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. 2021 Aug 28;16:59. doi: 10.1186/s13024-021-00465-0

Table 1.

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

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, 63–65]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, 31–33, 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 [51–53, 56]e,b,j,d [32, 33]f,j† HCf, FCtxj†
Complement C1s subcomponent [51–53, 56]e,b,j,d [32, 33]f,j† HCf, FCtxj† [74]:↓C
Complement C3

[50]a

0.3 μM (Aβ42PF)a

 [51–53, 56, 72, 75]e,b,j,d,w,y [26, 28, 31–33, 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 [51–53, 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 [51–53, 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, 81–84]a,z,a†,b†,d†

3 μM (Aβ42PF)a,

6 nM (Aβ40M)d†

 [51–53, 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† [87–89]:↓ S/P, [90]:↑C
Apolipoprotein A-II [50, 82]a,a† [51–53, 56, 85]e,b,j,d,e† [32, 33]f,j† HCf, FCtxj†
Apolipoprotein A-IV [50, 83]a,b† [51–53, 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 [51–53, 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, 82–84]a,k,a†,b†,d†

3 nM (Aβ42PF)a,

19 nM (Aβ40M)d†

 [51–53, 56, 85]e,b,j,d,e† [28, 31–33, 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, 81–83, 99, 100]a,z,a†,b†,k†,l†

4.8 nM (Aβ40M)k†,

2 nM (AβM)l†

 [51–53, 56, 85]e,b,j,d,e† [28, 31–33, 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, 31–33, 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, 31–33, 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 [31–33, 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 [51–53, 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 [31–33]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 [51–53, 56]e,b,j,d [32, 33]f,j† HCf, FCtxj†
Vitamin K-dependent protein S [51–53, 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 [31–33, 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 [31–33, 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 [31–33, 59, 66]r,f,j†,g,s FCtx and TCtxr, HCf, FCtxj†, HCg, PreFCtxs
Serum albumin

[50, 83, 117–120]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‡

 [51–53, 56, 109]e,b,j,d,u† [31–33]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 [51–53, 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 [31–33, 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† [51–53, 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† [51–53, 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 [51–53, 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 [31–33, 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 [31–33, 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, 135–137]a,w‡,x‡,y‡

1.38 μM (Aβ40M)w‡

 [51–53, 56]e,b,j,d [31–33, 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

Abbreviations used in Table:

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

Table note:

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