a tangled web is heart failure alzheimer’s of the heart? · federica del monte, md, phd. a...
TRANSCRIPT
![Page 1: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/1.jpg)
Federica del Monte, MD, PhD
A Tangled WebIs Heart Failure Alzheimer’s of
the Heart?
FINANCIAL DISCLOSURE:No relevant financial relationship exists
![Page 2: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/2.jpg)
Brain and Heart Amyloid
AL or Transtyretin-related
![Page 3: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/3.jpg)
*
iDCM plaques-& tangles-like
![Page 4: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/4.jpg)
Gianni et Al Circulation 2010
7 variants in PSEN 120 variants in PSEN 2
Common and specific genetic variants
![Page 5: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/5.jpg)
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
![Page 6: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/6.jpg)
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
![Page 7: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/7.jpg)
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
![Page 8: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/8.jpg)
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
![Page 9: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/9.jpg)
PSEN
What forms iDCM aggregates
![Page 10: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/10.jpg)
![Page 11: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/11.jpg)
Cofilin
![Page 12: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/12.jpg)
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.
![Page 13: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/13.jpg)
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
![Page 14: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/14.jpg)
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
![Page 15: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/15.jpg)
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
![Page 16: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/16.jpg)
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
![Page 17: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/17.jpg)
DAPIα-Sarcomeric ActinRFPPhalloidin
Phosphomimetic cofilin
DAPIα-Sarcomeric ActinRFPPhalloidin
Constitutively active cofilin
DAPIα-Sarcomeric ActinRFPPhalloidin
Wild type cofilin
Cofilin phosphorylation induced stress fiber formation
![Page 18: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/18.jpg)
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
![Page 19: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/19.jpg)
Aging a promisquous disease
Presenilin Cofilin
PAO Toxicity
![Page 20: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/20.jpg)
Ca2+
AcquiredGeneticA
ggre
gate
inde
pend
ent
Agg
rega
te d
epen
dent
Cell death/dysfunction
A Tangled Web
![Page 21: A Tangled Web Is Heart Failure Alzheimer’s of the Heart? · Federica del Monte, MD, PhD. A Tangled Web. Is Heart Failure Alzheimer’s of the Heart? FINANCIAL DISCLOSURE: No relevant](https://reader030.vdocuments.net/reader030/viewer/2022011812/5e28c57ae881cd44516efb44/html5/thumbnails/21.jpg)
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