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Ass. Prof. Carmela MatroneAarhus University, Dept of Biomedicine
ABNORMAL PHOSPHORYLATION OF AMYLOID PRECURSOR PROTEIN TYROSINE RESIDUES
ALTERS THE APP TRAFFICKING IN NEURONS FROM ALZHEIMER'S DISEASE AFFECTED
PATIENTS
Faculty DisclosureX No, nothing to disclose
Yes, please specify:
March 30 - April 2, 2014Sheraton Sonoma CountyPetaluma, California
Off-Label Product UseWill you be presenting or referencing off-label or investigational use of a therapeutic product? X No
Yes, please specify:
THE Y682ENPTY687 DOMAIN
Y 682
ENPT
Y 687
Matrone C. 2013
THE Y682ENPTY687 DOMAIN
A SINGLE TYROSINE RESIDUE IN THE AMYLOID PRECURSOR PROTEIN INTRACELLULAR DOMAIN IS ESSENTIAL FOR DEVELOPMENTAL FUNCTION.
Barbagallo AP et al., J Biol Chem. 2011DEFECTIVE NEUROMUSCULAR SYNAPSE DEVELOPMENT EARLY POSTNATAL LETHALITY WHEN CROSSED WITH APLP2-/-
Tyr682 IN THE Aβ-PRECURSOR PROTEIN INTRACELLULAR DOMAIN REGULATES SYNAPTIC CONNECTIVITY, CHOLINERGIC FUNCTION, AND COGNITIVE
PERFORMANCE. Matrone C, et al., Aging Cell. 2012 Dec;11(6):1084-93.
AGING-DEPENDENT REDUCTION IN DENDRITIC SPINE DENSITYPROGRESSIVE AGE-DEPENDENT MEMORY AND LEARNING IMPAIRMENTREDUCTION IN MUSCULAR STRENGTH AND IN PHYSICAL PERFORMANCE
The APPY682G MICE PHENOTYPE
YGW
T
F
B
EEA1
E
A
APP
G
C
Merge
H
D
APP DECREASES IN EEA1-POSITIVE VESICLES IN APPY682G MICE
La Rosa et al., 2015
YGW
T
F
B
MergeGiantin
E
A
APP
G
C
H
D
APP DECREASES IN GIANTIN-POSITIVE VESICLES IN APPY682G MICE
La Rosa et al., 2015
APP INCREASES IN RAB7-POSITIVE VESICLES IN APPY682G MICE
MED
WT
BA
Rab7APP
YG
G
H
C
F
Merge
La Rosa et al., 2015
YGW
T
Lamp1APP
FE
BA
H
D
Merge
G
C
APP INCREASES IN LAMP1-POSITIVE VESICLES IN APPY682G MICE
FIBROBLASTS WT YG
LAMP1/nuclei 100±9.3 7.3±5.7*
CF 1.13±1.1 10-5 1.11±9.7 10-5
Area (pixel) 5.46 101±0.54 101 2.26 102±2.36 101*
La Rosa et al., 2015
CLATHRIN AND AP2 FAIL IN BINDING THE Y682ENPTY687PEPTIDE WHEN Y682 IS REPLACED BY G682
Poulsen et al., 2015
CLATHRIN AND AP2 FAIL IN BINDING APP BECAUSE OF THE Y682G MUTATION
Poulsen et al., 2015
DISEASE AXOL LINE
Control Ax0016 (C16) Cord Blood CD34+ cells, new born, female
Ax0018 (C18) Healthy volunteer. Male 74 yr.
Alzheimer’sDisease
Ax0112Presenilin 1 L286V(LV)
The donor (caucasian) is clinically affected with Alzheimer's disease. Onset was atage 38. Female.
Ax0114Presenilin 1 A246E(AE)
The donor (caucasian), now deceased, was affected with Alzheimer's disease. Onsetwas at age 45. Female.
Ax0113Presenilin 1 M146L(ML)
The donor (caucasian) is clinically affected with Alzheimer's disease. Onset was at53. Male.
GENERAL DESCRIPTION OF HUMAN NEURAL PROGENITORS
(AXOL BIOSCIENCE, UK)
Poulsen et al., 2017
MAP-2 Aββ III TUB
M14
6LC1
8L2
86V
A246
E
AFFECTED NEURONS DEVELOP AN AD LIKE PHENOTYPE IN VITRO
Zollo et al., 2017
pTyr
C18
IP:pTyr
C18
AE
Sun PP2
C18
Sun PP2 LV
LV
Sun PP2 ML
ML
Sun PP2MW
AE
APP75100
150
100
250
75100
150
100
250
IP:pTyr
Poulsen et al., 2017
APP TYR RESIDUE PHOSPHORYLATION IS INCREASED IN AD NEURONS
APP BINDING TO CLATHRIN AND AP2 IS COMPROMISED IN AD NEURONS.
Total lysate
Clathrin
β actin
C16 AELVC18 ML
APP
C16 AELVC18 ML
AP1
CoIP: APP
AP2
250
150
75
150
75
15075
150
50
37
Poulsen et al., 2017
APP/AP2
M14
6LCt
rl18
L286
VA2
46E
APP/Clathrin
THE EXTENT OF CLATHRIN-APP AND AP2-APP COLOCALIZATION IS REDUCED IN AD NEURONS
Poulsen et al., 2017
APP/AP2 APP/Clathrin
Vehi
cle
Suni
tinibL2
86V
C18
Vehi
cle
Suni
tinib
M14
6LVe
hicl
eSu
nitin
ibTYR KYNASE INHITORS RESCUE THE CLATHRIN-
APP AND AP2-APP BINDING IN AD NEURONS
Poulsen et al., 2017
TC
IP:pTyr
75
100 BVTC18
100
250
TYR PHOSPHATASE INHIBITORS REDUCE APP COLOCALIZATION WITH CLATHRIN AND AP2
Poulsen et al., 2017
APP/AP2 APP/Clathrin
C18
TC
2153
Vehi
cle
APP
APP/ClathrinAPP/AP2
CoIP: APP
PS1WT
Cortex
Ctrl PS1
Fibroblasts
Clathrin
APP
AP2
β-actin
PS1WT
Cortex
Ctrl PS1
Fibroblast
Clathrin
AP2
APP
Total lysate
250
150
75
15075
100
250
150
75
100
150
75
100
150
Suni
tinib
PS1
Ctr
l
APP-AP2 AND APP-CLATHRIN BINDING IN CORTICAL TISSUES AND FIBROBLASTS OF GÖTTINGEN MINIPIGS WITH M146I
MUTATION IN THE PS1 GENE.
Poulsen et al., 2017
SutPS1Ctrl
Fibroblasts
TC
β actin
pTyr420
Pan Fyn
PS1Ctrl
Fyn
TCPS1Ctrl
Cortex
APP
Fibroblasts
CoIP Fyn
50
75
100
150
FYN BINDS THE 682YENPTY687 DOMAIN OF APP IN CORTICAL TISSUES FROM GÖTTINGEN MINIPIGS
Poulsen et al., 2017
AEC16 LV ML
pTyr420
pTyr531
CoIP: Fyn
C18
APP
Pan Fyn
75100
50
75
50
75
50
75
FYN IS OVERACTIVATED IN NEURONS FROM AD PATIENTS
Poulsen et al., 2017
APP/TGN46C1
8M
146L
L286
V
APP INCREASES IN TGN46-POSITIVE VESICLES IN AD NEURONS
Poulsen et al., 2017
APP/EEA1C1
8M
146L
L286
V
APP DECREASES IN EEA1-POSITIVE VESICLES IN AD NEURONS
Poulsen et al., 2017
APP/Rab7
APP INCREASES IN Rab7-POSITIVE VESICLES IN AD NEURONS
C18
M14
6LL2
86V
Poulsen et al., 2017
CONCLUSIONSAPP TYR PHOSPHORYLATION CONTROLS THE APPBINDING TO CLATHRIN AND AP2.
INCREASED APP TYR PHOSPHORYLATION AFFECTS APPTRAFFICKING IN NEURONS.
FYN BINDS THE 682YENPTY687 DOMAIN OF APP
PERPECTIVESAPP TYR PHOSPHORYLATION MIGHT BE A
NEW VALUABLE TARGET FOR AD
ACKNOWLEDGEMENTSAarhus UniversityDept of Biomedicine
PhD Filomena IannuzziMsc Helle F RasmussenPhD Mette HabekostAss Prof Arne L JørgensenAss Prof Agnete Larsen
Dept of Molecular BiologyProf Joan J EnghildPhD Ebbe T Poulsen
Axol Bioscience (UK)Dr Shi YichenDr Zoe AllenDr Priyanka Dutta
University of Sannio (Benevento)Msc Zollo Alen
Goethe University (Frankfurt)Ass. Prof. Maier TJ
University of Tor Vergata (Rome)Ass. Prof. Nadia Canu
Coriell University (USA)
