Cell adhesion molecules in Alzheimer’s disease

Figures & data

Figure 1 Schematic illustration of the various CAM structures. Ig-like CAMs are defined by one or more extracellular Ig repeats of 60 to 100 amino acids that form the active adhesion site and a transmembrane segment with a cytoplasmic tail. Classical cadherins have five extracellular cadherin repeats, a single transmembrane domain, and an intracellular tail. Integrin heterodimeric receptors are formed by α and β transmembrane units. Selectins have a short cytoplasmic carboxyl terminus, a transmembrane sequence followed by complement regulatory-like molecules, and an extracellular component containing an epidermal growth factor-like domain and an amino terminal domain that is homologous to C-type lectins. Adapted with permission from Marchetti PJ, O’Connor P. Cellular adhesion molecules in neurology. Can J Neurol Sci. 1997;24(3):201.¹¹

Abbreviations: CAM, cell adhesion molecule; Ig, immunoglobulin.

Table 1 Representative CAMs and expression distribution

CAMs	Expression distribution
Selectins
E-selectin	Endothelium, activated astrocytes
P-selectin	Endothelium, platelets
L-selectin	Leukocytes
Integrins
α5β1	B- and T-cells, astrocytes, endothelium
α1β1	Astrocytes, endothelium
α6β1	T-cells, microglia, oligodendroglia endothelium
αvβ3	B- and T-cells, monocytes, endothelium, microglia, oligodendroglia
αLβ2	Leukocytes, macrophages, T-cells, microglia
αMβ2	B-cells, NK-cells, macrophages, microglia
αXβ2	Dendritic cells, B-cells, macrophages, microglia
Immunoglobulin superfamily
ICAM-1	Endothelium, astrocytes, microglia
NCAM	Neurons
VCAM-1	Endothelium, monocytes
PECAM-1	Endothelium, leukocytes
L1CAM	Neurons
Cadherins
Classical cadherins
N-cadherin	Neurons
E-cadherin	Endothelium, neurons
Protocadherins
Clustered	Neurons
Nonclustered	Neurons

Abbreviations: CAM, cell adhesion molecule; E-cadherin, epithelial cadherin; E-selectin, endothelial leukocyte cell adhesion molecule; ICAM-1, intercellular cell adhesion molecule 1; L1CAM, L1 cell adhesion molecule; L-selectin, leukocyte selectin; N-cadherin, neuronal cadherin; NCAM, neural cell adhesion molecule; PECAM-1, platelet endothelial cell adhesion molecule 1; P-selectin, platelet-activation-dependent granule-external protein; VCAM-1, vascular cell adhesion molecule 1.

Table 2 CAMs linked to AD pathological events

Cell adhesion molecule	Mechanism	Reference
Neuronal plasticity
NCAM	Increased expression in hippocampus of AD brain, decreased expression in frontal/temporal cortex of AD brain, tendency to increased CSF levels in AD patients	^Citation43^–^Citation46
L1CAM	Increased in CSF from AD patients	^Citation49
N-cadherin	Cleavage inhibited and upregulated/downregulated in response to Aβ in vivo, synapse stabilization dependent on presenilin cleavage	^Citation18,Citation52^–^Citation54,Citation56,Citation57,Citation59,Citation60
Integrin unit αv	Mediate Aβ-induced LTP inhibition	^Citation61
Aβ metabolism
Integrin unit α4	Increased in aged brain, found adjacent to plaques	^Citation62
Integrin unit β3	Found adjacent to plaque and tangles	^Citation63
α5β1	Involved in degradation of Aβ in vitro	^Citation67
Integrin/FAK	Involved in modulation of Aβ neurotoxicity	^Citation65
α1β1	Downregulated by Aβ in vitro, rescued by estradiol	^Citation66
N-cadherin	Increased APP dimerization, Aβ release, decrease Aβ42/40 ratio	^Citation70,Citation71
E-cadherin	Promote APP derivate, inhibit Aβ production	^Citation75
Integrin unit β1	Mediate microglial internalization of fibrillar Aβ	^Citation68
Immunological events
ICAM-1	Upregulated in response to Aβ in vitro, increased plasma levels in AD patients, increased expression in Aβ plaque, identified in plaque, correlated with hyaluronic acid in female AD	^Citation84,Citation90,Citation92^–^Citation96
VCAM-1	Upregulated in response to Aβ in vitro, increased plasma levels in AD patients, decreased CSF levels in AD patients,	^Citation84,Citation92,Citation93
PECAM-1	Involved in Aβ-induced transendothelial migration of monocytes, increased plasma levels in AD patients	^Citation84,Citation92
α6β1	Mediate fibrillar Aβ induced microglial activation	^Citation100
αvβ3/5	Mediate neuronal phagocytic signal to microglial	^Citation101
αLβ2	Increased expression in AD brain	^Citation143
αMβ2	Increased expression in AD brain, mediate Aβ induced neuroinflammation	^Citation103,Citation143
αXβ2	Increased expression in AD brain	^Citation143
Vascular changes
E-selectin	Increased in plasma of AD patients with vascular changes	^Citation93,Citation108
P-selectin	Increased in plasma of AD patients with fast cognitive decline
αvβ3	Increased in angiogeneic vessels in AD brain	^Citation114

Abbreviations: Aβ, amyloid-β; AD, Alzheimer’s disease; APP, amyloid precursor protein; CAM, cell adhesion molecule; CSF, cerebrospinal fluid; E-cadherin, epithelial cadherin; E-selectin, endothelial leukocyte cell adhesion molecule; FAK, focal adhesion kinase; ICAM-1, intercellular cell adhesion molecule 1; L CAM, L cell adhesion molecule; LTP, long-term potentiation; N-cadherin, neuronal cadherin; NCAM, neural cell adhesion molecule; PECAM-1, platelet endothelial cell adhesion molecule 1; P-selectin, platelet-activation-dependent granule-external protein; VCAM-1, vascular cell adhesion molecule 1.

MarchettiPJO’ConnorPCellular adhesion molecules in neurologyCan J Neurol Sci19972432002099276104

 PubMed Web of Science ®Google Scholar

MikkonenMSoininenHTapiolaTAlafuzoffIMiettinenRHippocampal plasticity in Alzheimer’s disease: changes in highly polysialylated NCAM immunoreactivity in the hippocampal formationEur J Neurosci19991151754176410215928

 PubMed Web of Science ®Google Scholar

YewDTLiWPWebbSELaiHWZhangLNeurotransmitters, peptides, and neural cell adhesion molecules in the cortices of normal elderly humans and Alzheimer patients: a comparisonExp Gerontol199934111713310197733

 PubMed Web of Science ®Google Scholar

StrekalovaHBuhmannCKleeneRElevated levels of neural recognition molecule L1 in the cerebrospinal fluid of patients with Alzheimer disease and other dementia syndromesNeurobiol Aging20062711916298234

 PubMed Web of Science ®Google Scholar

KopanRIlaganMXγ-Secretase: proteasome of the membrane?Nat Rev Mol Cell Biol20045649950415173829

 PubMed Web of Science ®Google Scholar

UemuraKKuzuyaAAoyagiNAmyloid beta inhibits ectodomain shedding of N-cadherin via down-regulation of cell-surface NMDA receptorNeuroscience2007145151017257767

 PubMed Web of Science ®Google Scholar

AndoKUemuraKKuzuyaAN-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein: implications for neurodegeneration in Alzheimer diseaseJ Biol Chem201128697619762821177868

 PubMed Web of Science ®Google Scholar

HeiligEAXiaWShenJKelleherRJ3rdA presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activityJ Biol Chem201028529223502235920460383

 PubMed Web of Science ®Google Scholar

MarambaudPWenPHDuttAA CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutationsCell2003114563564513678586

 PubMed Web of Science ®Google Scholar

KouchiZBarthetGSerbanGGeorgakopoulosAShioiJRobakisNKp120 catenin recruits cadherins to gamma-secretase and inhibits production of Abeta peptideJ Biol Chem200928441954196119008223

 PubMed Web of Science ®Google Scholar

UemuraKKuzuyaAShimohamaSProtein trafficking and Alzheimer’s diseaseCurr Alzheimer Res20041111015975080

 PubMed Web of Science ®Google Scholar

RowanMJKlyubinIWangQHuNWAnwylRSynaptic memory mechanisms: Alzheimer’s disease amyloid beta-peptide-induced dysfunctionBiochem Soc Trans200735Pt 51219122317956317

 PubMed Web of Science ®Google Scholar

Van GoolDCarmelietGTriauECassimanJJDomRAppearance of localized immunoreactivity for the alpha 4 integrin subunit and for fibronectin in brains from Alzheimer’s, Lewy body dementia patients and aged controlsNeurosci Lett1994170171738041517

 PubMed Web of Science ®Google Scholar

AkiyamaHKawamataTDedharSMcGeerPLImmunohistochemical localization of vitronectin, its receptor and beta-3 integrin in Alzheimer brain tissueJ Neuroimmunol199132119281705945

 PubMed Web of Science ®Google Scholar

MatterMLZhangZNordstedtCRuoslahtiEThe alpha5beta1 integrin mediates elimination of amyloid-beta peptide and protects against apoptosisJ Cell Biol19981414101910309585419

 PubMed Web of Science ®Google Scholar

CaltagaroneJJingZBowserRFocal adhesions regulate Abeta signaling and cell death in Alzheimer’s diseaseBiochim Biophys Acta20071772443844517215111

 PubMed Web of Science ®Google Scholar

BozzoCGraziolaFChiocchettiACanonicoPLEstrogen and beta-amyloid toxicity: role of integrin and PI3-KMol Cell Neurosci2010452859120538057

 PubMed Web of Science ®Google Scholar

Asada-UtsugiMUemuraKNodaYN-cadherin enhances APP dimerization at the extracellular domain and modulates Aβ productionJ Neurochem2011119235436321699541

 PubMed Web of Science ®Google Scholar

UemuraKLillCMBanksMN-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratioJ Neurochem2009108235036019046403

 PubMed Web of Science ®Google Scholar

AgiostratidouGMurosRMShioiJMarambaudPRobakisNKThe cytoplasmic sequence of E-cadherin promotes non-amyloidogenic degradation of A beta precursorsJ Neurochem20069641182118816417575

 PubMed Web of Science ®Google Scholar

KoenigsknechtJLandrethGMicroglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanismJ Neurosci200424449838984615525768

 PubMed Web of Science ®Google Scholar

GiriRShenYStinsMbeta-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1Am J Physiol Cell Physiol20002796C1772C178111078691

 PubMed Web of Science ®Google Scholar

RentzosMMichalopoulouMNikolaouCThe role of soluble intercellular adhesion molecules in neurodegenerative disorders. J Neurol Sci1520052282129135

 Google Scholar

NielsenHMLondosEMinthonLJanciauskieneSMSoluble adhesion molecules and angiotensin-converting enzyme in dementiaNeurobiol Dis2007261273517270454

 PubMed Web of Science ®Google Scholar

RozemullerJMEikelenboomPPalsSTStamFCMicroglial cells around amyloid plaques in Alzheimer’s disease express leucocyte adhesion molecules of the LFA-1 familyNeurosci Lett198910132882922549464

 PubMed Web of Science ®Google Scholar

ZulianiGCavalieriMGalvaniMMarkers of endothelial dysfunction in older subjects with late onset Alzheimer’s disease or vascular dementiaJ Neurol Sci20082721–216417018597785

 PubMed Web of Science ®Google Scholar

BambergerMEHarrisMEMcDonaldDRHusemannJLandrethGEA cell surface receptor complex for fibrillar beta-amyloid mediates microglial activationJ Neurosci20032372665267412684452

 PubMed Web of Science ®Google Scholar

NeniskyteUNeherJJBrownGCNeuronal death induced by nanomolar amyloid beta is mediated by primary phagocytosis of neurons by microgliaJ Biol Chem201128646399043991321903584

 PubMed Web of Science ®Google Scholar

AkiyamaHMcGeerPLBrain microglia constitutively express beta-2 integrinsJ Neuroimmunol199030181931977769

 PubMed Web of Science ®Google Scholar

RyuJKMcLarnonJGA leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brainJ Cell Mol Med2009139A2911292518657226

 PubMed Web of Science ®Google Scholar

BorroniBColciaghiFPastorinoLApoE genotype influences the biological effect of donepezil on APP metabolism in Alzheimer disease: evidence from a peripheral modelEur Neuropsychopharmacol200212319520012007670

 PubMed Web of Science ®Google Scholar

GrammasPSanchezATripathyDLuoEMartinezJVascular signaling abnormalities in Alzheimer diseaseCleve Clin J Med201178Suppl 1S50S5321972332

 PubMedGoogle Scholar