title: Chronic kidney disease accelerates cognitive impairment in a mouse model of Alzheimer's disease, through angiotensin II.
abstract: Epidemiological studies suggest that chronic kidney disease (CKD) is a significant risk factor in the development of cognitive decline. However, the exact role of CKD in cognitive impairment or dementia is unclear. This work was performed to examine the potential impact of CKD on cognitive impairment in Alzheimer's disease (AD), focusing on angiotensin II. (1) CKD was induced in 5XFAD mice, an AD model mouse, and wild-type mice by feeding an adenine-containing diet and the effect on cognitive function was compared between both strains. There was no significant difference regarding the severity of CKD induced by adenine between the strains. In 5XFAD mice, the CKD group exhibited significant cognitive impairment while the control group (control diet-fed group) did not, as evidenced by a passive avoidance test. On the other hand, in wild-type mice, neither the CKD group nor the control group showed cognitive impairment. Thus, CKD itself appears to accelerate cognitive impairment in AD mice. (2) We also examined the effect of olmesartan, an angiotensin II receptor blocker, on 5XFAD mice with CKD to elucidate the potential involvement of angiotensin II. As evidenced by the findings of the water maze test, olmesartan treatment significantly ameliorated the impairment of spatial learning and memory function induced by CKD in 5XFAD mice. Olmesartan treatment significantly ameliorated blood-brain barrier (BBB) disruption induced by CKD in 5XFAD mice. Furthermore, olmesartan reduced hippocampal oxidative stress in 5XFAD with CKD to similar levels to the control group of 5XFAD fed standard diet. Hence, the amelioration of CKD-induced cognitive impairment in 5XFAD mice by olmesartan appears to be mediated by the suppression of BBB disruption or oxidative stress. In conclusion, we obtained the evidence suggesting that CKD itself accelerates cognitive impairment in AD mice, through angiotensin II. Thus, our work provides a novel insight into the underlying mechanism of the link between CKD and AD.
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Uekawa
authors.affiliation: Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: mitsuyam@gpo.kumamoto-u.ac.jp.
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D000375:Aging / Q000187:drug effects*; D000544:Alzheimer Disease / Q000150:complications*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage*; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan
keywords: Aging; Alzheimer's disease; Angiotensin; Blood-brain barrier; CKD