Alzheimer 2014 Poro amiloide
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Transcript of Alzheimer 2014 Poro amiloide
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Algo viejo, algo nuevo y algo usado en Alzheimer; La idea del poro, del etanol y los
ovocitos para comprender la enfermedad
Jorge [email protected]
http://nucleo-nipa.uct.cl/reproduccion-animal/
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Janssen, J.C. et al. Neurology 2003;60:235-239
Figure. The amyloid precursor protein molecule with localization of the A{beta} and p3 proteins, showing pathogenic mutations and the novel sequence variant identified in this
study
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Benilova et al 2012 Nature Neuroscience
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Parodi et al 2014
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Selkoe, revisión 2001 “Alzheimer is a synaptic failure”
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Lorenzo & Yankner. 1994 PNAS.
Efecto neurodegenerativo de agregados del péptido amiloide
MAP-2
Sinaptofisina
Control Soluble 20 µM
Agregados 20 µM
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Stéphan et al., 2001 J. Neuroscience
Presencia del péptido amiloide bloquea el fenómeno de LTP
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Verde M94 (ADDL´s)Rojo, en B Anti α-CaMKIIRojo ,en C Anti PSD-95 Lacor et al., 2004 J. Neurosci.
La presencia del péptido amiloide en la sinápsis
PSD-95 Ab Merged
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CPP, bloqueador de NMDABTX, bloqueador Colinergico
Conclusion,Oligomeros, disminuyen el numero de espinas, reduciendo la actividad por un mecanismo que involucra a receptores de NMDAShankar et al., 2007 J of Neuroscience.
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Parodi et al 2010
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Solokov et al 2006 JGP
Kawahara et al., 1997 Biophysical Journal
Péptido amiloide, induce cambios en las bicapasLipidicas, ¿poro amiloide?
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CCVD, tipo N y L Yagami et al., 2004; Bobich et al., 2004Poro amiloide, Arispe et al., 1994
CCVD
ReceptoresNMDACanales
potasio
Receptores nicotínico
Canales de potasio, Ye et al 2003Receptores nicotínico, Tran et al., 2002Receptores NMDA, Snyder et al., 2005
Poro amiloide
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Demuro et al., 2004 JBC
Modelo, para bloqueo del “poro” amiloideTomado de Arispe 2004, construcción delNa7, para ser usado como bloqueadorSelectivo de los efectos del péptido amiloide
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Parodi et al 2010
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Sepulveda et al 2014
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Lal et., al. 2007
CStrideDSSPPDB, 1BA4
A B
CStrideDSSPPDB, 1BA4
A B
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Jang et al 2007
NMR, 17-42
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Modeling
0 50 100 150 200
0,0
0,2
0,4
0,6
0,8
1,0
1,2
Tiempo (min)
Tu
rbim
etri
a (D
.O. 4
05
nm
)
Control 5 mM Etanol 10 mM Etanol 50 mM EtanolA B
C D E
Ormeño et al 2013
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C
BA
D
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Parodi et al 2008
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-6 -5 -4 -3 -2 -1 0 10,0
0,5
1,0
1,5
Num
ber
of events
Amplitude (nA)
Control Gramicidin Amphotericin B Aggregate
A B C
-200 -150 -100 -50 0 50 100
-8
-6
-4
-2
0
2
4
6
8
nA
mV
Aggregate Gramicidin Amphotericin Control
Contro
l
Gramicidin
Amph
otericin B
Aggr
egates
0
-200
-400
-600
-800
-1000
**
Mem
bra
ne c
onducta
nces (nS
)
*
Parodi et al 2012
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B
C
A
D
+ 20 mV0 mV
Control
Aggregate
High Ca2+
NR
High Ca2+
NR
-100 mV
+ 20 mV0 mV
-100 mV
100 nA250 ms
4 min
200
nA
Rabbit serum
15 min Aggregate
0 min 15 min
NR
0
50
100
150
200
250
300
Aggregate
High Ca2+NR
*
*
Curr
ent a
mplit
ude
(% o
f co
ntr
ol a
t +20
mV)
*
NR High Ca2+
0
50
100
150
200
15 min Aggregate15 min
*
Curr
ent am
plit
ude
(% o
f co
ntr
ol ) NR
0 min
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20
0 n
A
60 s
100 μM ATP0 min 15 min
15 min AggregateNR
0
20
40
60
80
100
120
15 min Aggregate15 min
Cu
rre
nt
(% o
f c
on
tro
l)
0 min
*
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Demuro & Parker 2013
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Demuro & Parker 2013
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Parodi et al 2014
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Colaboradores• Dr. Luis Aguayo• Dr. Carlos Opazo
Agradecimientos
Colaboradores Internos
• Fernando Sepulveda• Magdalena Cuevas• Gretchen Wandersleben
• Dr. Marcelo Kogan• Dr. Bob Peoples• Dr. Jorge Roa
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….Gracias a la Fundación Parodi por todo su cariño y amor.Viejo, ya te extraño mucho!!!
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Control
Trata
das 1 5 10 25 50 100
0,0
0,5
1,0
1,5
2,0
2,5
*
*
**
Etanol (mM)
Agregados amilodes
Fre
cuen
cia
(Hz)
Act
ivid
ad S
ináp
tica
Esp
on
tán
ea
Control
Agregados A 0.5 M (24 h)
Agregados A 0.5 M + 10 mM Etanol (24 h)
Agregados A 0.5 M + 50 mM Etanol (24 h)
50 mM Etanol (24 h)
0.2 s 20 p
A
0.2 s 20 p
A
0.2 s 20 p
A0.2 s 20
pA
0.2 s 20 p
A
Sv2
Control
Aaggregates 0.5 M
Aβ aggregates 5 M
Aβ aggregates 10 M
10 mM etanol
50 mM etanol
Aaggregates 0.5 M
Aguayo Lab. Parodi tesis 2007
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¿… y el mecanismo Parodi???
..Posiblemente efectos agudos, como el de 4-AP o LTX
¿… y lo demostró Parodi???
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0 500 1000 15000,0
0,6
0,7
0,8
0,9
1,0
1,1
Control Agregados A Agregados A/Sin calcio Agregados A/Cadmio
*
Flu
ore
sc
en
cia
No
rma
liza
da
(F
/Fi)
Tiempo (Seg)
Los agregados Aβ aumentan la liberación de vesículas sinápticas en la presencia de calcio
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Control
Cadmio
Agregados Aβ
Agregados Aβ / cadmio
Control
Agregad
os Aß
Agregad
os Aß /
cadm
io
0
1
2
3
4
530 min
*
*
Fre
cuen
cia
(Hz)
Co
rrie
nte
en
min
iatu
ra
A B
El efecto agudo de los agregados Aβ sobre la actividad sináptica es bloqueado por cadmio
20
0 p
A
10 seg
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Control
Agregad
os Aß
Control
Agregad
os Aß
0,0
0,5
1,0
1,5
2,0
*
Sin Calcio
Fre
cuen
cia
(Hz)
Co
rrie
nte
en
min
iatu
ra
Control
Agregad
os Aß
Control
Agregad
os Aß
0,0
0,5
1,0
1,5
2,0
2,5
Fre
cuen
cia
(Hz)
Co
rrie
nte
en
min
iatu
ra
*
Cadmio
Control
Agregad
os Aß
Bicucu
lina
CNQX
Bicucu
lina
CNQX
0,0
0,5
1,0
1,5
2,0
2,5
3,0
*
*
*
Agregados A
Fre
cuen
cia
(Hz)
Co
rrie
nte
en
min
iatu
ra
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Abramov et al, 2004 BBA
Mattson et al, 1992 J. Neuroscience
4 dias, 2 µM
5 µMNADH inhibiciónEvidencia Stress
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2 dias, de incubación
100-300 pM por IP
Shankar et al., 2007 J of Neuroscience.
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10 a 15 dias¿Cómo aislaron?
Bicu, TTX, Picrotoxina yNimodipino.
Shankar et al., 2007 J of Neuroscience.
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Abramov et al, 2004 BBA
5 µM
Presencia del péptido amiloide genera muerte, por cambio en calcio
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Chen 2005, BBRC
Presencia del péptido amiloide aumenta la entrada de calcio
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Hsieh et al., 2006 Neuron.
Péptido amiloide, induce cambios en losReceptores del tipo AMPA.Todos efectos post sinápticos interesantesPermite explicar efectos en el LTP
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Katayama et al., 2004, J of Chemical Neuroanatomy
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Plakoutsi et., al. 2005 JMB
Kirkitadzey & kowalka 2005 ABP
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Re
cep
tor
GA
BA
A
Re
cep
tor
AM
PA
Re
cep
tor
NM
DA
Agregados
CaMKII
GSK3β
PKC
Calcio
Tau
Snare
SNAP
Canal Ca2+
Canal K*
R-AMPA
R-NMDA
Agregados
¿ ? GSK3β
PKC
Calcio
Tau
CREBP
Stress
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Los efectos son dependientes del calcio, ¿pero como entra el calcio?
Aβ
24 Hrs
Aβ
¿Ca+2?
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CNQX (4µM)
D-AP5 (50 µM)
Coctel
Agregados Aß
Control
0,00,20,41,0 1,2 1,4 1,6 1,8 2,0
Ag
regad
os A
Fluorescencia normalizadaF/F
0
A
B
0 50 100 150 200 250
1,0
1,2
1,4
1,6
1,8
Flu
ore
scen
cia
no
rmal
izad
a(
F/F
0 )
Tiempo (seg)
Agregados A Agregados A coincubados con:
1 M CNQX 50 M D-AP5 Cóctel: 1 µM conotoxine (GVIA)+
1 µM agatoxine (AGA)+ 3 µM nifedipino
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0,0
0,5
1,0
1,5
2,0
Fre
cuen
cia
(Hz)
Corr
ient
e en
min
iatu
ra
*
A Bcontrol
Agregados Aβ
Agregados Aβ / Na7 100 µM
200 pA
10 seg
Aβ Aβ
Na7Ca2+
0,0
0,5
1,0
1,5
2,0
Fre
cuen
cia
(Hz)
Corr
ient
e en
min
iatu
ra
*
A Bcontrol
Agregados Aβ
Agregados Aβ / Na7 100 µM
200 pA
10 seg
control
Agregados Aβ
Agregados Aβ / Na7 100 µM
200 pA
10 seg
200 pA
10 seg
Aβ Aβ
Na7Ca2+
Aβ Aβ
Na7Ca2+
0,0
0,2
0,4
0,6
0,8
1,0
**n =30
Agregados A
Na7200 M
Na7100 M
Na7 10M
Na70 M
Flu
ore
scen
cia
no
rmal
izad
a(
F/F
0)
0 20 40 60 80 1000,0
0,9
1,0
1,1
1,2
1,3
1,4
1,5
Flu
ore
scen
cia
no
rmal
izad
a(
F/F
0)
Tiempo (seg)
Agregados A Agregados A / Na7
A B
0,0
0,2
0,4
0,6
0,8
1,0
**n =30
Agregados A
Na7200 M
Na7100 M
Na7 10M
Na70 M
Flu
ore
scen
cia
no
rmal
izad
a(
F/F
0)
0 20 40 60 80 1000,0
0,9
1,0
1,1
1,2
1,3
1,4
1,5
Flu
ore
scen
cia
no
rmal
izad
a(
F/F
0)
Tiempo (seg)
Agregados A Agregados A / Na7
A B
control
control
Agregados 1µM
Agregados 1µM/ Na7 100 µM
Na7 100 µM
200 pA
200 pA
10 s
10 s
Contro
l
Agregad
os
Agreg
ados/
Na7
0
1
2
3
4
5 *
Fre
cuen
cia
(Hz)
Act
ivid
ad S
ináp
tica
Esp
on
tán
ea
control
control
Agregados 1µM
Agregados 1µM/ Na7 100 µM
Na7 100 µM
200 pA
200 pA
10 s
10 s
Contro
l
Agregad
os
Agreg
ados/
Na7
0
1
2
3
4
5 *
Fre
cuen
cia
(Hz)
Act
ivid
ad S
ináp
tica
Esp
on
tán
ea
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http://www.alz.org/alzheimers_disease_alternative_treatments.asp
Caprylic acid and coconut oil ConcernsCoenzyme Q10Coral calciumGinkgo bilobaHuperzine AOmega-3 fatty acidsPhosphatidylserineTramiprosate
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Conclusion Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.
Snitz et al 2009 JAMA
Test Placebo Ginko
Memory 0,15 0,14
Executive test 3,27 3,47
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Date of download: 7/14/2012Copyright © 2012 American Medical Association.
All rights reserved.
From: Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease: A Randomized Trial
JAMA. 2010;304(17):1903-1911. doi:10.1001/jama.2010.1510
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Danitz and Parsons 2008 IJNP
Donepezil and Memantine for Moderate-to-Severe Alzheimer's Disease
Conclusions In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months JAMA 2012
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Palmer 2002 Trends in Phar