Title of project: Novel peptide based cannabinoids for Alzheimer’s.
Director of Studies: Dr Nathaniel G N Milton
Second Supervisor: Dr Steve Martin
Advisor Dr Andrew W J Paterson
Overview of project
The original discovery that endogenous cannabinoids (endocannabinoids) were neuroprotective
against amyloid-beta (Aβ) toxicity (Milton 2002) suggested that activation of the endocannabinoid
system has the potential for development as a potential therapeutic route for Alzheimer’s disease
(AD). Subsequent studies have shown that cannabinoid based compounds are effective in both in
vitro and in vivo models of AD (Aso & Ferrer 2014). The pepcans are a recently discovered group of
cannabinoid receptor-1 (CB1) binding peptides derived from α- and β- chains of haemoglobin (Bauer
et al 2012). The pepcans are found throughout the CNS, and the N-terminally extended forms are
specific CB1 agonists (Gomes et al 2009) that may have potential as neuroprotective agents against
Aβ as a result (Milton 2002; Milton 2005). Studies have suggested that the levels of α- and βhaemoglobin expression in the CNS of AD patients are reduced (Ferrer et al 2011). There is also
evidence that administration of erythropoietin has the potential to increase the expression of alpha
and β-haemoglobin expression in the CNS (Schelshorn et al 2009).
AD currently has no effective therapeutic and cannabinoids have been suggested as possible
candidates to take to clinic (Aso & Ferrer 2014). The pepcans have the advantages of specificity for
the CB1 receptors, ability to cross the blood brain barrier (Heimann et al 2007) and have also been
found to be secreted from neuronal cells (Hofer et al 2015); as such they represent novel endogenous
cannabinoids that could be used as potential therapeutics for AD.
Link to Faculty Research Themes
Centre for Biomedical Research
5A Biological Sciences or 3A Allied Health Professions
Outline of project including proposed timescales
The project will specifically evaluate the effect of pepcans in a neuronal cell line model of AD (Milton
2002). Using neuronal overexpression of pepcan, haemoglobin and erythropoietin genes and/or
modified sequences the role of these compounds in protection against Aβ toxicity will be examined
(Milton et al 2012; Chilumuri et al 2013). All of the techniques to be used have previously been used
in research projects by the supervisory team and the Centre for Biomedical Research at Leeds
Beckett University has all the necessary facilities to allow the student to carry out this research.
The project has the novel components of evaluating a new group of compounds as potential
therapeutics for AD, which makes it highly suitable for a PhD project. The supervisory team has
expertise in the areas relevant to the project and includes a world leading expert in the field of
Cannabinoids and Alzheimer’s disease. As such the student will be given high quality training and
have the opportunity to take the project in a range of directions dependant on the results obtained.
The student will be trained in cell culture, molecular cloning, overexpression, SI-RNA, assay
development and HPLC techniques during the project. The project will produce publishable data and
it is anticipated that the PhD student will have the opportunities to present findings at International
meetings plus publish data based papers during the project. The Director of Studies’ last PhD student
completed a project characterising cell lines overexpressing neuroprotective compounds, presented
data at two International meetings and published five full papers during the project.
References
Aso E, Ferrer I. (2014) Cannabinoids for treatment of Alzheimer's disease: moving toward the clinic.
Front Pharmacol. 5:37.
Bauer M, Chicca A, Tamborrini M, Eisen D, Lerner R, Lutz B, Poetz O, Pluschke G, Gertsch J. (2012)
Identification and quantification of a new family of peptide endocannabinoids (pepcans) showing
negative allosteric modulation at CB1 receptors. J Biol Chem. 287(44):36944-67.
Chilumuri A, Odell M, Milton NG. (2013) Benzothiazole aniline tetra(ethylene glycol) and 3-amino1,2,4-triazole inhibit neuroprotection against amyloid peptides by catalase overexpression in vitro.
ACS Chem Neurosci. 4(11):1501-12.
Ferrer I, Gómez A, Carmona M, Huesa G, Porta S, Riera-Codina M, Biagioli M, Gustincich S, Aso
E.(2011) Neuronal hemoglobin is reduced in Alzheimer's disease, argyrophilic grain disease,
Parkinson's disease, and dementia with Lewy bodies. J Alzheimer’s Dis. 23(3):537-50.
Gomes I, Grushko JS, Golebiewska U, Hoogendoorn S, Gupta A, Heimann AS, Ferro ES, Scarlata S,
Fricker LD, Devi LA. (2009) Novel endogenous peptide agonists of cannabinoid receptors. FASEB J.
23(9):3020-9
Heimann AS, Gomes I, Dale CS, Pagano RL, Gupta A, de Souza LL, Luchessi AD, Castro LM, Giorgi
R, Rioli V, Ferro ES, Devi LA. (2007) Hemopressin is an inverse agonist of CB1 cannabinoid
receptors. Proc Natl Acad Sci U S A. 104(51):20588-93.
Hofer SC, Ralvenius WT, Gachet MS, Fritschy JM, Zeilhofer HU, Gertsch J. (2015) Localization and
production of peptide endocannabinoids in the rodent CNS and adrenal medulla.
Neuropharmacology. doi: 10.1016/j.neuropharm.2015.03.021. [Epub ahead of print]
Milton NG. (2002) Anandamide and noladin ether prevent neurotoxicity of the human amyloid-β
peptide. Neurosci Lett. 332(2):127-30.
Milton NG. (2005) Phosphorylated amyloid-β: the toxic intermediate in Alzheimer's disease
neurodegeneration. Subcell Biochem. 38:381-402
Milton NG, Chilumuri A, Rocha-Ferreira E, Nercessian AN, Ashioti M. (2012) Kisspeptin prevention of
amyloid-β peptide neurotoxicity in vitro. ACS Chem Neurosci. 3(9):706-19.
Schelshorn DW, Schneider A, Kuschinsky W, Weber D, Krüger C, Dittgen T, Bürgers HF, Sabouri F,
Gassler N, Bach A, Maurer MH. (2009) Expression of hemoglobin in rodent neurons. J Cereb Blood
Flow Metab. 29(3):585-95.
Further information
To apply you must be eligible for NHS Continuing Professional Development (CPD) funding and have
the support of your line manager in writing. General enquiries should be directed by email to the
Faculty Research Director r.hogston@leedsbeckett.ac.uk to discuss the project further please contact
the Director of Studies http://www.leedsbeckett.ac.uk/staff/dr-nathaniel-milton/
Applications should be made on line here
http://www.leedsbeckett.ac.uk/research/research-degrees/research-studentships-andfees-only-bursaries/