Dr. Sigal fleisher-Berkovich

Neuroinflammation is regulated by angiotensin related drugs: possible implications for neurodegenerative

diseases

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.

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

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

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.

IN VITRO EXPERIMENTS

CANDESARTAN

***

****

TELMISARTAN

***

**

***

IN VIVO EXPERIMENTS

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)

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

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

***

*

The effect of 3 weeks treatment of Telmisartan 1mg/kg/day on amyloid deposition in 5XFAD mice

The effect of 3 weeks treatment of Telmisartan 1mg/kg/day on CD11b staining in 5XFAD mice

**

**

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

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

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

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

***

ns

The effect of 2 months treatment of Telmisartan 1mg/kg/day on amyloid deposition in 5XFAD mice

***

**

The effect of 2 months treatment of Telmisartan 1mg/kg/day on CD11b staining in 5XFAD mice

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

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

***

ns

The effect of 3 weeks treatment of Perindopril 1mg/kg/day on amyloid deposition in 5XFAD mice

***

ns

The effect of 3 weeks treatment of Perindopril 1mg/kg/day on CD11b staining in 5XFAD mice

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

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