Cellular Phenotyping of Hippocampal Progenitors Exposed to Patient Serum Predicts Conversion to Alzheimer’S Disease

Supplementary Materials for:

Cellular phenotyping of hippocampal progenitors exposed to patient serum predicts conversion to Alzheimer’s Disease

Aleksandra Maruszak, Tytus Murphy, Benjamine Liu, Chiara de Lucia, Abdel Douiri, Alejo J Nevado,

Charlotte E Teunissen, Pieter Jelle Visser, Jack Price, Simon Lovestone, Sandrine Thuret*

*Corresponding author: [email protected]

This file includes:

Fig. S1. Receiver-operator characteristic-curve for the cross-validation model predicting conversion to Alzheimer’s disease.

Fig. S2. Receiver-operator characteristic-curve for predicting conversion to Alzheimer’s disease using a panel of 207 proteins.

Table S1. Comparison of AUC for logistic regression models for individual predictors.

Table S2. 207 proteins significantly differentially expressed between MCI converters and non- converters.

Fig. S1. Receiver-operator characteristic-curve for the cross-validation model predicting conversion to Alzheimer’s disease. Area under the curve, AUC=0.93, Sensitivity 90.3%,

Specificity 79.0%.

Fig. S2. Receiver-operator characteristic-curve for predicting conversion to Alzheimer’s disease using a panel of 207 proteins. Area under the curve, AUC=0.943 Sensitivity= 91.65%,

Specificity= 81.68%.

Table S3. Comparison of AUC for logistic regression models for individual predictors. P- value refers to the model.

AUC OR SE 95% CI R2 p

Education (years) 0.7562 0.79 0.06 0.68-0.93 0.1433 0.001

Average cell count 0.8080 1.01 0.004 1.01-1.024 0.3069 <0.0001

(proliferation)

%Ki67+ cells (proliferation) 0.5728 1.04 0.05 0.94-1.15 0.0104 0.3919

%CC3+ cells (differentiation) 0.7972 2.97 1.08 1.45-6.08 0.2154 0.0001

Table S4. 207 proteins significantly differentially expressed between MCI converters and non-converters. No Bonferroni correction was applied.

Protein Name Protein UniProt EntrezGeneSymbol p-value Fold

Symbol change

(log10)

Gro-beta/gamma Gro-b/g P19876, CXCL3, CXCL2 0.0004 -0.028

P19875

Solute carrier family S35G2 Q8TBE7 SLC35G2 0.0005 0.016

35 member G2

Interferon-induced CIG49 O14879 IFIT3 0.0006 -0.022

protein with

tetratricopeptide

repeats 3

C-C motif chemokine MDC O00626 CCL22 0.0014 -0.023

Protein quaking QKI Q96PU8 QKI 0.0017 -0.034

CREB-binding CREB- Q92793 CREBBP 0.0017 0.009

protein binding

protein

Patched domain- PTHD3 Q3KNS1 PTCHD3 0.0018 -0.011

containing protein 3

Semaphorin-4D SEM4D Q92854 SEMA4D 0.0020 0.018

Inactive dipeptidyl DPP10 Q8N608 DPP10 0.0028 -0.010

peptidase 10

Profilin-2 Profilin II P35080 PFN2 0.0040 0.010

Connective tissue- CTAP-III P02775 PPBP 0.0041 -0.008

activating peptide III

Neuralized-like NEUL4 Q96JN8 NEURL4 0.0042 0.014

protein 4

AH receptor- AIP O00170 AIP 0.0049 0.012

interacting protein

Carbonic anhydrase 2 carbonic P00918 CA2 0.0053 -0.030

anhydrase

MIP18 family protein FA96A Q9H5X1 FAM96A 0.0057 -0.022

FAM96A

Ribosome-binding RRBP1 Q9P2E9 RRBP1 0.0058 -0.022

protein 1

COP9 signalosome CSN2 P61201 COPS2 0.0059 0.014

complex subunit 2

Immunoglobulin IGDC3 Q8IVU1 IGDCC3 0.0064 -0.011

superfamily DCC

subclass member 3

Secreted frizzled- SARP-2 Q8N474 SFRP1 0.0067 0.055

related protein 1

Malonyl-CoA DCMC O95822 MLYCD 0.0067 -0.012

decarboxylase,

mitochondrial

Dickkopf-related DKK1 O94907 DKK1 0.0068 -0.020

protein 1

Interferon lambda-3 IFN- Q8IZI9 IFNL3 0.0075 -0.020

lambda 3

Translationally- TCTP P13693 TPT1 0.0076 0.007

controlled tumor

protein

Platelet-derived PDGF-AA P04085 PDGFA 0.0080 -0.014

growth factor subunit

Semaphorin-3A Semaphorin Q14563 SEMA3A 0.0080 0.011

Ubiquitin carboxyl- UBP21 Q9UK80 USP21 0.0081 0.010

terminal hydrolase 21

Plasminogen activator PAI-1 P05121 SERPINE1 0.0081 -0.020

inhibitor 1

Neuropilin and NETO2 Q8NC67 NETO2 0.0084 0.012

tolloid-like protein 2

Oxysterols receptor NR1H2 P55055 NR1H2 0.0088 0.008

LXR-beta

Vasorin VASN Q6EMK4 VASN 0.0090 0.008

Glycoprotein Xg XG P55808 XG 0.0093 0.010

NKG2D ligand 1 ULBP-1 Q9BZM6 ULBP1 0.0094 -0.019

Basic leucine zipper BATF3 Q9NR55 BATF3 0.0096 -0.006

transcriptional factor

ATF-like 3

Protein transport SC61B P60468 SEC61B 0.0098 -0.015

protein Sec61 subunit

beta

Integral membrane ITM2A O43736 ITM2A 0.0100 0.009

protein 2A

FAS-associated factor FAF2 Q96CS3 FAF2 0.0102 -0.013

Dickkopf-related Dkk-4 Q9UBT3 DKK4 0.0102 -0.020

protein 4

NACHT, LRR and NALP4 Q96MN2 NLRP4 0.0105 -0.008

PYD domains-

containing protein 4

C-C motif chemokine TARC Q92583 CCL17 0.0108 -0.031

Progonadoliberin-1 GON1 P01148 GNRH1 0.0111 0.010

Platelet factor 4 PF-4 P02776 PF4 0.0115 -0.005

Transmembrane CP054 Q6UWD8 C16orf54 0.0119 -0.055

protein C16orf54

Biotinidase Biotinidase P43251 BTD 0.0121 0.022

Uncharacterized CA115 Q9H7X2 C1orf115 0.0123 -0.006

protein C1orf115

C-X-C motif ENA-78 P42830 CXCL5 0.0131 -0.011

chemokine 5

Interleukin-36 alpha IL-1F6 Q9UHA7 IL36A 0.0132 0.040

GTP-binding protein GEM P55040 GEM 0.0134 0.021

GEM

Glycerol-3-phosphate GPDA P21695 GPD1 0.0134 0.034

dehydrogenase

[NAD(+)],

cytoplasmic

Interleukin-1 IL-1 R AcP Q9NPH3 IL1RAP 0.0134 0.028

Receptor accessory

protein

Tumor necrosis factor BAFF Q96RJ3 TNFRSF13C 0.0136 0.028

receptor superfamily Receptor

member 13C

Probable DIM1 Q9UNQ2 DIMT1 0.0139 -0.022

dimethyladenosine

transferase

Fermitin family URP2 Q86UX7 FERMT3 0.0141 -0.028

homolog 3

Histidine triad HINT2 Q9BX68 HINT2 0.0142 0.012

nucleotide-binding

protein 2,

mitochondrial

2-phosphoxylose ACPL2 Q8TE99 ACPL2 0.0142 0.009

phosphatase 1

Glutamate receptor 4 GRIA4 P48058 GRIA4 0.0146 0.010

Mesencephalic ARMET P55145 MANF 0.0146 -0.028

astrocyte-derived

neurotrophic factor

Carbohydrate CHST3 Q7LGC8 CHST3 0.0148 -0.009

sulfotransferase 3

C1GALT1-specific C1GLC Q96EU7 C1GALT1C1 0.0151 0.009

chaperone 1

ETS domain- ELK1 P19419 ELK1 0.0151 0.007

containing protein

Elk-1

Prolactin-releasing PRRP P81277 PRLH 0.0152 0.010

peptide

Calpain-2 catalytic CAN2 P17655 CAPN2 0.0154 -0.014

subunit

Amphoterin-induced AMGO1 Q86WK6 AMIGO1 0.0158 -0.058

protein 1

Acid-sensing ion ASIC4 Q96FT7 ASIC4 0.0159 0.007

channel 4

72 kDa inositol INP5E Q9NRR6 INPP5E 0.0161 -0.005

polyphosphate 5-

phosphatase

A disintegrin and ATS3 O15072 ADAMTS3 0.0164 0.006

metalloproteinase

with thrombospondin

motifs 3

Protein eva-1 F176C P58658 EVA1C 0.0166 0.012

homolog C

Lysosome membrane LIMP II Q14108 SCARB2 0.0167 -0.010

protein 2

Calcium/calmodulin- CAMK1 Q14012 CAMK1 0.0179 0.006

dependent protein

kinase type 1

Retinaldehyde- RLBP1 P12271 RLBP1 0.0181 0.010

binding protein 1

Protein lin-7 homolog LIN7B Q9HAP6 LIN7B 0.0182 -0.006

DNA primase small PRI1 P49642 PRIM1 0.0183 -0.011

subunit

T-cell surface CD3E P07766 CD3E 0.0184 0.010

glycoprotein CD3

epsilon chain

C-type lectin domain CLC2L P0C7M8 CLEC2L 0.0186 -0.009

family 2 member L

Protein SERAC1 SRAC1 Q96JX3 SERAC1 0.0186 0.011

Arylamine N- ARY1 P18440 NAT1 0.0188 0.010

acetyltransferase 1

Fibrinogen C domain- FBCD1 Q8N539 FIBCD1 0.0191 0.007

containing protein 1

Microtubule- MLP3B Q9GZQ8 MAP1LC3B 0.0191 -0.011

associated proteins

1A/1B light chain 3B

Persulfide ETHE1 O95571 ETHE1 0.0191 0.012

dioxygenase ETHE1,

mitochondrial

Ferritin, FTMT Q8N4E7 FTMT 0.0194 0.026

mitochondrial

Sulfhydryl oxidase 1 QSCN6 O00391 QSOX1 0.0203 0.008

Kinesin light chain 1 KLC1 Q07866 KLC1 0.0203 0.011

Protein FAM171A2 F1712 A8MVW0 FAM171A2 0.0203 0.011

Syntaxin-6 Syntaxin-6 O43752 STX6 0.0204 -0.004

Cytohesin-interacting CYTIP O60759 CYTIP 0.0207 -0.016

protein

SPARC-related SMOC1 Q9H4F8 SMOC1 0.0208 0.007

modular calcium-

binding protein 1

Leucine-rich repeat, LRIT3 Q3SXY7 LRIT3 0.0211 -0.010

immunoglobulin-like

domain and

transmembrane

domain-containing

protein 3

Protein Z-dependent protein Z Q9UK55 SERPINA10 0.0214 0.019

protease inhibitor inhibitor

Fatty acid-binding FABPE Q01469 FABP5 0.0218 0.009

protein, epidermal

TYMS opposite CR056 Q8TAI1 TYMSOS 0.0221 0.011

strand protein

Microtubule- tau P10636 MAPT 0.0222 -0.014

associated protein tau

Dedicator of DOCK9 Q9BZ29 DOCK9 0.0223 0.005

cytokinesis protein 9

Tumor necrosis factor RELT Q969Z4 RELT 0.0223 0.007

receptor superfamily

member 19L

Apolipoprotein A-V Apo A-V Q6Q788 APOA5 0.0225 0.018

Tumor necrosis factor TRAIL R1 O00220 TNFRSF10A 0.0226 0.010

receptor superfamily

member 10A

Caseinolytic peptidase CLPB Q9H078 CLPB 0.0227 0.020

B protein homolog

Collagen alpha-1(XX) COKA1 Q9P218 COL20A1 0.0232 -0.041

chain

Insulin-like peptide INSL5 Q9Y5Q6 INSL5 0.0232 0.022

INSL5

Glial fibrillary acidic GFAP P14136 GFAP 0.0233 -0.017

protein

Zinc fingers and ZHX1 Q9UKY1 ZHX1 0.0233 -0.019

homeoboxes protein 1

Platelet-derived PDGF-BB P01127 PDGFB 0.0236 -0.014

growth factor subunit

Peptidase inhibitor 15 PI15 O43692 PI15 0.0237 0.008

Regulator of G- RGS7 P49802 RGS7 0.0246 0.017

protein signaling 7

Colipase-like protein CF126 Q6UWE3 CLPSL2 0.0248 0.009

Epididymal secretory EP3B P56851 EDDM3B 0.0254 -0.006

protein E3-beta

DnaJ homolog DJC17 Q9NVM6 DNAJC17 0.0259 0.010

subfamily C member

SAGA-associated SGF29 Q96ES7 CCDC101 0.0259 -0.008

factor 29 homolog

Trem-like transcript 1 TRML1 Q86YW5 TREML1 0.0260 -0.019

protein

Peptidyl-glycine AMD P19021 PAM 0.0260 0.017

alpha-amidating

monooxygenase

E3 ubiquitin-protein RNF8 O76064 RNF8 0.0268 0.009

ligase RNF8

Selenoprotein S SELS Q9BQE4 VIMP 0.0269 0.010

Protein FAM107B FAM107B Q9H098 FAM107B 0.0275 0.006

WSC domain- WSCD2 Q2TBF2 WSCD2 0.0277 0.008

containing protein 2

Alpha-enolase Alpha P06733 ENO1 0.0277 0.019

enolase

Hemoglobin subunit HBAZ P02008 HBZ 0.0277 0.009

zeta

Interferon-induced IFIT2 P09913 IFIT2 0.0280 0.012

protein with

tetratricopeptide

repeats 2

Leucine-rich repeats LRIG3 Q6UXM1 LRIG3 0.0280 0.013

and immunoglobulin-

like domains protein 3

PRKC apoptosis WT1 PAWR Q96IZ0 PAWR 0.0287 -0.013

regulator protein

Uncharacterized CQ078 Q8N4C9 C17orf78 0.0287 -0.007

protein C17orf78

Vesicle-trafficking SC22A Q96IW7 SEC22A 0.0288 -0.032

protein SEC22a

Alcohol ADH4 P08319 ADH4 0.0289 0.044

dehydrogenase 4

Stromal cell-derived SDF-1 P48061 CXCL12 0.0290 -0.014

factor 1

Protein APCDD1 APCD1 Q8J025 APCDD1 0.0290 -0.004

Neutrophil-activating NAP-2 P02775 PPBP 0.0296 -0.008

peptide 2

Myc-associated zinc MAZ P56270 MAZ 0.0298 0.008

finger protein

Protein DEPP DEPP Q9NTK1 DEPP 0.0298 0.018

Serine protease 27 Marapsin Q9BQR3 PRSS27 0.0299 0.010

Protein YIPF6 YIPF6 Q96EC8 YIPF6 0.0301 -0.023

Tumor necrosis factor TNFSF15 O95150 TNFSF15 0.0309 0.014

ligand superfamily

member 15

Noncompact myelin- CA130 Q5T1S8 NCMAP 0.0310 0.008

associated protein

Cocaine- and CART Q16568 CARTPT 0.0315 -0.009

amphetamine-

regulated transcript

protein

Drebrin-like protein DBNL Q9UJU6 DBNL 0.0322 -0.016

Osteocrin OSTN P61366 OSTN 0.0326 -0.020

A/G-specific adenine MutY Q9UIF7 MUTYH 0.0326 -0.030

DNA glycosylase homolog

Beta-defensin 104 HBD-4 Q8WTQ1 DEFB104A 0.0332 0.013

Pleckstrin homology PKHA1 Q9HB21 PLEKHA1 0.0333 -0.018

domain-containing

family A member 1

Interleukin-5 IL-5 P05113 IL5 0.0339 0.011

E3 ubiquitin-protein FANCL Q9NW38 FANCL 0.0339 -0.010

ligase FANCL

Dipeptidyl peptidase 2 DPP2 Q9UHL4 DPP7 0.0342 -0.019

WNT1-inducible- WISP-1 O95388 WISP1 0.0342 -0.027

signaling pathway

protein 1

Bcl-2-like protein 2 Apoptosis Q92843 BCL2L2 0.0345 -0.018

regulator

Bcl-W

Amyloid beta A4 APBB3 O95704 APBB3 0.0349 0.007

precursor protein-

binding family B

member 3

FAS-associated factor FAF2 Q96CS3 FAF2 0.0357 -0.006

Versican core protein CSPG2 P13611 VCAN 0.0358 -0.011

E3 ubiquitin-protein DTX3L Q8TDB6 DTX3L 0.0359 -0.024

ligase DTX3L

Oxytocin-neurophysin NEU1 P01178 OXT 0.0360 -0.010

IQ domain-containing IQCF1 Q8N6M8 IQCF1 0.0367 0.010

protein F1

Growth/differentiation BMP-14 P43026 GDF5 0.0367 0.023

factor 5

C-C motif chemokine PARC P55774 CCL18 0.0372 -0.023

Transmembrane GPNMB Q14956 GPNMB 0.0374 0.016

glycoprotein NMB

Tumor necrosis factor HVEM Q92956 TNFRSF14 0.0375 0.005

receptor superfamily

member 14

Homeodomain- HIPK3 Q9H422 HIPK3 0.0376 0.019

interacting protein

kinase 3

Sodium/potassium- AT1B1 P05026 ATP1B1 0.0378 0.009

transporting ATPase

subunit beta-1

Corticoliberin CRH P06850 CRH 0.0380 0.005

Ephrin-B3 Ephrin-B3 Q15768 EFNB3 0.0384 0.011

Platelet endothelial PEAR1 Q5VY43 PEAR1 0.0393 -0.026

aggregation receptor 1

R-spondin-3 RSPO3 Q9BXY4 RSPO3 0.0393 0.014

SLAM family SLAF6 Q96DU3 SLAMF6 0.0396 0.020

member 6

Interleukin-20 IL-20 Ra Q9UHF4 IL20RA 0.0398 -0.008

receptor subunit alpha

Protein LEG1 CF058 Q6P5S2 LEG1 0.0399 -0.015

homolog

Annexin A6 annexin VI P08133 ANXA6 0.0402 -0.011

E3 ubiquitin-protein PELI2 Q9HAT8 PELI2 0.0403 -0.021

ligase pellino

homolog 2

Protein Wnt-7a WNT7A O00755 WNT7A 0.0408 -0.028

CD109 antigen CD109 Q6YHK3 CD109 0.0411 0.018

ATPase family AAA ATAD2 Q6PL18 ATAD2 0.0413 0.006

domain-containing

protein 2

Selenide, water SPS1 P49903 SEPHS1 0.0415 0.010

dikinase 1

Integrin alpha-V: Integrin P06756, ITGAV, ITGB5 0.0417 0.035

beta-5 complex aVb5 P18084

Zona pellucida- ZPBP2 Q6X784 ZPBP2 0.0422 0.008

binding protein 2

Mannan-binding MASP3 P48740 MASP1 0.0422 0.011

lectin serine protease

Arrestin domain- ARRD3 Q96B67 ARRDC3 0.0425 0.019

containing protein 3

Renin Renin P00797 REN 0.0431 -0.031

Kremen protein 1 KREM1 Q96MU8 KREMEN1 0.0433 0.010

Pro-neuregulin-2, NRG2 O14511 NRG2 0.0434 -0.010

membrane-bound

isoform

ETS homologous EHF Q9NZC4 EHF 0.0434 -0.014

factor

Carbonic anhydrase 9 Carbonic Q16790 CA9 0.0436 -0.013

anhydrase 9

Heparin-binding HB-EGF Q99075 HBEGF 0.0436 -0.020

EGF-like growth

factor

Histone H2A MYSM1 Q5VVJ2 MYSM1 0.0437 0.009

deubiquitinase

MYSM1

Mothers against SMAD3 P84022 SMAD3 0.0440 0.011

decapentaplegic

homolog 3

Protein GPR107 GP107 Q5VW38 GPR107 0.0442 0.010

Suppressor of SOCS7 O14512 SOCS7 0.0443 -0.008

cytokine signaling 7

Choline/ethanolamine CHKB Q9Y259 CHKB 0.0443 0.011

kinase

Sterol-4-alpha- NSDHL Q15738 NSDHL 0.0444 0.009

carboxylate 3-

dehydrogenase,

decarboxylating

NAD-dependent SIRT5 Q9NXA8 SIRT5 0.0447 -0.010

protein deacylase

sirtuin-5,

mitochondrial

E3 ubiquitin-protein LNX1 Q8TBB1 LNX1 0.0448 -0.007

ligase LNX

tRNA (cytosine(38)- TRDMT O14717 TRDMT1 0.0452 -0.013

C(5))-

methyltransferase

Synaptogyrin-3 SNG3 O43761 SYNGR3 0.0456 0.009

Growth/differentiation GDF-11 O95390 GDF11 0.0456 0.006

factor 11

Janus kinase and JKIP3 Q5VZ66 JAKMIP3 0.0457 0.005

microtubule-

interacting protein 3

Protein kinase C and PACN3 Q9UKS6 PACSIN3 0.0460 -0.009

casein kinase

substrate in neurons

protein 3

Thioredoxin domain- TXD11 Q6PKC3 TXNDC11 0.0463 -0.016

containing protein 11

Tumor necrosis factor Fas, soluble P25445 FAS 0.0463 0.007

receptor superfamily

member 6

Complement C3b C3b P01024 C3 0.0465 0.037

Engulfment and cell ELMO1 Q92556 ELMO1 0.0468 0.016

motility protein 1

NKG2-E type II NKG2E Q07444 KLRC3 0.0470 0.007

integral membrane

protein

C-C motif chemokine HCC-4 O15467 CCL16 0.0470 0.016

Apolipoprotein E Apo E2 P02649 APOE 0.0472 -0.004

(isoform E2)

Protein transport SC61G P60059 SEC61G 0.0474 -0.006

protein Sec61 subunit

gamma

Glia-derived nexin Protease P07093 SERPINE2 0.0476 -0.017

nexin I

Testis-specific CDY1 Q9Y6F8 CDY1 0.0478 -0.013

chromodomain

protein Y 1

Signal transducer and STAT1 P42224 STAT1 0.0481 0.008

activator of

transcription 1-

alpha/beta

Leucine-rich repeat LRRK2 Q5S007 LRRK2 0.0482 0.014

serine/threonine-

protein kinase 2

Protein E7_HPV16 HPV E7 P03129 E7 0.0487 -0.008

Type 16

Apolipoprotein A-V Apo A-V Q6Q788 APOA5 0.0487 0.019

Ladinin-1 LAD1 O00515 LAD1 0.0491 -0.003

Beta-mannosidase MANBA O00462 MANBA 0.0491 -0.010

Serine/threonine- PAK4 O96013 PAK4 0.0493 0.006

protein kinase PAK 4

A disintegrin and ATS15 Q8TE58 ADAMTS15 0.0497 -0.003

metalloproteinase

with thrombospondin

motifs 15

Peregrin BRPF1 P55201 BRPF1 0.0499 0.005