P. ANGÉLICA MILLA VEGA

The ectodomain of APP can act as a cell surface receptor (Kang et al., 1987; Reinhard et al., 2013). The search for potential APP binding partners has shown APP interacts with various receptors and ligand molecules. The presence of two heparin binding sites in the extracellular APP favours it to act as a growth factor receptor in either its membrane bound state or as sAPPα. APP can undergo dimerization with its family members APLP1 or APLP2, and this promotes neurite outgrowth (Soba et al., 2005) (Table 1.5). Since sAPPα is secreted, it could interact with plasma membrane, synaptic or extracellular matrix proteins.

Table 1.5: List of sAPPα interacting proteins

Protein Function Reference

Soluble APP alpha (sAPPα) Cell adhesion and neurite outgrowth

(Soba et al., 2005)

Amyloid precursor-like protein 1 & 2 (APLP1, APLP2)

Cell adhesion and neurite outgrowth

(Soba et al., 2005; Rice et al., 2019)

31 Extracellular matrix proteins: The extracellular matrix proteins include proteoglycans (HSPGs, chondroitin sulphate proteoglycans), glycoproteins (laminin, fibronectin), structural proteins (collagen, elastin) and other matricellular proteins. The ectodomain of APP interacts with various extracellular proteins (Table 1.6), and sAPPα is known to interact with HSPGs (Narindrasorasak et al., 1991). Presence of heparin binding sites in D1 and D6a domains favours APP interaction with HSPGs, reelin and laminin to promote neurite outgrowth (Kibbey et al., 1993; Small et al., 1994; Hoe et al., 2009).

Table 1.6: List of sAPPα interacting extracellular matrix proteins

Protein Function Reference

Heparan sulphate proteoglycan Neurite outgrowth (Narindrasorasak et al., 1991)

Heparin APP dimerization in E1 domain (Small et al., 1994; Hoefgen et al., 2014)

Reelin Neurite outgrowth (Hoe et al., 2009)

F-spondin Alter APP proteolytic processing

by inhibiting β-secretase

(Ho and Sudhof, 2004)

Laminin Neurite outgrowth (Kibbey et al., 1993)

Netrin-1 Regulate amyloid beta production (Lourenco et al., 2009)

Fibulin-1 Fibulin-1 modulates APP

mediated neurotrophic activities

(Ohsawa et al., 2001)

Collagen Cell adhesion (Beher et al., 1996)

Glypican Inhibits APP induced neurite

outgrowth

(Williamson et al., 1996; Reinhard et al., 2013)

Syndecan -- (Reinhard et al., 2013)

Slit Axonal guidance and neural circuit

formation

(Wang et al., 2017)

Extracellular matrix protein 2 (SPARl1)

32 Synaptic proteins: The APP is an active component of pre and postsynapse and plays a role in synaptic vesicle recycling (Iwai et al., 1995; Marquez-Sterling et al., 1997; Wang et al., 2009; Rice et al., 2019). The binding of sAPPα to the inhibitory neurotransmitter, gamma- aminobutyric acid type B receptor subunit 1 and 2 regulates presynaptic vesicle release and synaptic transmission (Rice et al., 2019). The APP deficient mice show neuromuscular dysfunction resulting in poor motor function (Zheng et al., 1995). Also, APP null mice showed age-dependent cognitive deficits and impairment of long-term potentiation correlated with loss of presynaptic terminals and increased reactivate gliosis in the hippocampus and frontal cortex (Dawson et al., 1999). Lack of APP expression attenuates synaptic vesicle proteins, include synaptophysin, synaptotagmin-1 and synaptic vesicle protein 2A, but the opposite trend observed in APLP1-/- and APLP2-/- mice (Laßek et al., 2014). This suggests that APP and its family members regulate presynaptic machinery and sAPPα interacting synaptic membrane proteins listed in table 1.7.

Table 1.7: List of sAPPα interacting synaptic proteins

Protein Function Reference

Synaptotagmin-1,2,9 Promote amyloid beta generation (Kohli et al., 2012; Gautam et al., 2015) α- or β-synuclein Promote amyloid beta generation (Kohli et al., 2012;

Roberts et al., 2017)

Synaptic vesicle glycoprotein-2A -- (Kohli et al., 2012)

Glutamate receptors (GluN1, N2) Enhance cell surface expression of GluN1 and N2

(Cousins et al., 2015)

Gamma-amino butyric acid B receptor 1 & 2

Inhibit presynaptic vesicle release and transmission

(Bai et al., 2008; Rice et al., 2019)

33 Cell adhesion molecules: In addition to synaptic and extracellular matrix proteins, APP is reported to interact with various cell adhesion molecules (Table 1.8) and transmembrane receptors (Table 1.9). The cell adhesion molecules are membrane bound cell surface proteins support cell adhesion with the extracellular region. These include immunoglobulin, contactins, cadherins, neuroligins/neurexins and leucine rich repeat superfamily proteins (de Wit and Ghosh, 2016). These proteins play a role in nervous system development, synapse formation and regulate synaptic plasticity (Tan et al., 2017). APP act as a cell adhesion molecule and promote neuronal migration, axonal growth and guidance and synaptogenesis (Sosa et al., 2013; Chen et al., 2016).

The interaction of APP with neural cell adhesion molecule has a synergistic effect on promoting neurite outgrowth (Chen et al., 2016). Moreover, APP interacts with contactin and promote neuronal migration (Ramaker et al., 2016). APP and APLPs interact with integrin-1β and regulate neurite outgrowth (Young-Pearse et al., 2008). sAPPα competes with the full- length APP and interacts with integrin-1β to promote neurite outgrowth (Young-Pearse et al., 2008). However, recent study contradicted APP and integrin-1β mediated neurite outgrowth, showing the growth cone adhesion mediated axonal outgrowth function of APP is independent of integrin-1β (Sosa et al., 2013).

34 Table 1.8: List of sAPPα interacting cell adhesion proteins

Protein Function Reference

Immunoglobulin superfamily Neuron-glia cell

adhesion molecule (L1 / NgCAM)

Enhance APP expression and axonal growth and development

(Osterfield et al., 2008)

Neural cell adhesion molecule 1

Neurite outgrowth (Bai et al., 2008; Chen et al., 2016)

Down syndrome cell adhesion molecule

-- (Jia et al., 2017)

Thy1 cell surface antigen -- (Bai et al., 2008)

Neurofascin -- (Bai et al., 2008)

Contactin superfamily

Contactin Enhance APP expression and axonal growth and development

(Osterfield et al., 2008; Ramaker et al., 2016) Cadherin superfamily

N-Cadherin Promotes APP cis-dimerization and enhance amyloidogenic APP processing

(Asada-Utsugi et al., 2011)

Calsyntenin 1 Axonal transport alters APP processing and increase amyloid beta production

(Bai et al., 2008; Steuble et al., 2012; Vagnoni et al., 2012)

Leucine rich repeat molecules

Lingo-1 Promote lysosomal degradation of the amyloid beta peptide

(Bai et al., 2008; de Laat et al., 2015)

Nogo receptor Reduces surface expression of APP and favours APP processing by β-secretase resulting in amyloid beta production

(Zhou et al., 2011)

Nogo 66 receptor Reduce the amyloid beta level (Park et al., 2006b) Notch receptors Activates notch signalling pathway (Fischer et al., 2005; Oh

et al., 2005) Integrin superfamily

Integrin β1 Neurite outgrowth (Young-Pearse et al.,

35 Table 1.9: List of sAPPα interacting other transmembrane receptors

Protein Function Reference

Epidermal growth factor Neuronal proliferation (Caille et al., 2004)

Neurotrophin receptor p75 Neurite outgrowth (Hasebe et al., 2013)

Death receptor 6 Regulate APP mediated neuronal survival

(Xu et al., 2015)

Prion protein CNS development (Bai et al., 2008; Kaiser et

al., 2012) British precursor protein (BRI2) Enhance cellular APP and

modulate APP processing

(Fotinopoulou et al., 2005)

Pancortin (AMY, AMZ, BMY, BMZ isoforms)

Cortical precursor cell migration (Rice et al., 2012)

Calreticulin Regulate amyloid beta production by modulating γ-secretase activity

(Stemmer et al., 2013)

Homer 2 & 3 Inhibit APP processing (Parisiadou et al., 2008)

Plasma membrane calcium ATPase 2 (ATP2b2)

36