Coventry University Featured PhD Programmes
Birkbeck, University of London Featured PhD Programmes
Engineering and Physical Sciences Research Council Featured PhD Programmes
Sheffield Hallam University Featured PhD Programmes
University of Lincoln Featured PhD Programmes

Using retro-inverso A peptide inhibitors for the treatment of cerebral amyloid angiopathy


Project Description

Alzheimer’s disease (AD) is the most common cause of dementia and affects >860,000 people in the UK alone. Over 99% of clinically tested treatments for AD have failed and currently approved drugs, which include acetylcholinesterase inhibitors (AChEI) do not stop or reverse the course of dementia [1]. -amyloid (A) is one of the principal pathological species in AD and deposits as A42-positive plaques in the brain and as A40 in the cerebral blood vessels, which is termed cerebral amyloid angiopathy (CAA). CAA is associated with hypoperfusion, microhaemorrhage and cognitive impairment [2, 3]. Work from the Hawkes lab has shown that CAA develops in part because of impaired clearance of A from the brain along the walls of cerebral blood vessels [4, 5]. The importance of this vascular clearance pathway is underscored by findings from human A immunisation trials showing that A42 removed from the brain accumulates in CAA-positive vessels [6]. This suggests that disease-modifying treatments that taget A clearance may continue to fail if vascular function is compromised.

The Allsop group has developed two retro-inverso peptide inhibitors, RI-OR2-TAT and nanoliposomes decorated with RI-OR2-TAT (PINP), that prevent the aggregation of A42, reduce plaque pathology in vivo and significantly improve cognitive performance in Tg mouse models of AD [7, 8]. However, whether these compounds are similarly effective in preventing and/or removing CAA is unknown. In addition, recent findings from the Hawkes group indicate that loss of cholinergic innervation of cerebral blood vessels reduces A clearance and results in increased CAA pathology. Thus, combining currently approved AChEIs with inhibitors of A aggregation may significantly improve A clearance from the brain and reduce associated cognitive impairment. This project will test the hypothesis that administration of the RI-OR2-TAT inhibitors will facilitate vascular-mediated clearance of A from the brain by reducing CAA pathology and that this will be more effective when combined with an AChEI.

Project aims:
1) test the effectiveness of RI-OR2-TAT and PINP to prevent the aggregation of A40 using dose and time-course in vitro aggregation assays[7-9]. Results from these experiments will help determine which inhibitor is most effective at preventing and/or disassembling A40 oligomers.

2) compare the efficiency of fluorescently labelled RI-OR2-TAT and PINP to i) cross the blood-brain barrier and ii) bind to A40 and A42 in vivo [7, 8]. Results from these experiments will be used to determine if one inhibitor shows preferential brain uptake and/or binds preferentially to CAA.

3) based on results from aims 1 and 2, animal models of AD will be treated with RI-OR2-TAT or PINP alone and in combination with an AChEI before and after onset of CAA. At the end of the treatment, cognitive testing will be assessed [10, 11]. Following this, brains will be processed using immunohistochemistry, Western blotting and ELISA to evaluate plaque and CAA pathology, A species and markers of vascular health [12].

Results from these experiments will determine if retro-inverso peptide inihibition can prevent and/or reverse CAA and improve vascular health as well as the subsequent effects on parenchymal A pathology and cognitive function.

Funding Notes

Applications should be made directly to Dr Cheryl Hawkes and should include:

CV (max 2 A4 sides), including details of two academic references
A cover letter outlining their qualifications and interest in the studentship (max 2 A4 sides)

References

Mehta D, Jackson R, Paul G, Shi J, Sabbagh M. Why do trials for Alzheimer's disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opin Investig Drugs 2017; 26: 735-739.
2. Arvanitakis Z, et al. Cerebral amyloid angiopathy pathology and cognitive domains in older persons. Ann Neurol 2011; 69: 320-327.
3. Pfeifer M, et al. Cerebral hemorrhage after passive anti-A-beta immunotherapy. Science 2002; 298: 1379.
4. Hawkes CA, et al. Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-beta from the mouse brain. Aging Cell 2013; 12: 224-36.
5. Hawkes CA, et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol 2011; 121: 431-43.
6. Boche D, et al. Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. Brain 2008; 131: 3299-3310.
7. Gregori M, et al. Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Abeta peptide. Nanomedicine 2017; 13: 723-732.
8. Parthsarathy V, et al. A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1DeltaE9 mouse model of Alzheimer's disease. PLoS One 2013; 8: e54769.
9. Sun Y, et al. Synthesis of scyllo-inositol derivatives and their effects on amyloid beta peptide aggregation. Bioorg Med Chem 2008; 16: 7177-84.
10. Hawkes CA, Deng LH, Shaw JE, Nitz M, McLaurin J. Small molecule beta-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer's disease. Eur J Neurosci 2010; 31: 203-13.
11. McLaurin J, et al. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med 2006; 12: 801-8.
12. Nizari S, Carare RO, Hawkes CA. Increased Abeta pathology in aged Tg2576 mice born to mothers fed a high fat diet. Sci Rep 2016; 6: 21981.

Email Now

Insert previous message below for editing? 
You haven’t included a message. Providing a specific message means universities will take your enquiry more seriously and helps them provide the information you need.
Why not add a message here
* required field
Send a copy to me for my own records.

Your enquiry has been emailed successfully





FindAPhD. Copyright 2005-2020
All rights reserved.