Strain differences in the effects of Angiotensin IV on mouse cognition

Golding, Bruno; Overall, Andrew; Brown, G. A.; Gard, Paul R.

doi:10.1016/j.ejphar.2010.05.041

Cited by 18 publications

(12 citation statements)

References 37 publications

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“…As such they may be more beneficial than ACE-Is as an AD therapy, but as with ACE-Is, the mechanisms through which ARBs may confer cognitive benefits also remain to be fully verified. Yet, currently the proposed mechanisms through which ARBs may confer symptomatic benefits are twofold following direct blockade of Ang II binding to AT 1 R and could stem from a combination of excess unbound Ang II-activating AT 2 R or through increased processing of the excess Ang II to Ang III and in turn Ang IV ( Figure 2) which has been suggested to promote long-term potentiation [98] and cognitive improvement [99]. Recent studies have also shown that losartan significantly inhibits Ang II-induced GSK3b-mediated tau phosphorylation [100] and Ab production [26] in rats continually infused with Ang II.…”

Section: Considerations For Inhibition Of Ang II In Relation To Dementiamentioning

confidence: 98%

Current status of renin–aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease

Ashby¹,

Kehoe²

2013

Expert Opinion on Investigational Drugs

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Section: Considerations For Inhibition Of Ang II In Relation To Dementiamentioning

confidence: 98%

Current status of renin–aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease

Ashby¹,

Kehoe²

2013

Expert Opinion on Investigational Drugs

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“…The literature, reviewed in Gard (2002), reports a complex relationship with angiotensin II seen to both enhance and diminish learning and memory in animal models, depending when the animals were tested after administration of the angiotensin II. Angiotensin IV consistently improves learning and memory in animal models (eg Golding et al, 2010) and it is the metabolism of angiotensin II to angiotensin IV that probably underlies the observed beneficial effects of angiotensin II (Braszko et al, 2006). Clinically, drugs which decrease angiotensin II activity such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists, are associated with improved cognition (Nelson et al, 2013), but whether this observed effect is associated with increased activity of angiotensin IV remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Changes of renin-angiotensin system-related aminopeptidases in early stage Alzheimer's disease

Gard

Fidalgo

Lotter

et al. 2017

Experimental Gerontology

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Activities of aminopeptidases A, B, and N (ApA, ApB & ApN) and insulin-regulated aminopeptidase (IRAP) have been seen to be decreased amongst patients with Alzheimer's disease (AD). All of these enzymes are involved with the brain renin-angiotensin system which is believed to be involved with learning and memory. This study aimed to explore the time course and the mechanisms underlying these changes. Serum samples were collected from 45 AD patients at the start of the study, and again 13 months later (n=37). The control group was 22 healthy, older, adults. Enzyme activity was determined at two substrate concentrations to allow Michaelis-Menten analysis of the enzyme activity. The results indicated that there was decreased activity of ApA, ApB and ApN amongst AD patients but no difference in serum IRAP activity. There were no associations between enzyme activity and age, gender nor scores on psychomotor tests. Consideration of the data for the two time points for AD patients showed that the changes in ApB occurred at an early stage of the disease and persisted, whilst those of ApA and ApN only became apparent at later stages of the disease. Although differences in MichaelisMenten parameters were not statistically significant, consideration of the values suggested that the decrease in ApB activity may be a result of changes in enzyme protein conformation, whilst that of ApN may be a consequence of decreased enzyme expression. Importantly, the different time courses of the effects and the differential changes in enzyme affinity and expression indicated that the observed changes with progression of AD were not a 'class effect' for serum aminopeptidases but were idiosyncratic for the individual enzymes.

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“…administration in the present study and, as a hexapeptide, is not thought to be readily transported across the blood-brain-barrier (Chua et al, 2004). Although some procognitive effects following systemic administration of Ang IV have been observed in different strains of mice (Gard, 2008; Golding et al, 2010), Ang IV is rapidly metabolized in circulation with a half-life of ˜10 sec (Handa et al, 2000). Given the conserved distribution of Ang IV in brain regions associated with mnemonic performance, this peptide has important therapeutic potential for cognitive enhancement.…”

Section: Discussionmentioning

confidence: 99%

Central administration of angiotensin IV rapidly enhances novel object recognition among mice

et al. 2013

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Angiotensin IV (Val1-Tyr2-Ile3-His4-Pro5-Phe6) has demonstrated potential cognitive-enhancing effects. The present investigation assessed and characterized: (1) dose-dependency of angiotensin IV's cognitive enhancement in a C57BL/6J mouse model of novel object recognition, (2) the time-course for these effects, (3) the identity of residues in the hexapeptide important to these effects and (4) the necessity of actions at angiotensin IV receptors for pro-cognitive activity. Assessment of C57BL/6J mice in a novel object recognition task demonstrated that prior administration of angiotensin IV (0.1, 1.0, or 10.0, but not 0.01, nmol, i.c.v.) significantly enhanced novel object recognition in a dose-dependent manner. These effects were time dependent, with improved novel object recognition observed when angiotensin IV (0.1 nmol, i.c.v.) was administered 10 or 20, but not 30, min prior to the onset of the novel object recognition testing. An alanine scan of the angiotensin IV peptide revealed that replacement of the Val1, Ile3, His4, or Phe6 residues with Ala attenuated peptide-induced improvements in novel object recognition, whereas Tyr2 or Pro5 replacement did not significantly affect performance. Administration of the angiotensin IV receptor antagonist, divalinal-Ang IV (20 nmol, i.c.v.), reduced (but did not abolish) novel object recognition; however, this antagonist completely blocked the pro-cognitive effects of angiotensin IV (0.1 nmol, i.c.v.) in this task. Rotorod testing demonstrated no locomotor effects for any angiotensin IV or divalinal-Ang IV dose tested. These data demonstrate that angiotensin IV produces a rapid enhancement of associative learning and memory performance in a mouse model that was dependent on the angiotensin IV receptor.

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Strain differences in the effects of Angiotensin IV on mouse cognition

Cited by 18 publications

References 37 publications

Current status of renin–aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease

Current status of renin–aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer's disease

Changes of renin-angiotensin system-related aminopeptidases in early stage Alzheimer's disease

Central administration of angiotensin IV rapidly enhances novel object recognition among mice

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