Identification and development of specific inhibitors for insulin-regulated aminopeptidase as a new class of cognitive enhancers

Albiston, Anthony L.; Diwakarla, Shanti; Fernando, Ruani; Mountford, Simon J.; Yeatman, Holly R.; Morgan, Broden J.; Pham, Vi; Holien, Jessica K.; Parker, Michael W.; Thompson, Phillip E.; Chai, Siew Yeen

doi:10.1111/j.1476-5381.2011.01402.x

Cited by 79 publications

(74 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…AP-N activity was significantly reduced in AD in contrast to protein levels that either remained unchanged (determined by ELISA) or appeared to be elevated (immunohistochemical analysis). A reduction in AP-N activity could however potentially mediate reduced conversion of Ang-III to Ang-IV resulting in elevated Ang-III level, which would not only impact on disease pathology but could also influence downstream signalling pathways involved in cognition -Ang-IV mediated inhibition of its receptor IRAP is heavily implicated in learning and memory processes [30,31]. Serum and plasma AP-N activities are also reduced in AD [32,33].…”

Section: Discussionmentioning

confidence: 99%

“…Orally administered AP-A inhibitors, resulting in Ang-III reduction, are cardioprotective [25][26][27][28] suggesting that Ang-III, rather than Ang-II, may be the central effector protein in RAS (reviewed in [3]). Ang-III is metabolised by aminopeptidase-N (AP-N) (EC 3.4.11.2) to generate Ang IV [29], a peptide that via inhibition of insulin-regulated aminopeptidase (IRAP), is heavily implicated in learning and memory consolidation [30,31]. This APA/Ang-III/APN/Ang-IV/AT4R pathway remains poorly characterised within the brain and its potential role in AD is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Angiotensin-III is Increased in Alzheimer’s Disease in Association with Amyloid-β and Tau Pathology

Kehoe

Hibbs

Palmer

et al. 2017

JAD

View full text Add to dashboard Cite

Hyperactivity of the renin-angiotensin system (RAS) is associated with the pathogenesis of Alzheimer's disease (AD) believed to be mediated by angiotensin-II (Ang-II) activation of the angiotensin type 1 receptor (AT1R). We previously showed that angiotensin-converting enzyme-1 (ACE-1) activity, the rate-limiting enzyme in the production of Ang-II, is increased in human postmortem brain tissue in AD. Angiotensin-III (Ang-III) activates the AT1R and angiotensin type-2 receptor (AT2R) but its potential role in the pathophysiology of AD remains unexplored. We measured Ang-II and Ang-III levels by ELISA, and the levels and activities of aminopeptidase-A (AP-A) and aminopeptidase-N (AP-N) (responsible for the production and metabolism of Ang-III respectively) in human post-mortem brain tissue in the mid-frontal cortex (Brodmann area 9) in a cohort of AD (n=90) and age-matched non-demented controls (n=59), for which we had previous measurements of ACE-1 activity, Aβ level and tau pathology (also in the mid-frontal cortex). We found that both Ang-II and Ang-III levels were significantly higher in AD compared to age-matched controls and that Ang-III, rather than Ang-II, was strongly associated with Aβ load and tau load.Levels of AP-A were significantly reduced in AD but AP-A enzyme activity was unchanged whereas AP-N activity was reduced in AD but AP-N protein level was unchanged. Together, these data indicate that the APA/Ang-III/APN/Ang-IV/AT4R pathway is dysregulated and that elevated Ang-III could contribute to the pathogenesis of AD.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Angiotensin-III is Increased in Alzheimer’s Disease in Association with Amyloid-β and Tau Pathology

Kehoe

Hibbs

Palmer

et al. 2017

JAD

View full text Add to dashboard Cite

show abstract

“…GLUT4 вносит существенный вклад в поглоще-ние глюкозы клетками, что необходимо для па-мяти и реализации когнитивных функций [14]. Аналогичным образом ангиотензин IV влияет на обучение и память, ингибируя активность IRAP [15]. Так, было показано, что синтезированные 13-членные макроциклические конкурентные ин-гибиторы IRAP, разработанные путем имитации N-конца окситоцина и вазопрессина, увеличива-ли синаптическую пластичность при исследова-нии гиппокампа у крыс [16].…”

Section: Introductionunclassified

The effect of insulin resistance on amygdale glucose metabolism alterations in experimental Alzheimer’s disease

Горина¹,

Комлева²,

Lopatina³

et al. 2017

Bûll. sib. med.

View full text Add to dashboard Cite

“…For instance, peptide antagonists of AngIV binding sites and small molecule inhibitors of IRAP activity produced divergent physiological effects [31,32]. Moreover, IRAP knockout mice were not altered in their cognitive behavioural response to AngIV.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin Receptors: Structure, Function, Signaling and Clinical Applications

Singh

Karnik

2017

J Cell Signal

View full text Add to dashboard Cite

Angiotensinogen -a serpin family protein predominantly produced by the liver is systematically processed by proteases of the Renin Angiotensin system (RAS) generating hormone peptides. Specific cell surface receptors for at least three distinct angiotensin peptides produce distinct cellular signals that regulate system-wide physiological response to RAS. Two well characterized receptors are angiotensin type 1 receptor (AT1 receptor) and type 2 receptor (AT2 receptor).They respond to the octapeptide hormone angiotensin II. The oncogene product MAS is a putative receptor for Ang (1-7). While these are G-protein coupled receptors (GPCRs), the in vivo angiotensin IV binding sites may be type 2 trans-membrane proteins. These four receptors together regulate cardiovascular, hemodynamic, neurological, renal, and endothelial functions; as well as cell proliferation, survival, matrix-cell interactions and inflammation. Angiotensin receptors are important therapeutic targets for several diseases. Thus, researchers and pharmaceutical companies are focusing on drugs targeting AT1 receptor than AT2 receptor, MAS and AngIV binding sites. AT1 receptor blockers are the cornerstone of current treatment for hypertension, heart failure, renal failure and many types of vascular diseases including atherosclerosis, aortic aneurism and Marfan syndrome.

show abstract

Identification and development of specific inhibitors for insulin-regulated aminopeptidase as a new class of cognitive enhancers

Cited by 79 publications

References 76 publications

Angiotensin-III is Increased in Alzheimer’s Disease in Association with Amyloid-β and Tau Pathology

Angiotensin-III is Increased in Alzheimer’s Disease in Association with Amyloid-β and Tau Pathology

The effect of insulin resistance on amygdale glucose metabolism alterations in experimental Alzheimer’s disease

Angiotensin Receptors: Structure, Function, Signaling and Clinical Applications

Contact Info

Product

Resources

About