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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)


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.

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