Table 2 Additional references supporting the network diagram in Figure 1

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

AMPA receptors

AMPA glutamate receptor density is reduced by Aβ oligomers via reduction of CamKII

ApoE

Decreased levels of ApoE lead to increased β-cleavage

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

Ca²⁺

sAPPα modulates Ca²⁺ signalling by activating high conductance K⁺ channels via a mechanism dependent on cGMP

CD74

Interacts with APP and reduces expression of Aβ

Cholesterol

Interactions of cholesterol and APP may allow APP to react to cholesterol status of the cell

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

Aβ binds lipids and has high affinity for cholesterol. Aggregated Aβ_(1-40) may affect lipid transport.

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

Dishevelled

Dvl-1 increases sAPPα production mediated via JNK and PKC/MAPK but not via p38 MAPK

Electrophysiology

Hippocampal and cortical electrophysiological processes are modulated by sAPPα

Aβ_(1-40) suppresses epileptiform activity in hippocampal neurons

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

Furin

Furin enhances cleavage to active forms of ADAM10 and ADAM17, leading to enhanced α-cleavage

Glucose/glutamate transport

sAPPα enhances transport of glucose and glutamate in synapses and protects from oxidative stress via a mechanism involving cGMP

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

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

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

HDL

Aβ binds ApoA-I, ApoA-II, ApoE and ApoJ; binding modulates Aβ solubility

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

IL-1β

Enhanced α-cleavage by ADAM10/17 via up-regulation of P2Y2 receptors and may increase levels of ADAM10/17 by approximately threefold

Increases expression of APP and β-cleavage in astrocytes

Insulin degrading enzyme

Aβ competes with insulin for IDE and reduced IDE availability may contribute to dementia

Integrins

sAPPα competes with APP for binding sites on integrin-β-1 and promotes neurite outgrowth

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

Lipids

Binding of Aβ to acidic lipid molecules promotes Aβ aggregation. Aβ binds membrane gangliosides, sphingolipids and cholesterol, which enhance Aβ aggregation

Association of APP and BACE1 with lipid rafts increases Aβ

Aβ endocytosis may also involve lipid rafts

Sphingolipids enhance α-cleavage via MAPK/ERK signalling

LTP

Aβ suppresses LTP in hippocampal neurons via a mechanism involving α4β2 nAChRs; Aβ affects cascades downstream of NMDA GluR signaling

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

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

MAPK/ERK signalling

MAPK cascade may mediate the independent effects of PKC and tyrosine kinase in human astrocytes

Neurite outgrowth

APP enhances neurite outgrowth independently from sAPPα

NF-κB

May reduce expression of BACE1

NF-κB upregulation by capacitive Ca²⁺ entry enhances sAPPα release via mAChR signalling

Nicotinic ACh signalling

Aβ_(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

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⁺

Aβ_(1-42) has approximately 5,000-fold greater affinity for α7 nAChR than for Α4β2 nAChR

NMDA GluR

Aβ promotes endocytosis of NMDARs in cortical neurons with the involvement of protein phosphatase 2B and the tyrosine phosphatase STEP

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

numb

APP binds numb when Y₆₈₂ is unphosphorylated and inhibits Notch signalling

PKA/CREB

Aβ inhibits PKA via increased persistence of its regulatory subunit PKAIIα, resulting in reduced CREB phosphorylation in response to glutamate

PKC

PKC activators enhance α-cleavage

Aβ inhibits PKC

Reelin

Reelin interacts with APP and Α3/β1-integrins and promotes neurite extension; APP endocytosis is reduced. Reelin signalling opposes the actions of Aβ

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

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

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