نوره سعد خليفه الملحم

الاسم الاول: 
نوره
اسم العائلة: 
الملحم
الدرجة العلمية: 
دكتوراة
مجال الدراسة: 
Medicine
المؤسسة التعليمية: 
University of Bristol

 

 

مجال التميز

تميز دراسي وبحثي

 

 

البحوث المنشورة

 

البحث (1):

 

عنوان البحث:

Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology

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تاريخ النشر:

  25 November 2016

موجز عن البحث:

Background

Hyperactivity of the classical axis of the renin-angiotensin system (RAS), mediated by angiotensin II (Ang II) activation of the angiotensin II type 1 receptor (AT1R), is implicated in the pathogenesis of Alzheimer’s disease (AD). Angiotensin-converting enzyme-2 (ACE-2) degrades Ang II to angiotensin 1–7 (Ang (1-7)) and counter-regulates the classical axis of RAS. We have investigated the expression and distribution of ACE-2 in post-mortem human brain tissue in relation to AD pathology and classical RAS axis activity.

Methods

We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores.

Results

ACE-2 activity was significantly reduced in AD compared with age-matched controls (P < 0.0001) and correlated inversely with levels of Aβ (r = −0.267, P < 0.001) and phosphorylated tau (p-tau) pathology (r = −0.327, P < 0.01). ACE-2 was reduced in individuals possessing an APOE ε4 allele (P < 0.05) and was associated with ACE1 indel polymorphism (P < 0.05), with lower ACE-2 activity in individuals homozygous for the ACE1 insertion AD risk allele. ACE-2 activity correlated inversely with ACE-1 activity (r = −0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to Ang (1–7) (a proxy measure of ACE-2 activity indicating  conversion of Ang II to Ang (1–7)) is reduced in AD.

Conclusions

Together, our findings indicate that ACE-2 activity is reduced in AD and is an important regulator of the central classical ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway likely plays a significant role in the pathogenesis of AD. 

 

 

البحث (2): 

 

عنوان البحث:

Divergence in the activity of the N- and C- catalytic domains of ACE1 - implications for the role of the renin-angiotensin system in Alzheimer’s disease 

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تاريخ النشر:

  24 April 2019

موجز عن البحث:

Angiotensin II converting enzyme-1 (ACE1) now has a recognised role in the pathogenesis of Alzheimer’s disease (AD). ACE1 converts angiotensin-I (Ang-I) to angiotensin-II (Ang-II) and is the rate-limiting enzyme of the classical RAS axis that is commonly known for regulating blood pressure. ACE1 is overactive within the brain in AD and is associated with cognitive decline and disease pathology [16] via overproduction of Ang-II (a potent vasoconstrictor) and its downstream effects mediated by angiotensin-II type 1 receptor (AT1R) sig- nalling. The angiotensin hypothesis of AD describes how Ang-II signalling contributes both directly and indirectly to the development of disease pathology in AD [9], which is supported by clinical observational and pharmaco-epidemiological studies indicating that com- monly prescribed ACE1 inhibitors (ACE1 Is), used to treat hypertension, lower the incidence and rate of cog- nitive decline in AD [2, 10, 15] and are associated with reduced Aβ and Tau pathology [5, 6]. Yet, the role of ACE1 in AD is complicated by seemingly paradoxical associations whereby polymorphisms in ACE1, associ- ated with lower levels of enzyme production (akin to a net result of ACEIs), are risk factors for AD [4, 12, 14]. This divergent role of ACE1 may be partly explained by studies in cell and mouse models of AD showing that ACE1 has both endopeptidase and carboxypeptidase activity and is capable of degrading Aβ in vitro [7, 8, 18, 19] and in vivo [21] although not all studies are support- ive [3]. These dual properties of ACE1 seem somewhat contradictory and make understanding the role of ACE1 in AD challenging, particularly as ACE1 activity in brain tissue in AD correlated with, rather than inversely corre- lated with, measures of Aβ pathology [16].

We studied brain tissue from 72 AD and 48 controls obtained from South West Dementia brain bank tissue bank, University of Bristol, UK with ethics committee approval. Cohorts were approximately matched for age-at-death (AD Mean = 78.04, SD = 10.41; controls Mean = 79.42, SD = 9.89), post-mortem delay (PM) (AD Mean = 45.86, SD = 25.8; controls Mean = 48.25, SD = 37.96) and gender (AD = 27 M: 45 F; controls = 29 M: 19 F). AD cases were diagnosed according to international neuropathological guidelines [17]. Controls were cogni- tively normal and had few or absent neurofibrillary tan- gles, a Braak stage less than 3, and no other neuropathological abnormalities. ACE1 C-domain and N-domain activity was measured by immunocapture -based FRET assays. Our findings show that ACE1 catalytic domain activity is significantly altered in AD. ACE1 C-domain activity, largely responsible for Ang-II production is significantly increased in AD by ~ 25%, whereas N-domain activity, likely contributing to Aβ cleavage and clearance, is reduced by ~ 50% in AD. 

 

 

المؤتمرات العلمية:

 

المؤتمر (1):

 

عنوان المؤتمر:

Alzheimer's Research UK Conference 2018

تاريخ الإنعقاد:

  21 March 2018 

مكان الإنعقاد:

London, UK

طبيعة المشاركة:

Poster presentation

عنوان المشاركة:

New discoveries in the brain renin angiotensin system in Alzheimer's disease

ملخص المشاركة:

Background: The classical brain RAS axis (ACE-1/Ang-II/AT1R) exerts damaging effects in the brain in both animal and human studies. Hyperactivity of this axis contributes to the pathogenesis of Alzheimer’s disease (AD). Alternative RAS pathways ((ACE-2/Ang(1-7)/MasR) and (APN/Ang-IV/IRAP)) have recently been discovered that counter-regulate the damaging effects of classical RAS signalling whilst are also implicated in boosting learning and memory. However, the involvement of these alternative RAS pathways in relation to AD pathogenesis remains unclear. We have measured brain angiotensins and their receptors involved in the alternative RAS signalling in relation to AD in a well-characterised cohort of post-mortem brains. 

Methods: Human post-mortem brain tissue was obtained from the South West Dementia Brain Bank, University of Bristol, with local Research Ethics Committee approval. The AD cases (n=72) and the age-matched controls (n=48) were matched closely for age-at-death and post-mortem delay. The levels of Ang(1-7) and Ang-IV were measured in the mid-frontal cortex (Brodmann area 8/9) by ELISA. The expression and distribution of MasR, and insulin-regulated aminopeptidase (IRAP) (Ang-IV receptor), were determined by ELISA and immunohistochemistry. Pre-existing data on Ang-II level, and amyloid (Aβ) level (by ELISA) and Tau load (field fraction analysis), Braak staging information was also available for analyses. 

Results: MasR level was significantly reduced in AD however Ang-(1-7) remained unchanged. Also, Ang-IV level was also reduced in AD with no changes in IRAP level in AD group. 

Conclusions: Our recent studies show that dysregulation of alternative brain regulatory RAS components, that are modifiable pharmacologically, are associated with the pathogenesis of AD. 

 

 

المؤتمر (2):

 

عنوان المؤتمر:

The 9th International Conference of The International Society of Vascular Behavioural and Cognitive Disorders 

تاريخ الإنعقاد:

 14-17 November 2018

مكان الإنعقاد:

Hong Kong

طبيعة المشاركة:

Poster Presentation

عنوان المشاركة:

Alternative Regulatory Pathways of the brain Renin Angiotensin System in Alzheimer’s disease

ملخص المشاركة:

Background:  The classical brain RAS axis (ACE-1/Ang-II/AT1R) exerts damaging effects in the brain in both animal and human studies. Hyperactivity of this axis contributes to the pathogenesis of Alzheimer’s disease (AD)1. Alternative RAS pathways ((ACE-2/Ang(1-7)/MasR) and (APN/Ang-IV/IRAP)) have recently been discovered that counter-regulate the damaging effects of classical RAS signalling whilst are also implicated in boosting learning and memory2,3. However, the involvement of these alternative RAS pathways in relation to AD pathogenesis remains unclear. We previously showed that ACE-2 activity was reduced in AD in association with disease pathology4. In this study, we have measured brain angiotensins and their receptors involved in the alternative RAS signalling in relation to AD and vascular markers in a well-characterised cohort of post-mortem brains.

Methods: Human post-mortem brain tissue was obtained from the South West Dementia Brain Bank, University of Bristol, with local Research Ethics Committee approval. The AD cases (n=72) and the age-matched controls (n=48) were matched closely for age-at-death and post-mortem delay. The levels of Ang(1-7) and Ang-IV were measured in the mid-frontal cortex (Brodmann area 8/9) by ELISA. The expression and distribution of MasR, and insulin-regulated aminopeptidase (IRAP) (Ang-IV receptor) were determined by ELISA and immunohistochemistry. The activity of IRAP was measured by catalytic activity assay. Pre-existing data on Braak staging information, ischemic markers (VEGF level and MAG:PLP ratio) was also available for analysis.

Results: Mas receptor level was significantly reduced in AD but Ang(1-7) remained unchanged. Ang-IV level was also reduced in AD with no changes in IRAP level and activity in the AD group. MasR and Ang(1-7) level, and  AngIV and IRAP level, were all inversely correlated with VEGF level.

Conclusions: Our studies show dysregulation of alternative brain regulatory RAS pathways in AD are associated with vascular dysfunction, indicated by a strong association with VEGF and MAG:PLP.

 

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Vascog attendance 2018.pdf108.6 KB
ARUK abstract 2018 (5).pdf526.58 KB