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MECHANISMS RESPONSIBLE FOR BETA-AMYLOID- DEPENDENT REDUCTION OF ERYTHROCYTE DEFORMABILITY Francesco Misiti University of Cassino and Southern Lazio Cassino (Italy)

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MECHANISMS RESPONSIBLE FOR BETA-AMYLOID-DEPENDENT REDUCTION OF ERYTHROCYTE DEFORMABILITY Francesco Misiti University of Cassino and Southern Lazio Cassino (Italy). Conflict of Interest. Francesco Misiti Has no real or apparent conflicts of interest to report. Erythrocytes and Alzheimer. - PowerPoint PPT Presentation

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Page 1: Conflict of Interest

MECHANISMS RESPONSIBLE FOR BETA-AMYLOID-DEPENDENT

REDUCTION OF ERYTHROCYTE DEFORMABILITY

Francesco MisitiUniversity of Cassino and Southern Lazio

Cassino (Italy)

Page 2: Conflict of Interest

Conflict of Interest

• Francesco Misiti

• Has no real or apparent conflicts of interest to report

Page 3: Conflict of Interest

o A are associated with cerebral blood vessels

o A are transferred to blood

o A are produced by platelets

o Blood cells are exposed to A(1-42) and (1-40)

o Erythrocytes interact with A(1-42)

o A alters erythrocyte shape and deformability

o A impairs oxygen delivery to brain

Erythrocytes and Alzheimer

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ControlAmyloid

Effects of Aβ on erythrocyte morphology

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Membrane AChE activity as a marker of membrane integrity

* P < 0.05 vs. control

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Objective

o Nitric Oxide: a regulatory factor of erythrocyte mechanical properties

o Nitric Oxide synthase (eNOS) is expressed in erythrocyteso PKC andCaspase 3responsible for regulation on eNOS

function o Pentose Phosphate Pathway (PPP): responsible for

erythrocyte antioxidant defense

Clarify the role played by Nitric Oxide synthase (eNOS) signaling pathway in the A-dependent alteration of erythrocyte morphology

Page 7: Conflict of Interest

Western blot analysis showing the conformational species of A

Piacentini et al. J Neurochem (2008)

Page 8: Conflict of Interest

Western blot analysis showing the conformational species of A

Piacentini et al. J Neurochem (2008)

Page 9: Conflict of Interest

Control

Amyloid

Immuno-histochemical staining of erythrocyte activated nitric oxide synthase (eNOS)

* P< 0.05 vs. control;

Page 10: Conflict of Interest

Time course of the effects of Aβ on nitrite and nitrate levels in erythrocytes

suspensions

* P < 0.05 vs. control; # P < 0.05 vs. Aβ at 24 hours.

Page 11: Conflict of Interest

* P < 0.05 vs. control; # P < 0.05 vs. Aβ at 24 hours.

Time course of the effects of Aβ on nitrite and nitrate levels in erythrocytes

suspensions

Page 12: Conflict of Interest

AChE inhibitors abrogate the effects of Aβ on nitrite and nitrate levels in

erythrocytes suspensions

* P < 0.05 vs. control; # P < 0.05 vs. Aβ at 24 hours.

Page 13: Conflict of Interest

cytosol

membrane

Ctr A + PMA

(80 kDa) PKC

(80 kDa) PKC

+ PMA

amyloid

control

PKC activation by A

Page 14: Conflict of Interest

cytosol

membrane

Ctr A + PMA

(80 kDa) PKC

(80 kDa) PKC

+ PMA

amyloid

control

PKC activation by A

Page 15: Conflict of Interest

Clementi et al. Int J Biochem Cell Biol. 39: 727-735 (2007)

Caspase 3 activation by Aactivity

Page 16: Conflict of Interest

Ctr A

Misiti et al. Biochem Cell Biol.86: 1-8 (2008)

--32kDa

--20 kDa

Caspase 3 activation by AWB

Page 17: Conflict of Interest

Misiti et al. Biochem Cell Biol.86: 1-8 (2008) Mandal et al. JBC 278: 52551-52558 (2003)

Band 3 degradation by Caspase 3

Ctr A A

Ctr A

--32kDa

--20 kDa

Page 18: Conflict of Interest

Reduction in antioxidant defense (Pentose Phosphate Pathway)

Clementi et al. Int. J. Biochem Cell Biol., 36(10):2066-76 (2004)

Ctr A

** P < 0.05 vs. A at 24 hours

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Misiti et al. Biochem Cell Biol.86: 1-8 (2008)

A dependent reduced stimulus for endogenous NO synthesis in the vasculature

Ctr A

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Conclusions

A/erythrocyte interaction induces :

o an imbalance in the antioxidant defense (PPP flux reduction)

o Caspase 3 activationo PKCactivation o eNOS down-regulationo NO levels reduction

Page 21: Conflict of Interest

Conclusions

A/erythrocyte interaction induces :

o an imbalance in the antioxidant defense (PPP flux reduction)

o Caspase 3 activationo PKCactivation o eNOS down-regulationo NO levels reduction

Page 22: Conflict of Interest

Acknowledgements

University of Cassino and Southern Lazio- Cassino

Cristiana Carelli Alinovi

Catholic University-School of Medicine- Rome

Bruno Giardina

Research National Council (CNR)-ICRM & ISM

Beatrice SampaoleseMarco Girasole

:

Page 23: Conflict of Interest

UNIVERSITY OF CASSINO AND SOUTHERN LAZIO