dr. sigal fleisher-berkovich neuroinflammation is regulated by angiotensin related drugs: possible...
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Dr. Sigal fleisher-Berkovich
Neuroinflammation is regulated by angiotensin related drugs: possible implications for neurodegenerative
diseases
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THE RENIN-ANGIOTENSIN SYSTEM (RAS)
Local RAS systems were described in all tissues studied,
including the brain.
Excessive AT1 receptor stimulation is a major factor in
the development and progression of brain
inflammation.
AT2 receptor stimulation may counterbalance AT1
receptor activation and play a protective role during
brain injury.
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ALZHEIMER’S DISEASE AND BRAIN INFLAMMATION
Excessive brain inflammation is
increasingly recognized as a major
factor participating in pathogenesis
of brain disease as AD.
Hallmarks of AD:
Brain amyloid-β plaques
neurofibrillary tangles (NFT) caused
by hyperphosphorylation Tau
protein
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ANGIOTENSIN II AT1 RECEPTOR BLOCKERS (ARBS)/ ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEI)
ARBs and ACEI are currently a
mainstream treatment for cardiovascular
and metabolic disease, including
essential hypertension.
The beneficial effects: reduction of
vasoconstriction and a significant
decrease in vascular and organ
inflammation.
(Juan M.Saavedra 2012)
ARBsTelmisartan
Candesartan
ACEI
Perindopril
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AIMS
To examine the effect of ARBs on the synthesis of inflammatory
mediators in microglial cell line.
To examine the effect of I.N administration of ARBs or ACEI on
amyloid plaques’ formation and brain inflammation in 5XFAD mice.
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IN VITRO EXPERIMENTS
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CANDESARTAN
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TELMISARTAN
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IN VIVO EXPERIMENTS
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THE MODEL: 5XFAD MICE
Transgenic C57BL/6 mice with 3 mutations in the gene for APP
(Amyloid precursor protein) and 2 mutations in the gene for PS1
(presenilin 1)
Accelerated over production in total Amyloid, and specifically in
Amyloid beta42
Amyloid plaques develop at 2 months of age
Significant neurodegeneration and neuronal loss, and impaired
memory in the Y-maze
(Robert Vassar et al. 2006)
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Telmisartan (3 weeks treatment) reduces CD11b expression in cortex 5XFAD mice
WT+Telmisartan TG+Telmisartan TG+ Saline
20 mm
DAPI DAPI DAPI
CD11b CD11b CD11b
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Telmisartan (3 weeks treatment) reduces amyloid burden in cortex of 5XFAD mice
WT+Telmisartan TG+Telmisartan TG+ Saline
20 mm
DAPI DAPI DAPI
Aβ Aβ Aβ
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The effect of 3 weeks treatment of Telmisartan 1mg/kg/day on amyloid deposition in 5XFAD mice
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The effect of 3 weeks treatment of Telmisartan 1mg/kg/day on CD11b staining in 5XFAD mice
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Telmisartan (2 months treatment) reduces CD11b expression in cortex of 5XFAD mice
20 mm
DAPI DAPI
CD11b CD11b CD11b
20 mm
DAPI
WT+Telmisartan TG+Telmisartan TG+ Solvent
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Telmisartan (2 months treatment) reduces amyloid burden in cortex of 5XFAD mice
WT+Telmisartan TG+Telmisartan TG+ Solvent
20 mm
DAPI DAPI DAPI
Aβ Aβ Aβ
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WT+Telmisartan TG+Telmisartan TG+ Solvent
20 mm
CD11b CD11b CD11b
DAPI DAPI DAPI
Telmisartan (2 months treatment) reduces CD11b burden in hippocampus of 5XFAD mice
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Telmisartan reduces amyloid burden in hippocampus of 4-month old 5XFAD mice
WT+Telmisartan TG+Telmisartan TG+ Solvent
20 mm
DAPI DAPI DAPI
Aβ Aβ Aβ
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ns
The effect of 2 months treatment of Telmisartan 1mg/kg/day on amyloid deposition in 5XFAD mice
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***
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The effect of 2 months treatment of Telmisartan 1mg/kg/day on CD11b staining in 5XFAD mice
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WT+Perindopril TG+Perindopril TG+ Saline
DAPI DAPI DAPI
Aβ Aβ Aβ
20 mm
Perindopril (3 weeks treatment) reduces amyloid burden in cortex of 5XFAD mice
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Perindopril reduces CD11b expression in cortex of 3-month old 5XFAD mice
20 mm
CD11b CD11b CD11b
DAPI DAPI DAPI
WT+Perindopril TG+Perindopril TG+ Saline
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***
ns
The effect of 3 weeks treatment of Perindopril 1mg/kg/day on amyloid deposition in 5XFAD mice
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***
ns
The effect of 3 weeks treatment of Perindopril 1mg/kg/day on CD11b staining in 5XFAD mice
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SUMMARY
Intervention in the brain RAS with ARBs or ACEI may serve
as a new approach for the treatment of AD, where
inflammation plays a significant role
Candesartan/Telmisartan BV-2 cells:
• M-1 activation of microglia
5XFAD mice:
• % Area covered by Aβ deposition
• % Area covered by positive staining
to CD11b
Telmisartan/Perindopril
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Acknowledgements
Department of Clinical Pharmacology:
Dr. Sigal Fleisher- Berkovich Ella Mali Roaso Keren Asraf
Nofar Torika• Dr. Shira Ovadia• Mr. Shahada Aburatiush
Ben-Gurion University
Department of Microbiology and Immunology:
• Malka White• Anna Nemirovsky• Prof. Ron Apte• Prof. Alon Monsonego
Northwestern University
Department of cell and molecular biologyProf. Robert Vassar
Tel Aviv UniversityDepartment of Molecular Microbiology and Biotechnology:Dr. Dan Frenkel
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