title: Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer's disease mice.
abstract: The renin-angiotensin system (RAS) is a major circulative system engaged in homeostasis modulation. Angiotensin II (Ang II) serves as its main effector hormone upon binding to its primary receptor, Ang II receptor type 1 (AT1R). It is well established that an intrinsic independent brain RAS exists. Abnormal AT1R activation both in the periphery and in the brain probably contributes to the development of Alzheimer's disease (AD) pathology that is characterized, among others, by brain inflammation. Moreover, treatment with drugs that block AT1R (AT1R blockers, ARBs) ameliorates most of the clinical risk factors leading to AD. Previously we showed that short period of intranasal treatment with telmisartan (a brain penetrating ARB) reduced brain inflammation and ameliorated amyloid burden (a component of Alzheimer's plaques) in AD transgenic mouse model. In the present study, we aimed to examine the long-term effect of intranasally administrated telmisartan on brain inflammation features including microglial activation, astrogliosis, neuronal loss and hippocampus-dependent cognition in five-familial AD mouse model (5XFAD). Five month of intranasal treatment with telmisartan significantly reduced amyloid burden in the cortex and hippocampus of 5XFAD mice as compared with the vehicle-treated 5XFAD group. Similar effects were also observed for CD11b staining, which is a marker for microglial accumulation. Telmisartan also significantly reduced astrogliosis and neuronal loss in the cortex of 5XFAD mice compared with the vehicle-treated group. Improved spatial acquisition of the 5XFAD mice following long-term intranasal administration of telmisartan was also observed. Taken together, our data suggest a significant role for AT1R blockage in mediating neuronal loss and cognitive behavior, possibly through regulation of amyloid burden and glial inflammation.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva P.O.B 653, Israel.
authors.forename: Nofar
authors.initials: N
authors.lastname: Torika
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva P.O.B 653, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Asraf
authors.affiliation: Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ministry of Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Department of Psychology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Cohen
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva P.O.B 653, Israel. Electronic address: fleisher@bgu.ac.il.
authors.forename: Sigal
authors.initials: S
authors.lastname: Fleisher-Berkovich
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001565:Benzoates / Q000008:administration & dosage*; D016764:Cell Polarity / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D005911:Gliosis / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D065855:Spatial Processing / Q000187:drug effects; D000077333:Telmisartan
chemical_list: D016229:Amyloid beta-Peptides; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D000077333:Telmisartan
keywords: Alzheimer’s disease; Angiotensin II; Glial inflammation; Microglia; Telmisartan