AKT
COT
NDR
NIK
PAKA
PDHK
PDK1
PKA
PKCA
PKCD
PKCH
PKCI
PKD
PKG
PKN
RAF
RIPK
RSK
SGK
CAMK1
CAMK2
CAMKK
DAPK
DMPK
IKK
MARK
MLCK
PHK
RAD53
AMPK
BRSK
CHK1
LKB
MELK
NUAK
PAKB
PASK
QIK
SLK
CDK
CK2
CLK
DYRK
GSK
MAPKAPK
NMO
BARK2
GRK
ERK
JNK
P38
BUD32
CK1
HAL
NAK
NEK
PEK
PIM
PLK
TLK
TTK
ULK
VRK1
WNK
AUR
ATM
ATR
MTOR
PRKDC
FRAY
KHS
MLK
MOS
MSN
MST
STE11
STE7
TAO
IRAK
STKR
A
G
C
C
A
M
K
L
K
M
A
C
C
G
M
C
K
R
G
K
P
A
M
R
E
H
T
O
K
K
I
P
E
T
S
T
K
L
T
K
R
L
3xTG PFC F
3xTG PFC M
DLPFC Ch F
DLPFC Ch M
DLPFC Cy F
DLPFC Cy M
DLPFC Nuc F
DLPFC Nuc M
DLPFC F 3
DLPFC M 3
DLPFC F 2
DLPFC M 2
DLPFC F 1
DLPFC M 1
DLPFC F AD MCI
DLPFC M AD MCI
DLPFC F MCI CTL
DLPFC M MCI CTL
APP HPC F
APP HPC M
APP PFC F
APP PFC M
APP iAs o M V717I AB WT AB
APP iAs o M V717I AB WT
APP iAs o M V717I WT AB
APP iAs o M V717I WT
PS1 iAs o F in 4del AB WT AB
PS1 iAs o F in 4del AB WT
PS1 iAs o F in 4del WT AB
PS1 iAs o F in 4del WT
PS1 iAs o M Y115H AB WT AB
PS1 iAs o M Y115H AB WT
PS1 iAs o M Y115H WT AB
PS1 iAs o M Y115H WT
APP iNeu o M V717I AB WT AB
APP iNeu o M V717I AB WT
APP iNeu o M V717I WT AB
APP iNeu o M V717I WT
PS1 iNeu o F in 4del AB WT AB
PS1 iNeu o F in 4del AB WT
PS1 iNeu o F in 4del WT AB
PS1 iNeu o F in 4del WT
PS1 iNeu o M Y115H AB WT AB
PS1 iNeu o M Y115H AB WT
PS1 iNeu o M Y115H WT AB
PS1 iNeu o M Y115H WT
Z Sco e
−4
−2
0
2
4
Alzheime ’s Disease Kinome A las
John Ve gis1,, Nicholas Henkel1, Ali Sajid Imami1, Alyssa Walls um1, Jacob Wood1,
Robe E. McCullumsmi h1,2
Uni e si y o Toledo Depa men o Neu osciences and Psychia y, Toledo, OH; 2P omedica, Toledo, OH
Abs ac
In oduc ion. The lack o ea -
men s and success ul clinical ials
o Alzheime ’s disease (AD) ea -
men s highligh s a need o be e
unde s and he pa hogenesis o
AD. We assessed he se ine/ h e-
onine subkinome in AD using a
unc ional p o eomics app oach.
AD p og ession was in es iga ed in
pos mo em DLPFC b ain samples
om con ol, mild cogni i e impai -
men (MCI), and AD subjec s; iP-
SC-de i ed neu onal and as ocy e
cul u es om spo adic (la e onse )
and amilial AD cases we e also as-
sessed.
Me hods. We analyzed he ac i e
kinomic signa u e in AD samples
using he Pamgene’s PamS a-
ion®12 and se ine/ h eonine
kinase (STK) epo e chips. We
used he Kinome Random Sam-
pling Analyze (KRSA) package o
iden i y ups eam kinases om he
kinome a ay da ase s.
Resul s. Female and male AD
b ain had AKT1 and AMPK1 as hi s
in ea ly (CTL s MCI) and la e (MCI
s AD) clinical p og ession. In e-
males, RSK4 was a hi in ea ly and
la e p og ession, while PAK5 was
only a hi in la e p og ession. In
males, PAK5, TAOK3, and RSK4 we e
hi s in he la e s age. PAK5, TAOK3,
and RSK4 a e unde s udied in AD,
and conside ed “da k” kinases o e -
all due o he pauci y o biochemi-
cal anno a ions o hei p o ein
a ge s. Bayesian ne wo ks alida -
ed he AMPK kinase ele ance in
AD p og ession ia eme gen and
newly absen ela ionships o e
ime.
Conclusion. Majo changes in STK
subkinome e ealed insigh s such
as:
• Alzheime ’s Disease shows a sig-
ni ican ly educed (p < 0.05) o e -
all phospho yla ion signal as com-
pa ed o con ol issues
• AMPK may be a clinically ele an
a ge
• Da k kinases wi h inc eased ac i i-
y we e iden i ied in Alzheime ’s,
suppo ing kinase unc ion eluci-
da ion and u he unde s anding
o he disease p ocess
• This esea ch suppo s u he
bioma ke disco e y and se es as
a ouchs one o u u e kinase in-
hibi o s udies
• High po en ial o new d ug de-
elopmen in Alzheime ’s Disease
o imp o e pa ien ou comes and
quali y o li e.
DEPARTMENT OF
NEUROSCIENCES
AND PSYCHIATRY
UNIVERSITY OF TOLEDO
Subjec s
Human AD, MCI
Pos mo em
DLPFC
FAD Mu an
Mice
FAD iPSC
Neu on &
As ocy e
Cul u es
*
7.0
7.5
8.0
AD
CTL
G oup
Mean Signal
O e all Signal
Da a Collec ion
on PamS a ion®12
kinome a ay
om Pamgene
P ocessing
Da a P ocessing
& Analysis
Kinome Random
Sampling Analyze
Analysis
46 Expe imen al
Compa isons:
Males s Females,
AD s MCI,
MCI s CTL,
AD s CTL,
APP s CTL,
3xTG s CTL,
PS1 s CTL
Aβ s VEH.
HPC, PFC, and DPLFC.
Design
Homogenized
samples we e
pooled by
diagnosis and sex
o kinome a ay
analyses.
Glossa y
L
i
g
h
K
i
n
a
s
e
s
P
e
i
o
u
s
l
y
U
n
l
i
n
k
e
d
o
A
l
z
h
e
i
m
e
’
s
D
i
s
e
a
s
e
D
a
k
K
i
n
a
s
e
s
P
e
i
o
u
s
l
y
U
n
l
i
n
k
e
d
o
A
l
z
h
e
i
m
e
’
s
D
i
s
e
a
s
e
PAKA
(PAK3,
PAK5,
PAK6)
NDR
NMO
BARK2
BUD32
COT
FRAY
KHS
HAL
STE7
STKR
STE11
VRK1
(O e whelmingly
ound in exci a o y
and inhibi o y
neu ons)
• 3xTG: T iple
ansgene mouse
Alzheime ’s Disease
model, ca ying
APPswe, TauP301L,
and PS1M146V.
• AB: “Amyloid be a” (A
β); upon
accumula ion
ep esen s a hallma k
o Alzheime ’s
Disease.
• AD: Sho hand o
Alzheime ’s Disease.
• APP: HGNC symbol
o he Amyloid-be a
p ecu so p o ein.
•Ch : “Ch oma in
ac ion”, indica ing
he ch oma in
subcellula ac ion
o pos mo em
DLPFC issue.
•CTL: “Con ol”.
•Cy : “Cy osolic
ac ion”, indica ing
he cy osolic
subcellula ac ion
o pos mo em
DLPFC issue.
•DLPFC: “Do sola e al
p e on al co ex”.
•F: “Female”. HPC:
“Hippocampus”.
•iAs o: “iPSCs om
FAD pa ien s,
di e en ia ed in o
as ocy es”.
• iNeu o: ”iPSCs om
FAD pa ien s,
di e en ia ed in o
neu ons”.
•in 4del: “in on 4
dele ion o PS1”. M:
“Male”
•MCI: “Mild cogni i e
impai men ”, an
in e media y s age
be ween heal hy
b ain and
Alzheime ’s Disease
• Nuc: Sho hand o
“nuclea ac ion”,
indica ing he
nuclea subcellula
ac ion o
pos mo em DLPFC
issue.
• PFC: P e on al
co ex.
• PS1: Indica ing
mu a ion o he
p esenilin-1 gene
(PSEN1).
•V717I: Valine o
isoleucine missense
a 717 h APP Amino
Acid.
•WT: “Wild ype”.
•Y115H: Ty osine o
his idine missense a
115 h PSEN1 Amino
Acid.
