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Table 2 Additional references supporting the network diagram in Figure 1

From: Relationships between the amyloid precursor protein and its various proteolytic fragments and neuronal systems

Factor Details Reference
Akt Aβ increases Akt phosphorylation in the short term via a mechanism involving α7-nAChR and NMDARs, with phosphorylation levels returning to baseline over the long term [99]
AMPA receptors AMPA glutamate receptor density is reduced by Aβ oligomers via reduction of CamKII [100, 101]
ApoE Decreased levels of ApoE lead to increased β-cleavage [102]
  ApoE promotes polymerisation of Aβ into fibrils and enhances fibrillar Aβ deposition in neuritic plaques. The high affinity binding of Aβ to ApoE reduces ability of ApoE to bind lipids [103105]
Ca2+ sAPPα modulates Ca2+ signalling by activating high conductance K+ channels via a mechanism dependent on cGMP [106]
CD74 Interacts with APP and reduces expression of Aβ [107]
Cholesterol Interactions of cholesterol and APP may allow APP to react to cholesterol status of the cell [108]
  Membrane cholesterol correlates with β-secretase activity and inhibition of β-secretase activity leads to increased membrane cholesterol levels. Moderate reductions in cholesterol enhance the co-expression of APP and BACE1 and promote the production of Aβ [109, 110]
  Aβ binds lipids and has high affinity for cholesterol. Aggregated Aβ(1-40) may affect lipid transport. [111, 112]
  Aβ binds 24-hydroxycholesterol and affects membrane choline carriers  
Complement cascade Aβ activates neuronal complement cascade to induce the membrane attack complex and reduces complement regulatory proteins, increasing complement-mediated cytotoxicity [113]
Dishevelled Dvl-1 increases sAPPα production mediated via JNK and PKC/MAPK but not via p38 MAPK [114]
Electrophysiology Hippocampal and cortical electrophysiological processes are modulated by sAPPα [115]
 (1-40) suppresses epileptiform activity in hippocampal neurons [116]
Fe65 APP binds Fe65 at the YENPTY sequence with effects on gene transcription, cytoskeleton and cell motility. Binding of Fe65 to APP is dependent on phosphorylation state of Y682; phosphorylation of T668 reduces the binding of Fe65 to YENPTY. Binding of Fe65 reduces Aβ [117121]
Furin Furin enhances cleavage to active forms of ADAM10 and ADAM17, leading to enhanced α-cleavage [122]
Glucose/glutamate transport sAPPα enhances transport of glucose and glutamate in synapses and protects from oxidative stress via a mechanism involving cGMP [123]
Glutamate signalling sAPPα suppresses NMDA currents rapidly and reversibly at concentrations of approximately 0.011 nM, possibly involving cGMP and a protein phosphatase. Reductions in sAPPα lead to reduced tetanically induced NMDA currents while increased sAPPα increased these currents and enhanced LTP [124, 125]
G-protein signalling Aβ directly increases TNF-α at high levels and at low levels increases TNF-α release by altering GPCR signaling at early stages of disease progression by indirect effects on GPCR kinase 2/5 [126]
  Full length and processed APP can potentially interact with G proteins via the cytoplasmic tail and this can be altered by APP mutations around the G protein binding site. This interaction has the potential to alter G-protein signalling with wide ranging effects, including Ca2+ regulation and cell cycle pathways [127129]
HDL Aβ binds ApoA-I, ApoA-II, ApoE and ApoJ; binding modulates Aβ solubility [130]
Heparins Proteolysis of immature BACE1 to its mature active form is promoted by low concentrations of heparin and inhibited at higher concentrations. Certain heparin derivatives may act as inhibitors of BACE1 and have therapeutic potential [70, 131, 132]
IL-1β Enhanced α-cleavage by ADAM10/17 via up-regulation of P2Y2 receptors and may increase levels of ADAM10/17 by approximately threefold [133, 134]
  Increases expression of APP and β-cleavage in astrocytes [135]
Insulin degrading enzyme Aβ competes with insulin for IDE and reduced IDE availability may contribute to dementia [136]
Integrins sAPPα competes with APP for binding sites on integrin-β-1 and promotes neurite outgrowth [137]
  Aβ binds focal adhesion molecules and integrins and modulates integrin/FA signalling pathways involved in cell cycle activation and cell death. The αv integrin subunit is required for Aβ-associated suppression of LTP [138, 139]
Lipids Binding of Aβ to acidic lipid molecules promotes Aβ aggregation. Aβ binds membrane gangliosides, sphingolipids and cholesterol, which enhance Aβ aggregation [140142]
  Association of APP and BACE1 with lipid rafts increases Aβ [143]
  Aβ endocytosis may also involve lipid rafts [144]
  Sphingolipids enhance α-cleavage via MAPK/ERK signalling [145]
LTP Aβ suppresses LTP in hippocampal neurons via a mechanism involving α4β2 nAChRs; Aβ affects cascades downstream of NMDA GluR signaling [146, 147]
Muscarinic Ach signaling Increases in mAChR-M1 and -M3 activation upregulate α-cleavage via PKC activation. Muscarinic upregulation of sAPPα secretion may involve the activation of a Src tyrosine kinase, leading to activation of PKCα and ERK1/2 Increased M2 activation decreases sAPPα secretion [75, 148151]
  Inhibition of muscarinic signalling promotes APP processing via β-pathway. Increased M1/M3 signalling promoted β-cleavage via PKC; MEK/ERK and increased expression of BACE1; M2 activation suppressed BACE expression [152, 153]
MAPK/ERK signalling MAPK cascade may mediate the independent effects of PKC and tyrosine kinase in human astrocytes [154]
Neurite outgrowth APP enhances neurite outgrowth independently from sAPPα [155]
NF-κB May reduce expression of BACE1 [156]
  NF-κB upregulation by capacitive Ca2+ entry enhances sAPPα release via mAChR signalling [157]
Nicotinic ACh signalling (1-40) and Aβ(1-42) reduced Α4β2 nAChR and α7 nAChR currents. Aβ(1-40) but not Aβ(1-42) increased glutamatergic AMPA. Signalling via Α4β2 nAChR is associated with reduced Aβ [40, 158]
  Aβ has high affinity for the α7 nAChR and this may be associated with increased Aβ accumulation. Differential effects of Aβ(1-40) and Aβ(1-42) on α7 nAChR as seen by different effects on ACh release and Ca2+ influx. Disruption of signalling by α7 nAChR may be associated with Aβ-mediated increases in pre-synaptic Ca2+ [39, 159, 160]
 (1-42) has approximately 5,000-fold greater affinity for α7 nAChR than for Α4β2 nAChR [161]
NMDA GluR Aβ promotes endocytosis of NMDARs in cortical neurons with the involvement of protein phosphatase 2B and the tyrosine phosphatase STEP [162]
Nucleotide signaling via P2Y2 receptors G-protein-coupled purine receptor, P2Y2 enhanced the release of sAPPα in a time- and dose-dependent manner; probably mediated via ADAM10 and ADAM17 [163]
numb APP binds numb when Y682 is unphosphorylated and inhibits Notch signalling [164]
PKA/CREB Aβ inhibits PKA via increased persistence of its regulatory subunit PKAIIα, resulting in reduced CREB phosphorylation in response to glutamate [73]
PKC PKC activators enhance α-cleavage [165, 166]
  Aβ inhibits PKC [167]
Reelin Reelin interacts with APP and Α3/β1-integrins and promotes neurite extension; APP endocytosis is reduced. Reelin signalling opposes the actions of Aβ [56, 168]
Src, Abl, Lyn, JNK/JIP1 These tyrosine kinases bind to APP when phosphorylated at Y682 with affinity increased by phosphorylation of T668. JNK phosphorylation of APP at T668 modulated by JIP1 [169, 170]
TIMP-3 Increases in TIMP-3 led to decreased surface expression of ADAM10 and APP. The production of Aβ and CTF is increased. TIMP-3 appears to promote endocytosis and β-secretase cleavage [171]
Transthyretin Neuroprotection in transgenic mice over-expressing mutant APP is associated with elevated levels of transthyretin and sAPPα and may be linked to increased proteolysis of Aβ [172, 173]
  1. Aβ, amyloid beta protein; ACh, acetylcholine; ADAM, a disintegrin and metalloproteinase domain-containing protein; Akt, RAC-alpha serine/threonine-protein kinase; AMPA, 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid; ApoE, apolipoprotein E; APP, amyloid precursor protein; CamKII, calcium/calmodulin dependent protein kinase type II; CD74, HLA class II histocompatibility antigen gamma chain; CREB, cyclic adenosine monophosphate response element-binding; CTF, carboxy-terminal fragment; ERK, extracellular signal-regulated kinase; FA, fatty acids; GluR, glutamate receptor; GPCR, G-protein-coupled receptor; HDL, high-density lipoprotein; IDE, insulin degrading enzyme; JIP1, C-Jun-amino-terminal kinase-interacting protein 1; JNK, C-Jun amino-terminal kinase; LTD, long-term depression; LTP, long-term potentiation; Lyn, tyrosine-protein kinase Lyn; MAPK, mitogen-activated protein kinase; mAChR, muscarinic acetylcholine receptor; MEK, ERK activator kinase; nAChR, nicotinic acetylcholine receptor; NMDAR, NMDA receptor; P2Y2, P2Y purinoceptor 2; PKA, protein kinase A; PKC, protein kinase C; sAPP, secreted amyloid precursor protein; Src, proto-oncogene tyrosine-protein kinase Src; TIMP, tissue inhibitor of metalloproteinases.