1. Dr. Sigal fleisher-Berkovich Neuroinflammation is regulated by angiotensin related drugs: possible implications for neurodegenerative diseases

2.  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.

3. 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

4.  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)ARBs Telmisartan Candesartan ACEI Perindopril

5.  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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10.  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 beta 42  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)

11. Telmisartan (3 weeks treatment) reduces CD11b expression in cortex 5XFAD mice 5XFAD mice WT+TelmisartanTG+Telmisartan TG+ Saline 20  m DAPI CD11b

12. Telmisartan (3 weeks treatment) reduces amyloid burden in cortex of 5XFAD mice 5XFAD mice WT+TelmisartanTG+Telmisartan TG+ Saline 20  m DAPI AβAβ AβAβ AβAβ

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

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

15. Telmisartan (2 months treatment) reduces CD11b expression in cortex of 5XFAD mice 5XFAD mice 20  m DAPI CD11b 20  m DAPI WT+TelmisartanTG+Telmisartan TG+ Solvent

16. Telmisartan (2 months treatment) reduces amyloid burden in cortex of 5XFAD mice 5XFAD mice WT+TelmisartanTG+Telmisartan TG+ Solvent 20  m DAPI AβAβ AβAβ AβAβ

17. WT+TelmisartanTG+Telmisartan TG+ Solvent 20  m CD11b DAPI Telmisartan (2 months treatment) reduces CD11b burden in hippocampus of 5XFAD mice

18. Telmisartan reduces amyloid burden in hippocampus of 4-month old 5XFAD mice 5XFAD mice WT+TelmisartanTG+Telmisartan TG+ Solvent 20  m DAPI AβAβ AβAβ AβAβ

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

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

21. WT+PerindoprilTG+Perindopril TG+ Saline DAPI AβAβAβAβAβAβ 20  m Perindopril (3 weeks treatment) reduces amyloid burden in cortex of 5XFAD mice

22. Perindopril reduces CD11b expression in cortex of 3-month old 5XFAD mice 5XFAD mice 20  m CD11b DAPI WT+PerindoprilTG+Perindopril TG+ Saline

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

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

25. 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

26. 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: Department of Microbiology and Immunology: Malka White Malka White Anna Nemirovsky Anna Nemirovsky Prof. Ron Apte Prof. Ron Apte Prof. Alon Monsonego Prof. Alon Monsonego Northwestern University Department of cell and molecular biology Prof. Robert Vassar Tel Aviv University Department of Molecular Microbiology and Biotechnology: Dr. Dan Frenkel