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Table 1 Biochemical and biophysical evidence of interactions of Aβ with other proteins, and their presence in senile plaque and potential for AD biomarker

From: Extracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology

Protein name Bound to Aβ in vitro Found in post-mortem AD plaque and CAA Candidate biomarker for AD
Aβ monomer, oligomers, and protofibrils Aβ fibrils
Reported by Brain region; and plaque types/CAA
Immunoglobulins      
Ig alpha-1 chain C region [50]a [52, 56]b,d [32, 33, 59, 60]f,j†,g,h HCf, FCtxj†, HCg, CCtx and Cveh [61]:↑P
[62]:↑C
Ig gamma-1 chain C region [50]a [51, 52, 56]e,b,d [26, 32, 33, 59]i,f,j†,g F-tCtxi, HCf, FCtxj†, HCg [61]:↓P
Ig gamma-2 chain C region [50]a [52, 56]b,d [26, 32, 33, 59]i,f,j†,g F-tCtxi, HCf, FCtxj†, HCg  
Ig gamma-3 chain C region [50]a [52, 56]b,d [26, 32, 33, 59]i,f,j†,g F-tCtxi, HCf, FCtxj†, HCg  
Ig kappa chain C region [50]a [51, 52, 56]e,b,d [26, 32, 33, 59, 60]i,f,j†,g,h F-tCtxi, HCf, FCtxj†, HCg, CCtx and Cveh [61]:↑P
Ig mu chain C region [50]a [51, 52, 56]e,b,d [32, 33]f,j† HCf, FCtxj† [61]:↓P
Immunoglobulin heavy constant alpha 2   [51, 56]e,d    
Immunoglobulin heavy variable 3-7   [51, 53]e,j    
Complement system      
Alpha-1-antichymotrypsin [50, 63,64,65]a,k,l,n [56]d [28, 31, 32, 59, 60, 66, 67]q,r,f,g,h,s,t FCtx and TCtxr, HCf,g, CCtx and Cveh, PreFCtxs [68]:↑P
[69]:↑C
C4b-binding protein alpha chain   [52, 53, 56]b,j,d [28, 32, 33]q,g,j† HCf, FCtxj†  
Complement C1q subcomponent subunit A/subunit B/subunit C [50, 70]a,u [51, 56, 71, 72]e,d,v,w [26, 28, 31,32,33, 59, 60, 66, 73]i,q,r,f,g,j†,h,s,x F-tCtxi, FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs, TLbx; CPx [74]:↓C (subunit B/C)
Complement C1r subcomponent   [51,52,53, 56]e,b,j,d [32, 33]f,j† HCf, FCtxj†  
Complement C1s subcomponent   [51,52,53, 56]e,b,j,d [32, 33]f,j† HCf, FCtxj† [74]:↓C
Complement C3 [50]a
0.3 μM (Aβ42PF)a
[51,52,53, 56, 72, 75]e,b,j,d,w,y [26, 28, 31,32,33, 59, 60, 66, 73]i,q,r,f,j†,g,h,s,x F-tCtxi, FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs, TLbx; CP and DPx [76, 77]:↑P/S, [78]:↑C
Complement C4-A/C4-B [50]a [51,52,53, 56, 72]e,b,j,d,w [26, 31, 32, 59, 60, 66, 73] i,r,f,g,h,s,x F-tCtxi, FCtx and TCtxr, HCf,g, CCtx and Cveh, PreFCtxs, TLbx; CP and DPx [61, 76]:↑↓S, [79]:↑C
Complement C5   [53, 56, 72]j,d,w [32, 33]f,j† HCf, FCtxj†  
Complement component C7   [51, 53, 56]e,j,d [32, 33]f,j† HCf, FCtxj†  
Complement component C8 gamma chain   [53, 56]j,d [32, 33, 60]f,j†,h HCf, FCtxj†, CCtx and Cveh  
Complement component C9   [51, 53, 56]e,j,d [32, 33]f,j† HCf, FCtxj†  
Complement factor H   [51,52,53, 56]e,b,j,d [32, 33, 59]f,j†,g HCf, FCtxj†, HCg [61, 76]:↑P/S
Complement factor H-related protein 5 [50]a [51, 56]e,d    
Inter-alpha-trypsin inhibitor heavy chain H4 [50]a [51, 53, 56]e,j,d [32, 33]f,j† HCf, FCtxj† [61]:↓P,
[80]:↑C
Monocyte differentiation antigen CD14 [50]a [51, 56]e,d [32, 33]f,j† HCf, FCtxj†  
Plasma protease C1 inhibitor   [51, 56]e,d [32, 33, 60]f,j†,h HCf, FCtxj†, CCtx and Cveh  
Lipid metabolism/transport      
Apolipoprotein A-I [50, 81,82,83,84]a,z,a†,b†,d†
3 μM (Aβ42PF)a,
6 nM (Aβ40M)d†
[51,52,53, 56, 85]e,b,j,d,e† [32, 33, 59, 60, 66, 86]f,j†,g,h,s,f† HCf, FCtxj†, HCg,, CCtx and Cveh, PreFCtxs, HCf† [87,88,89]:↓ S/P, [90]:↑C
Apolipoprotein A-II [50, 82]a,a† [51,52,53, 56, 85]e,b,j,d,e† [32, 33]f,j† HCf, FCtxj†  
Apolipoprotein A-IV [50, 83]a,b† [51,52,53, 56]e,b,j,d [32, 33]f,j† HCf, FCtxj† [88]:↑P,
[80]: ↑C
Apolipoprotein B-100 [50]a [52]b [32, 33, 60]f,j†,h HCf, FCtxj†, CCtx and Cveh [76, 89]:↑↓S
Apolipoprotein C-I   [51, 52, 56]e,b,d    [91]:↓C
Apolipoprotein C-II [92]g† [51, 52]e,b [32, 33]f,j† HCf, FCtxj†  
Apolipoprotein C-III   [51,52,53, 56]e,b,j,d [32, 33, 59]f,j†,g HCf, FCtxj†, HCg  
Apolipoprotein C-IV [50]a [51, 56]e,d    
Apolipoprotein D [50]a [51, 52, 56]e,b,d [32, 33, 59, 60, 66, 93, 94]f, j†,g,h,s,h†,i† HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs, CCtx and HCh†,i†; DP, around CP, and CAAh†,i† [95, 96]:↓C
Apolipoprotein E [50, 63, 82,83,84]a,k,a†,b†,d†
3 nM (Aβ42PF)a,
19 nM (Aβ40M)d†
[51,52,53, 56, 85]e,b,j,d,e† [28, 31,32,33, 59, 60, 66, 94] q,r,f,j†,g,h,s,i† FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs, CCtx and HCi†; CP, DP, and CAAi† [76]:↑S, [78, 97, 98]:↑↓C
Apolipoprotein L1   [51, 53, 56]e,j,d [32, 33]f,j† HCf, FCtxj†  
Beta-2-glycoprotein 1   [51, 56]e,d [32, 33]f,j† HCf, FCtxj†  
Clusterin (a.k.a, ApoJ) [50, 81,82,83, 99, 100]a,z,a†,b†,k†,l†
4.8 nM (Aβ40M)k†,
2 nM (AβM)l†
[51,52,53, 56, 85]e,b,j,d,e† [28, 31,32,33, 59, 60, 66, 73, 101]q,r,f,j†,g,h,s,x,n† FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs, TLbx, EntCtxn†;CPx,n† [102]:↓P,
[78]:↑C
Phospholipid transfer protein [50]a [51, 56]e,d [32, 33]f,j† HCf, FCtxj†  
Prostaglandin-H2 D-isomerase [50]a [51, 56]e,d [32, 59, 60, 66]f,g,h,s HCf,g, CCtx and Cveh, PreFCtxs [62, 103]:↑↓C
Serum amyloid A-4 protein [50]a [51, 53, 56]e,j,d [32, 33]f,j† HCf, FCtxj†  
Blood coagulation/hemostasis      
Adipocyte enhancer-binding protein 1   [51, 56]e,d    
Alpha-1-antitrypsin [50]a [51, 52, 56]e,b,d [28, 31,32,33, 59, 60, 66]q,r,f,j†,g,h,s FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs [89, 102, 104]:↑↓ P/S, [80, 96]:↑↓C
Alpha-2-macroglobulin [84, 105, 106]d†,r†,s†
0.34 μM (Aβ40M)d†,
0.35 μM (Aβ40M)r†, 38 μM (Aβ42M)s†
[53, 56]j,d [28, 31,32,33, 59, 60, 66]q,r,f,j†,g,h,s FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs [61, 76, 107]:↑ P/S
Angiotensinogen [50]a [51, 56]e,d [32, 33, 59]f,j†,g HCf, FCtxj†, HCg  
Antithrombin-III [50]a
0.6 μM (Aβ42PF)a
[51, 53, 56]e,j,d [32, 33, 59, 108]f,j†,g,t† HCf, FCtxj†, HCg, CCtxt†; CPt† [69, 80]:↑C
Beta-1,4-glucuronyltransferase1   [51, 56]e,d [32, 59]f,g HCf,g  
Carboxypeptidase B2   [53, 56]j,d [33]j† FCtxj†  
Coagulation factor V [50]a [51, 56]e,d [33]j† FCtxj†  
Coagulation factor X   [51, 52, 109]e,b,u† [33]j† FCtxj†  
Coagulation factor XII [110]v† [53, 56, 111]j,d,w† [32, 33, 66]f,j†,s HCf, FCtxj†, PreFCtxs  
Fibrinogen alpha−, beta−, and gamma−chain [50, 112]a,x†
26 nM (Aβ42M)x†
[51, 52, 56]e,b,d [31,32,33, 59, 60, 66, 113]r,f,j†,g,h,s,y† FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs, FCtxy†; CAAy† [77, 88, 89]:↑↓ P/S, [98]:↑C
Fibronectin [50]a [51,52,53, 56, 109]e,b,j,d, u† [32, 33, 59, 66]j†,f,g,s HCf, FCtxj†, HCg, PreFCtxs [89]:↑S
Growth arrest-specific protein 6   [51, 56]e,d [33]j† FCtxj† [114]:↑C
Heparin cofactor 2 [50]a [51, 56]e,d [32, 33]f,j† HCf, FCtxj†  
Histidine-rich glycoprotein [50]a [52, 56]b,d [32, 33, 59]j†,f,g FCtxj†, HCf,g [76]:↑S
Hyaluronan-binding protein 2   [52, 56]b,d [31,32,33]r,f,j† FCtx and TCtxr, HCf, FCtxj†  
Kininogen-1   [51, 53, 56]e,j,d [32, 33]f,j† HCf, FCtxj†  
Plasminogen   [51, 53, 109]e,j,u† [32, 33]f,j† HCf, FCtxj† [78]:↑C
[88]:↓P
Prothrombin [50]a [51,52,53, 56]e,b,j,d [32, 33]f,j† HCf, FCtxj†  
Vitamin K-dependent protein S   [51,52,53, 56]e,b,j,d [32, 33]f,j† HCf, FCtxj†  
Metabolism      
Alpha-enolase [50]a [51, 56]e,d [32, 33, 59, 60, 66, 115]f,j†,g,h,s,z† HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs  
Glyceraldehyde-3-phosphate dehydrogenase [50, 63]a,k [51, 56, 116]e,d,a‡ [31, 32, 59, 60, 66]r,f,g,h,s FCtx and TCtxr, HCf,g, CCtx and Cveh, PreFCtxs  
Phosphoglycerate kinase 1 [50]a [56]d [31,32,33, 59, 60, 66]r,f,j†,g,h,s FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs  
Procollagen C-endopeptidase enhancer 1 [50]a [51, 56]e,d    
Molecular transport      
Haptoglobin [50]a [53, 56]j,d [32, 33, 59, 60, 66]f,j†,g,h,s HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs [76]:↑S
Hemoglobin subunit alpha/subunit beta [50]a [51, 56]e,d [31,32,33, 59, 60, 66]r,f,j†,g,h,s FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs [76]:↑S
Hemopexin   [53, 56]j,d [32, 33, 59]f,j†,g HCf, FCtxj†, HCg [104]:↑P
Inter-alpha-trypsin inhibitor heavy chain H2 [50]a [53, 56]j,d [32, 33]f,j† HCf, FCtxj†  
Serotransferrin [50]a [53, 56]j,d [31,32,33, 59, 66]r,f,j†,g,s FCtx and TCtxr, HCf, FCtxj†, HCg, PreFCtxs  
Serum albumin [50, 83, 117,118,119,120]a,b†, b‡,c‡,d‡,e‡
1–100 nM (Aβ40O)b‡, 1.7 μM (Aβ42M)c‡, 5 μM (Aβ40M)d‡, ~0.1–1 mM (Aβ40M)e‡
[51,52,53, 56, 109]e,b,j,d,u† [31,32,33]r,f,j† FCtx and TCtxr, HCf, FCtxj† [61]:↑P, [62, 98]:↑↓C
Transthyretin [81, 121]z,f‡
~28 nM (Aβ40M/O)f‡
[51, 52, 56, 121] [122]e,b,d,f‡,h‡
~28 nM (Aβ42F)f‡
[32, 33, 66]f,j†,s HCf, FCtxj†, PreFCtxs [76]:↑S, [78]:↑C
Vitamin D-binding protein   [51,52,53, 56]e,b,j,d [32, 33, 59]f,j†,g HCf, FCtxj†, HCg [102]:↑P,
[78]:↑C
Neural proteins      
Amyloid-like protein 1   [51, 52, 56]e,b,d [32, 33, 59]f,j†,g HCf, FCtxj†, HCg [62, 123]:↑↓C
Brevican core protein   [51, 109]e,u† [32, 33, 59, 60, 66]f,j†,g,h,s HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs  
Neural cell adhesion molecule 1   [51, 56]e,d [31,32,33, 59, 60, 66]r,f,j†,g,h,s FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs [103]:↑C
Neurocan core protein   [51, 109]e,u†
11.7 nM (Aβ42F)e
[32, 33, 59, 60, 66]f,j†,g,h,s HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs  
Neurosecretory protein VGF   [51, 56]e,d [32, 33, 59, 66]f,j†,g,s HCf, FCtxj†, HCg, PreFCtxs [79, 90, 124, 125]:↓C
ProSAAS   [51, 52, 56]e,b,d [32, 33, 59, 60, 66]f,j†,g,h,s HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs [62, 78]:↑↓C
Cell adhesion, extracellular matrix, and proteoglycans      
Agrin   [51, 109, 126]e,u†,i‡
3.5 nM (Aβ42F)e
[32, 33, 59, 60, 66, 126]f,j†,g,h,s,j‡ HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs, FCtxj‡; CP, DP, and CCA j‡ [127]k‡
Basement membrane-specific heparan sulfate proteoglycan core protein   [51, 56]e,d [32, 33, 59, 60, 66]f,j†,g,h,s HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs  
Cartilage acidic protein 1 [50]a [51, 56]e,d [32, 33, 59, 60]f,j†,g,h HCf, FCtxj†, HCg, CCtx and Cveh  
Collagen alpha-1(XVIII) chain [50]a [51, 56]e,d [32, 33, 59, 66]f,j†,g,s HCf, FCtxj†, HCg, PreFCtxs  
Decorin [50, 128]a,l‡ [51, 56, 109]e,d,u† [32, 33, 129]f,j†,n‡ HCf, FCtxj†, HCn‡; CPn‡  
Desmoplakin [50]a [51, 56]e,d [32, 33, 59, 66]f,j†,g,s HCf, FCtxj†, HCg, PreFCtxs [61]:↑P
EGF-containing fibulin-like extracellular matrix protein 1 [50]a [51, 52]e,b [32]f HCf [74]:↓C
Extracellular matrix protein-1   [53, 109]j,u† [32]f HCf  
Extracellular matrix protein-2 [50]a [51, 56]e,d [32]f HCf  
Fibulin-1 [50, 83]a,b† [51,52,53, 56]e,b,j,d [32]f HCf [89]:↑S
Galectin-3-binding protein [50]a [51, 56]e,d [32, 33, 60, 66]f,j†,h,s HCf, FCtxj†, CCtx and Cveh, PreFCtxs  
Glypican-1   [51, 109, 130]e,u†q‡ [32, 33, 59]f,j†,g HCf, FCtxj†, HCg  
Microfibril-associated glycoprotein 4 [50]a [56]d [33, 66]j†,s FCtxj†, PreFCtxs  
Mimecan [50]a [51, 52, 56]e,b,d [33, 66]j†,s FCtxj†, PreFCtxs  
Osteomodulin   [51, 56]e,d    
Osteopontin   [51, 56]e,d [32, 33]f, j† HCf, FCtxj† [123]:↑C
Prolargin [50]a [51, 56]e,d [32, 33]f, j† HCf, FCtxj†  
SPARC-like protein 1   [51, 52, 56, 109]e,b,d,u†
6.2 nM (Aβ42F)e
[32, 33, 59, 60]f,j†,g,h HCf, FCtxj†, HCg, CCtx and Cveh [98]:↑C
Vitronectin [50, 83]a,b† [51,52,53, 56]e,b,j,d [32, 33, 59, 101, 131]f,j†,g,n†,s‡ HCf, FCtxj†, HCg, EntCtxn†,s‡; CPn†,s‡ [76]:↑S
Other proteins      
Actin, cytoplasmic 1 [50]a [51, 56]e,d [32, 59, 60, 115]f,g,h,z† HCf,g, CCtx and Cveh  
Alpha-1B-glycoprotein   [53, 56]j,d [32, 33]f,j† HCf, FCtxj†  
Alpha-2-HS-glycoprotein   [51,52,53, 56]e,b,j,d [32]f HCf [62, 79]:↓C, [88]:↓P
Beta-Ala-His dipeptidase   [51, 56]e,d [32, 33]f,j† HCf, FCtxj† [90]:↓C
Cystatin-C [50, 132, 133]a,t‡,u‡
11–17 nM (Aβ40/42M)u‡
[51, 52, 56]e,b,d [31,32,33, 59, 60, 66]r,f,j†,g,h,s FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs [91, 96, 97]:↑↓C
Dermcidin [50]a [51, 56]e,d [31,32,33, 59, 66]r,f,j†,g,s FCtx and TCtxr, HCf, FCtxj†, HCg, PreFCtxs  
Dickkopf-related protein 3   [51, 52, 56]e,b,d
26.2 nM (Aβ42F)e
[32, 33, 59, 134]f,j†,g,r‡ HCf, FCtxj†, HCg,r‡; CP and DPr‡ [134]v‡
Gelsolin [50, 135,136,137]a,w‡,x‡,y‡
1.38 μM (Aβ40M)w‡
[51,52,53, 56]e,b,j,d [31,32,33, 59, 60, 66]r,f,j†,g,h,s FCtx and TCtxr, HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs [89]:↑S
Hepatocyte growth factor activator   [53, 56]j,d [33]j† FCtxj†  
Latent-transforming growth factor beta-binding protein 4 [50]a [51, 56]e,d [32]f HCf  
Protein AMBP   [51, 53, 56]e,j,d [32, 33]f, j† HCf, FCtxj†  
Olfactomedin-like protein 3 [50]a [51, 56] [32, 33, 59]f,j†,g HCf, FCtxj†, HCg  
Secreted frizzled-related protein 3   [51, 56]e,d [32, 33]f,j† HCf, FCtxj†  
Secretogranin-1   [51, 56]e,d [32, 33, 59]f,j†,g HCf, FCtxj†, HCg [62, 138]:↓C
Serum amyloid P-component [50, 83, 139]a,b†z‡
6 nM (Aβ40M)z‡
[51, 56]e,d [28, 32, 33, 59, 60, 66]q,f,j†,g,h,s HCf, FCtxj†, HCg, CCtx and Cveh, PreFCtxs [61]:↑P
  1. Abbreviations used in Table:
  2. C Cerebrospinal fluid, CCtx Cerebral cortex, CP Core plaque, CVe Cerebral vessel, DP Diffuse plaque, EntCtx Entorhinal cortex, F Fibrils, FCtx Frontal cortex, F-tCtx Fronto-temporal cortex, HC Hippocampus, M Monomer, O Oligomers, P Plasma, PF Protofibrils, PreFCtx Prefrontal cortex, S Serum, TCtx Temporal cortex, TLb Temporal lobe
  3. Table note:
  4. aAβ42PF; pull-down from serum/CSF, LC-MS/MS, SPR. bAβ40; incubation with plasma/CSF, SDS-PAGE, LC-MS/MS. dAβ40F, Aβ42F; flow cytometry sorting from serum/CSF, LC-MS/MS. eAβ42F; pull-down from CSF, LC-MS/MS, SPR. f,g,hLCM; LC-MS/MS. iImmune-based detection. jAβ40; plasma protein corona, LC-MS/MS. kAβ40M; affinity isolation from rat brain, immunostaining, sequencing. lAβ42M; SDS-stable complex, WB. nAβ42M; incubation, gel electrophoresis. q,rLCM; LC-MS/MS, immune-based. sDetergent-insoluble plaque material; LC-MS/MS. tMolecular cloning, immune-based detection. uAβ28M, Aβ38M; dot blots. vAβ42F; EM, ELISA. wAβ42F; incubation with serum, WB. xImmune-based detection. yAβ42F; incubation with serum, WB. zAβ40M; SDS-stable complex, immune- and affinity-precipitation. a†Aβ40M; incubation with plasma, SEC, immunostaining. b†Aβ40M; affinity isolation from serum. d†Aβ40M; ELISA. e†Aβ; centrifugal isolation from serum, MS, WB. f†Immune-based detection. g†Aβ40M; pull-down from plasma, LC-MS/MS. h†– i†Immune-based detection. j†Tandem mass tag labeling, LC/LC-MS/MS. k†Aβ40M; ELISA. l†AβM; binding assay. n†Immune-based detection. r†Aβ40M; liquid phase interaction. s†Aβ42M; binding assay. t†Immune-based detection. u†Aβ42; SPR (KD not reported). v†Aβ42M; pull-down from plasma, WB. w†Aβ40F; dot blots. x†Aβ42M; pull-down, fluorescence polarization. y†Immune-based detection. z†Plaque material spatially targeted optical microproteomics. a‡Aβ42F; immunolabeling, TEM. b‡Aβ40O; NMR. c‡Aβ42M; SPR. d‡Aβ40M; CD titration. e‡Aβ40M; NMR. f‡Aβ42M, Aβ42O; binding assay. h‡Aβ40F, Aβ42F; SPR (KD not reported). i‡Aβ40F; ELISA. j‡Immune-based detection. k‡No significant changes, CSF. l‡Aβ28M, Aβ40M; affinity chromatography. n‡Immune-based detection. q‡Aβ40; dot blots. r‡–s‡Immune-based detection. t‡Aβ40M; incubation, SEC. u‡Aβ40M, Aβ42M; ELISA. v‡No changes, serum and CSF. w‡Aβ40M; ELISA. x‡–y‡Gelsolin used as probe to capture Aβ40/42M/O from rat brain and CSF. z‡Aβ40M; ELISA