a tangled web is heart failure alzheimer’s of the heart? · federica del monte, md, phd. a...
TRANSCRIPT
Federica del Monte, MD, PhD
A Tangled WebIs Heart Failure Alzheimer’s of
the Heart?
FINANCIAL DISCLOSURE:No relevant financial relationship exists
Brain and Heart Amyloid
AL or Transtyretin-related
*
iDCM plaques-& tangles-like
Gianni et Al Circulation 2010
7 variants in PSEN 120 variants in PSEN 2
Common and specific genetic variants
0
0.5
1
1.5
2
2.5
LWW/LWD
*
0
0.003
0.006
0.009
0.012
HW/BW HW/TL
PS2KO mouse model
*
0.005
0.007
0.009
0.011
0.013
0.015
0.017
QRS Interval (s)
*
PS2KOWT
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40 *LVEDD
3mo 6mo 9mo9 9 7 9 11 15
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
* ** **
FS
3mo 6mo 9mo9 9 7 9 11 15
SERCA2b and PS1/PS2 are co-localized and interact (Kim N; JBC)Cells lacking both presenilins exhibit a phenotype similar to SERCA knockdown and endogenous presenilins interact with SERCA (Green et al., 2008).
ER
SERCA RyRCa2+
Ca++L-type
Presenilin
Ca2+
Ca2+
ER Ca2+ reuptake
NF iDCM Supernatants GST
Presenilin 2
Presenilin-2 / SERCA2a direct binding
Sic L. JBC 2000
Presenilin have been shown to interact with the ryanodine receptor, via its N terminus, and to increase the open channel probability and mean current (Rybalchenko et al., 2008),
ER Ca2+ release
ER
SERCA RyRCa2+
Ca2+
L-type
Presenilin
Ca2+
Ca2+
WB: RYR2
NF iDCM
Presenilin 2/RYR2 Co-IP
400
nmol
/L
5 s
PS2KO
WT
0
20
40
60
80
100
WT PS2KO
SR [C
a2+] (
mm
ol/l
cyt
osol
)
16 18
#
180
0.4
0.8
1.2
1.6
WT PS2KO
Twitc
h [C
a2+]
i/Ca
ffein
e Δ
[Ca2
+]i
16 18
#
30
40
50
40 50 60 70
tetr
acai
ne-s
ensi
tive
Ca2+
leak
(μm
ol/l
cyt
osol
)
SR Ca2+ (μmol/l cytosol)
WT PS2KO
##
02468
1012
WT PS2KO
leak
/loa
d (a
rbrit
ary)
16 18
##
SR Ca2+ Content
PSEN
What forms iDCM aggregates
Cofilin
Hypo-phosyphorylation of Cofilin 1in neurons causes formation ofcofilin-actin rod precipitates
Cofilin in the pathogenesis of AD
Hyper-phosphorylation of Cofilin 1causes actin bundle accumulationwithin cell bodies and theformation of dystrophic neuritis.
Expression
0
0.5
1
1.5
2
2.5
Cof
ilin/
GA
PD
H R
atio
Inoluble
10 10 10 9
Soluble
*
p-co
filin
/GA
PD
H R
atio
0
0.5
1
1.5
2
2.5
10 910 10
InsolubleSoluble
***
iDCM
Donors
Activity
Cofilin in human iDCM
Soluble
Insoluble
Individual Donor Samples
Cof
ilin/L
oad
ratio
0
0.5
1
1.5
2
2.5
AVG
Individual iDCM samples
Cof
ilin/L
oad
ratio
0
0.5
1
1.5
2
2.5
3
AVGSubramanian et al JACC 2015
Cofilin & myocardial aging
CSC2
αMHC-Cre
WT littermate
Fractional ShorteningEjection Fraction
%
0
10
20
30
40
50
60
70
80
90
100
7 7 33 11 11
*#
*#
0.0
1.0
2.0
3.0
4.0
LVEDd LVEDs
#
#*
7 3 11 7 3 11
mm
WT littermates
0
0.5
1
1.5
2
2.5
3 4
Cof
ilin/
tot E
RK
Rat
io
WT littermates CSC2
CSC2
*
Cofilin-2
Total ERK
20
37
MW (kDa)
Pankaj Agrawal E. Dale Abel
Cofilin-2 KO mouse model
CSC2aMHC-CreWT Littermates
50 μm50 μm50 μm
100 nm
100 nm
100 nm100 nm
500 nm
CSC2
1
1
1
1
2
2
2
2
Human Nemaline iDCM
500 nm500 nm
500 nm
1
12
2
DAPIα-Sarcomeric ActinRFPPhalloidin
Phosphomimetic cofilin
DAPIα-Sarcomeric ActinRFPPhalloidin
Constitutively active cofilin
DAPIα-Sarcomeric ActinRFPPhalloidin
Wild type cofilin
Cofilin phosphorylation induced stress fiber formation
0
10
20
30
40
50
60
Non injected
WT CFLPhosphomimetic
Constit.active
FS
Cardiac function
Thick
WT + WT-COFCSC2 + P-COF
Dilated
Normal
WT
Adenoviral Expression of Phosphomimetic Cofilin
Aging a promisquous disease
Presenilin Cofilin
PAO Toxicity
Ca2+
AcquiredGeneticA
ggre
gate
inde
pend
ent
Agg
rega
te d
epen
dent
Cell death/dysfunction
A Tangled Web
Davide GianniJoakim Chan
Jim BamburgPankaj Agrawal
Gordon Huggins
Thank you
Anna Kilianova
Cristina Balla
NicoleKoulizis
Asma Mahamud
Edi GohibergBernhard Hiring
E. Dale Abel
Erik Kohlbrenner
Roger Hajjar
Weiqing Wang
KhaushikSubramanian
Carlo Bortolotti Fabrizio Bernini Marco Borsari Marcello PignataroMarco BorsariElena
Castellini
Giulio Agnetti Jennifer Van Eyk Peipei Ping
AsmaMahmud