HBP00042), p(HGNC:TNFRSF21)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

bp(GO:"synapse pruning") association complex(a(HBP:HBP00042), p(HGNC:TNFRSF21)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

complex(a(HBP:HBP00042), p(HGNC:TNFRSF21)) association bp(GO:"synapse pruning") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

complex(a(HBP:HBP00042), p(HGNC:TNFRSF21)) association bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence cc1099f5d0
JSON

Rab6, a member of the GTP-binding protein family of membrane trafficking regulators, is implicated in protein transport along biosynthetic and endocytic pathways and has also been found to affect APP processing

bp(HBP:HBP00073) association p(HGNC:RAB6A) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

p(HGNC:RAB6A) association bp(HBP:HBP00073) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 5d9af3635c
JSON

The APP gene is located on chromosome 21 in humans with three major isoforms arising from alternative splicing [3]. These are APP695, APP751 and APP770 (containing 695, 751, and 770 amino acids, respectively)

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

Appears in Networks:
Annotations
Confidence
High

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

Appears in Networks:
Annotations
Confidence
High

bp(HBP:HBP00077) increases p(HBP:HBP00065) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence f7df83b618
JSON

APP alphaCTF and betaCTF are further cleaved by gamma-secretase to generate p83 and Abeta, respectively

complex(FPLX:"Gamma_secretase") increases rxn(reactants(a(HBP:HBP00024)), products(a(CHEBI:"amyloid-beta"), a(HBP:HBP00072))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

Evidence 36d343635a
JSON

In addition to cleaving APP CTFs, gamma-secretase cleaves a series of functionally important transmembrane proteins, including Notch [120], cadherin [114], tyrosinase [121], ErbB4 [79], CD44 [70], etc.) (see review [122])

complex(FPLX:"Gamma_secretase") increases p(HBP:HBP00024, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

complex(FPLX:"Gamma_secretase") increases p(HGNC:NOTCH1, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

complex(FPLX:"Gamma_secretase") increases p(FPLX:Cadherin, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

complex(FPLX:"Gamma_secretase") increases p(HGNC:TYR, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

complex(FPLX:"Gamma_secretase") increases p(HGNC:ERBB4, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

complex(FPLX:"Gamma_secretase") increases p(HGNC:CD44, frag("?")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

Evidence 377d52f059
JSON

Overall, most studies suggest that APP plays some role in regulating protein trafficking

p(HGNC:APP) regulates bp(GO:"protein transport") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 5c8204ab70
JSON

Inhibition of dynamin-mediated but not clathrin-mediated Abeta internalization was also found to reduce Abeta-induced neurotoxicity [154]

complex(a(CHEBI:"amyloid-beta"), p(HGNC:DNM1)) decreases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons
MeSH
Down Syndrome

Evidence 556738cc69
JSON

Recently, a novel gamma-secretase activating protein (GSAP) was identified and GSAP was found to selectively increase Abeta production through interaction with both gamma-secretase and the APP CTF substrate [117]

complex(a(HBP:HBP00024), complex(FPLX:"Gamma_secretase"), p(HGNC:GSAP)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

Evidence c4fb12dcd5
JSON

One possible mechanism for C31’s toxicity is that C31 complexes with APP to recruit the interacting partners that initiate the signals related to cellular toxicity [136]

complex(a(HBP:HBP00069), p(HGNC:APP)) increases bp(HBP:HBP00061) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence aa2e65b24a
JSON

For example, the APP C-terminus has been found to interact with all three mint (X11) family members (mint1, mint2, and mint3) involved in trafficking regulation [163-165]

complex(p(HGNC:APBA1), p(HGNC:APP)) regulates bp(GO:"protein transport") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA2), p(HGNC:APP)) regulates bp(GO:"protein transport") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APBA3), p(HGNC:APP)) regulates bp(GO:"protein transport") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence ddca579589
JSON

During its transport, APP was found to interact with kinesin-I and functions as a kinesin-I membrane receptor to mediate axonal transport of beta-secretase (BACE1) and PS1 [26,27]

complex(p(HGNC:APP), p(HGNC:KIF5B)) regulates act(p(HGNC:BACE1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

complex(p(HGNC:APP), p(HGNC:KIF5B)) regulates act(p(HGNC:PSEN1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence d55810b475
JSON

Antagonizing the extracellular interaction between cell-surface APP and LRP increased the level of cell surface APP while decreasing Abeta generation [187]

complex(p(HGNC:APP), p(HGNC:LRP1)) decreases p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APP), p(HGNC:LRP1)) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence dd03a2c46c
JSON

An LRP-related protein 1B (LRP1B) has a similar effect, binding APP at the plasma membrane, preventing APP internalization, and leading to decreased Abeta generation and increased sAPPalpha secretion [189]

complex(p(HGNC:APP), p(HGNC:LRP1B)) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

complex(p(HGNC:APP), p(HGNC:LRP1B)) increases sec(a(HBP:HBP00067)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 15f42512a2
JSON

One study showed that the ectodomain of Nicastrin binds to APP and Notch and can recruit them into the g-secretase complex, suggesting that Nicastrin may act as the gamma-secretase receptor [108]

complex(p(HGNC:APP), p(HGNC:NCSTN), p(HGNC:NOTCH1)) increases complex(complex(FPLX:"Gamma_secretase"), p(HGNC:APP)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

Evidence d38c6613bf
JSON

On the other hand, Golgi-localized gamma-ear-containing ARF-binding (GGA) proteins have been found to interact with BACE1 and regulate its trafficking between the late Golgi and early endosomes; and depletion of GGA proteins increases the accumulation of BACE1 in acidic early endosomes for enhanced BACE1 stability and cleavage of APP [76-78]

complex(p(HGNC:BACE1), p(HGNC:GGA1)) decreases rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence cf92e93a53
JSON

The first step in Abeta generation is cleavage of APP by the beta-secretase

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 9103914a48
JSON

These results provide convincing evidence that BACE1 is the beta-secretase involved in APP metabolism [63-67]; and BACE1 activity is thought to be the rate-limiting factor in Abeta generation from APP

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

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence 1d332bdab4
JSON

BACE1 deficiency in AD model mice have been shown to rescue cholinergic dysfunction, neuronal loss and memory deficits, correlating with a dramatic reduction in Abeta40/42 levels [79-81]

p(HGNC:BACE1) increases bp(GO:"neuron death") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

p(HGNC:BACE1) decreases bp(GO:"synaptic transmission, cholinergic") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

p(HGNC:BACE1) decreases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

p(HGNC:BACE1) increases p(HGNC:APP, frag("672_713")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

p(HGNC:BACE1) increases p(HGNC:APP, frag("672_711")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

Evidence 4074233aa9
JSON

Some studies found that BACE1 can interact with reticulon/Nogo proteins, whose increased expression can block BACE1 in the ER with a neutral pH environment and thus inhibit BACE1 activity in Abeta generation [73-75]

complex(p(HGNC:BACE1), p(HGNC:RTN4)) decreases rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endoplasmic Reticulum
Confidence
High
MeSH
Neurons

Evidence 50acf2a31a
JSON

This PS1-PLD1 interaction recruits PLD1 to the Golgi/TGN and thus potentially alters APP trafficking as PLD1 overexpression promotes budding of vesicles from the TGN containing APP and increases cell surface levels of APP [176,177]

complex(p(HGNC:PLD1), p(HGNC:PSEN1)) increases p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 65ac4868ea
JSON

We and others have shown that PS1 can also regulate the intracellular trafficking of APP

p(HGNC:PSEN1) regulates p(HGNC:APP) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 32134cd517
JSON

Co-expression of ADAM9 with APP promoted sAPPalpha production upon phorbol ester treatment, suggesting that ADAM9 possesses alpha-secretase activity [51]

composite(a(CHEBI:"phorbol ester"), p(HGNC:ADAM9), p(HGNC:APP)) increases a(HBP:HBP00067) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neurons

Evidence a3ccda7cc1
JSON

APP751 and APP770 are expressed in most tissues and contain a 56 amino acid Kunitz Protease Inhibitor (KPI) domain within their extracellular regions

p(HBP:HBP00064) association p(UNIPROT:A0A293M1A7) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HBP:HBP00065) association p(UNIPROT:A0A293M1A7) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(UNIPROT:A0A293M1A7) association p(HBP:HBP00064) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(UNIPROT:A0A293M1A7) association p(HBP:HBP00065) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 7077656569
JSON

Alternatively, APP can be cleaved by alpha-secretase within the Abeta domain to release soluble APPa and preclude Abeta generation

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

Appears in Networks:
Annotations
Confidence
Medium

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

Appears in Networks:
Annotations
Confidence
Medium

Evidence 17a125ffb1
JSON

Cleavage of APP by alpha-secretase precludes Abeta generation as the cleavage site is within the Abeta domain (at the Lys16- Leu17 bond), and releases a large soluble ectodomain of APP called sAPPalpha

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

p(HGNC:ADAM10) increases rxn(reactants(p(HGNC:APP)), products(p(HGNC:APP, frag("17_*")), p(HGNC:APP, frag("1_16")))) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence 981030bc07
JSON

From the TGN, APP can be transported in TGN-derived secretory vesicles to the cell surface where it is either cleaved by alpha-secretase to produce a soluble molecule, sAPPalpha [37], or re-internalized via an endosomal/ lysosomal degradation pathway [38,39]

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

Evidence edf27cc95c
JSON

Manipulation of ADAM17 can alter alpha-cleavage of APP and Abeta generation, with regulated alpha-cleavage abolished in ADAM17-deficient cells, suggesting that ADAM17 is likely the alpha-secretase responsible for regulated APP cleavage [47]

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

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Neurons

Evidence 47c870a799
JSON

There are two main toxic species, Ab40 and Ab42, with Abeta42 more hydrophobic and more prone to fibril formation while only making up about 10% of the Abeta peptide produced [143]

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

Evidence 0bfe42edc0
JSON

Studies done on familial AD (FAD) mutations consistently show increases in the ratio of Abeta42/40 [105,144], suggesting that elevated levels of Abeta42 relative to Abeta40 is critical for AD pathogenesis, probably by providing the core for Abeta assembly into oligomers, fibrils and amyloidogenic plaques [145,146]

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence 3b81a870d2
JSON

As DS also results in Abeta accumulation, the genes location suggests a link between BACE2 and APP processing

p(HGNC:BACE2) association rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

path(MESH:"Down Syndrome") increases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta"))) association p(HGNC:BACE2) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Medium
MeSH
Neurons

Evidence 56484ecf64
JSON

Indeed, BACE2 cleaves beta-secretase substrates such as wild-type and Swedish mutant APP, similar to BACE1, in enzymatic In vitro assays [89]

p(HGNC:BACE2) increases rxn(reactants(p(HGNC:APP)), products(a(CHEBI:"amyloid-beta"))) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence 9623c1033b
JSON

Downregulation of CD147 increases Abeta production but its overexpression has no effect on Abeta generation [113]

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Neurons

p(HGNC:BSG) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
Low
MeSH
Neurons

Evidence fa3ece4899
JSON

Inhibition of cathepsin B has been found to reduce Abeta production both in vivo and in vitro [92,93]

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

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

Evidence 875693dc4b
JSON

The neurofibrillary tangles (NFTs) consist largely of hyperphosphorylated twisted filaments of the microtubule-associated protein tau [4,5]

p(HGNC:MAPT, pmod(Ph)) increases a(GO:"neurofibrillary tangle") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence a27e639416
JSON

In support of this, protein kinase A (PKA) has similar effects on reducing Abeta generation and stimulating the budding of APP-containing vesicles from the TGN [207]

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

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence a784f94665
JSON

PKC stimulates sAPPalpha secretion, reducing Abeta levels, even when the phosphorylation sites on APP are mutated or the entire cytoplasmic domain is deleted [204]

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

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

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

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 031daac6f3
JSON

While PKC can directly phosphorylate APP Ser655 [205], it appears to affect APP metabolism by phosphorylating a different target

p(HGNC:PRKCA) directlyIncreases p(HGNC:APP, pmod(Ph, Ser, 655)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 4861fdad7c
JSON

Additionally, estrogen has been found to facilitate binding of Rab11 to the TGN membrane and a dominant negative Rab11 mutant abolishes the estrogen-regulated change in APP trafficking, leading to increased Abeta formation [197]

p(HGNC:RAB11A) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cell Membrane
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 36170edfec
JSON

Recently it was found that SorLA/ LR11 overexpression redistributed APP to the Golgi, decreasing Abeta generation, while SorLA/LR11 knockout mice have increased levels of Abeta, as found in AD patients [182]

p(HGNC:SORL1) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Hippocampus
MeSH
Down Syndrome

Evidence 3b8804d7f0
JSON

However, another study failed to confirm the binding of TMP23/p21 to gamma-secretase, but rather suggested that TMP21/p23, which belongs to the p24 cargo family involved in vesicular trafficking regulation, influences APP trafficking and thus Abeta generation [116]

p(HGNC:TMED10) regulates a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Endosomes
Confidence
High
MeSH
Neurons

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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.