Intracerebroventricular Infusion of Angiotensin-(1–7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer’s Disease

Uekawa, Ken; Hasegawa, Yu; Senju, Satoru; Nakagata, Naomi; Ma, Mingjie; Nakagawa, Takashi; Koibuchi, Nobutaka; Kim‐Mitsuyama, Shokei

doi:10.3233/jad-150642

Cited by 35 publications

(25 citation statements)

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“…In the present study, we used 5XFAD mice because 5XFAD mice recapitulate major features of AD pathology and are regarded as 1 of the popular models of AD. [18][19][20]27 To examine spatial learning and memory function of 5XFAD mice, we used the Morris water maze test because it is the most popular behavioral assay for detecting AD-relevant cognitive impairments across species. 36,37 We found that 5XFAD mice were more prone to angiotensin II-induced cognitive impairment than control mice, as evidenced by the findings of the water maze test.…”

Section: Discussionmentioning

confidence: 99%

“…Implantation of an infusion cannula into the cerebral ventricles and an osmotic pump were performed on mice according to our previously reported method. 18 Briefly, the mice were anesthetized with 1.5% to 2% isoflurane through a face mask, and stainless steel cannulas (ALZET Brain Infusion Kit3, Durect Co, Cupertino, CA) were implanted in the right lateral ventricle, placed 1.0 mm lateral and 0.5 mm posterior from the bregma. The cannulas were fixed on the skull, and catheters were attached to extension tubes and linked to the ALZET osmotic pumps (Model 1004, Durect Co, Cupertino, CA), which were installed in subcutaneous pockets on the lateral backs of the mice.…”

Section: Implantation Of the Icv Infusion Cannula And Osmotic Pumpmentioning

confidence: 99%

“…Cryopreserved embryos, which were purchased from Jackson Laboratory (Bar Harbor, ME), were implanted into pseudopregnant foster mice to make 5XFAD mice. 18 5XFAD mice overexpress human amyloid precursor protein (APP695) with Swedish (K607N, M671L), Florida (I716V), and London (V717I) familial AD mutations, also with mutant human presenilin-1 (M146L, L286V) controlled by murine Thy-1 promotor. 19 5XFAD mice generate amyloid b (Ab) almost exclusively, rapidly accumulate amyloid plaque formation and also recapitulate major pathologic and behavioral characteristics of AD.…”

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confidence: 99%

“…[19][20][21] 5XFAD mice were backcrossed into the C57BL/6J background for at least 10 generations to reduce genetic variation. 18 Male wild-type mice were purchased from SLC Japan (Shizuoka, Japan). All mice were housed under a 12hour light/darkness cycle in an animal facility and were given standard chow and water ad libitum.…”

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Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure

Takane

Hasegawa

Lin

et al. 2017

JAHA

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BackgroundThe significance of brain angiotensin II in Alzheimer disease (AD) is unclear.Methods and ResultsTo examine the role of brain angiotensin II in AD, intracerebroventricular angiotensin II infusion was performed on 5XFAD mice, a mouse model of AD, and wild‐type mice, and the detrimental effects of brain angiotensin II was compared between the 2 strains of mice. Intracerebroventricular angiotensin II infusion significantly impaired cognitive function in 5XFAD mice but not in wild‐type mice. This vulnerability of 5XFAD mice to brain angiotensin II was associated with enhancement of hippocampal inflammation and oxidative stress and with increased cerebrovascular amyloid β deposition. We also compared the effect of brain angiotensin II on the heart and skeletal muscle between the 2 strains because AD is associated with heart failure and sarcopenia. We found that cardiac compensatory response of 5XFAD mice to brain angiotensin II–induced hypertension was less than that of wild‐type mice. Brain angiotensin II caused skeletal muscle atrophy and injury in 5XFAD mice more than in wild‐type mice.ConclusionsBrain angiotensin II seems to be involved in cognitive impairment and brain injury in AD, which is associated with oxidative stress, inflammation, and cerebral amyloid angiopathy. Further, brain angiotensin II may participate in cardiac disease and sarcopenia observed in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Implantation Of the Icv Infusion Cannula And Osmotic Pumpmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure

Takane

Hasegawa

Lin

et al. 2017

JAHA

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“…In a mouse model of Alzheimer's disease, i.c.v. infusion of Ang(1–7) ameliorated the cognitive impairments and memory dysfunction (Uekawa et al, ). In models of Alzheimer's and Parkinson's diseases, Ang(1–7) activity correlates with tau hyperphosphorylation (Wright et al, ; Jiang et al, ).…”

Section: Experimental Model Studiesmentioning

confidence: 99%

Significance of angiotensin 1–7 coupling with MAS1 receptor and other GPCRs to the renin‐angiotensin system: IUPHAR Review 22

Karnik

Singh

Tirupula

et al. 2017

British J Pharmacology

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This paper, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittees for the angiotensin receptors, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions, and their likely physiological roles in health and disease. More information on these receptor families can be found in the Concise Guide to PHARMACOLOGY Angiotensins are a group of hormonal peptides and include angiotensin II and angiotensin 1-7 produced by the renin angiotensin system. The biology, pharmacology and biochemistry of the receptors for angiotensins were extensively reviewed recently. In the review, the receptor nomenclature committee was not emphatic on designating MAS1 as the angiotensin 1-7 receptor on the basis of lack of classical G protein signalling and desensitization in response to angiotensin 1-7, as well as a lack of consensus on confirmatory ligand pharmacological analyses. A review of recent publications (2013-2016) on the rapidly progressing research on angiotensin 1-7 revealed that MAS1 and two additional receptors can function as 'angiotensin 1-7 receptors', and this deserves further consideration. In this review we have summarized the information on angiotensin 1-7 receptors and their crosstalk with classical angiotensin II receptors in the context of the functions of the renin angiotensin system. It was concluded that the receptors for angiotensin II and angiotensin 1-7 make up a sophisticated cross-regulated signalling network that modulates the endogenous protective and pathogenic facets of the renin angiotensin system.

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ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

et al. 2020

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Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ 42 and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9-10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12-13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.

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Intracerebroventricular Infusion of Angiotensin-(1–7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer’s Disease

Cited by 35 publications

References 30 publications

Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure

Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure

Significance of angiotensin 1–7 coupling with MAS1 receptor and other GPCRs to the renin‐angiotensin system: IUPHAR Review 22

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

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