Scholarship for the PhD in Medical Sciences in the field of Pathology of Neurodegenerative Diseases for the PhD Research Project ‘PHD-2023-4: Investigating the possible association of NRG1 and tau, in the development of Alzheimer’s Disease (AD)’

The PhD in Medical Sciences:

The University of Nicosia Medical School offers the degree PhD in Medical Sciences.  The degree is awarded to students who successfully complete an independent research programme leading to novel findings in the chosen field of study. The PhD programme aspires to empower students to become independent researchers, thus advancing innovation and development.

The Research Project:

We are currently inviting application through a competitive process for high calibre candidates to apply for one PhD Scholarship in the fields of Pathology of Neurodegenerative Diseases. The successful candidate will enrol in the PhD programme in Medical Sciences and will work under the Supervision of Professor Dimitrios Kanakis with expertise in the fields of Pathology and Neuropathology at the University of Nicosia Medical School.

Project Description:

Code and Title of research project: ‘PHD-2023-4: Investigating the possible association of NRG1 and tau, in the development of Alzheimer’s Disease (AD).’

Background and Rationale:

Neurodegenerative disorders constitute a major problem for the health care system globally. The number of newly diagnosed patients suffering from one of the known neurodegenerative diseases increases dramatically. Finding a treatment or even a preventative measure against such disorders is one of the major challenges of modern science. However, these scientific efforts, though intensive, have not yet achieved the expected result, that is the development of efficacious therapeutic schemes. The reason for this is the absence of sufficient knowledge of the pathogenesis of each of the various degenerative diseases. It is therefore of utmost importance to understand comprehensively the pathology of this category of diseases in order to focus our research explicitly.

Alzheimer’s disease (AD) is the commonest age-related neurodegenerative disorder, affecting millions of people worldwide. It is a progressive neurological disorder that drives to the irreversible loss of neurons, primarily in the entorhinal cortex and hippocampus. The amyloid-β plaques and the neurofibrillary tangles (NFTs) are the main histopathological hallmarks of the disease.

The amyloid hypothesis suggests that the abnormal cleavage of Amyloid Precursor Protein (APP) and the subsequent deposition of toxic amyloid peptides are a predominant step in the pathogenesis of the disease. However, tau hyperphosphorylation and neurofibrillary tangle (NFT) formation is a direct epiphenomenon of this abnormal deposition suggesting the close association of APP and MAPT (Microtubule Associated Protein Tau) genes.

Neuregulins (NRG) are a family of growth and differentiation factors involved in neuronal differentiation and migration, oligodendrocyte development, N-methyl-D-aspartate (NMDA) receptor function, myelination, neurite extension and arborization, synapse formation and neurotransmitter release.

There are four different neuregulin types: NRG1, NRG2, NRG3, and NRG4. NRG1 is the most widely studied growth factor of the neuregulin family. There are three NRG1 isoforms, namely NRG1 type I, NRG1 type II and NRG1 type III. NRG1 protein has been shown to be important in the development of the CNS, the circulatory system and accessory reproductive organs like the mammary glands. NRG1 plays a pivotal role in neurogenesis and neural differentiations (i.e. neural crest cell differentiation into Schwann cells). Its function is mediated by transmembrane tyrosine kinase receptors of the ErbB family, inducing receptor heterodimerization, which in turn initiates a signal transduction cascade.

A close association of Neuregulin-1 (NRG1), BACE1 and APP genes exists that suggest a potential link between NRG1 and Alzheimer’s disease, as the last two factors (i.e. BACE and APP) have been implicated in the development of this condition. NRG1 is a major physiological substrate of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which is cleaved within its ectodomain allowing the exposure of the EGF-like domain for ErbB signaling. In other words, NRG1 activation is mediated by the enzymatic cleavage of BACE1, a rate limiting enzyme for APP proteolysis and amyloid production.

Double immunofluorescence and electron microscopy analysis demonstrated that ErbB4 antibodies co-localized with hyper-phosphorylated tau inclusions and NFTs, proving the relationship between the neuregulin receptor ErbB4 and protein hyper-phosphorylated protein tau. The importance of ErbB/neuregulin signaling in AD pathogenesis, APP processing and tau hyper-phosphorylation has also been shown.

In vitro experiments demonstrated further that NRG1 eliminated the effect of amyloid beta-induced decrease in dendritic spine density in rat primary hippocampal neurons, and improved neural cell differentiation in mouse fetal neuronal stem cells. These results render Neuregulin-1 a potential therapeutic agent for Alzheimer’s disease.

It is therefore evident that the exact role of NRG1 is quite enigmatic, so there is an urgent need to “solve” the puzzle and understand the exact role of NRG1 in AD pathogenesis. Additionally, there is a missing link between NRG1 gene and tau hyper-phosphorylation. The main aim of the study is to elucidate the possible role of NRG-1 type III gene in the pathogenesis of Alzheimer’s disease, through direct or indirect MAPT interaction leading to tau hyper-phosphorylation and NFT formation.

Aims and Objectives:

The current Research Proposal has the following aims and objectives:

1. To examine the possible association of NRG1 with tau protein, tau hyper-phosphorylation and the development of toxic NFTs in AD mice.
2. To examine the potential co-localization of the NRG1 protein with the hyper-phosphorylated protein tau.
3. In a later stage, the association of NRG1 with BACE1 will be examined too, through RNAi technology. BACE1 inhibition will be performed on NRG1 transfected cells, in order to assess the possible change in NRG1 normal processing.

The Scholarship:

The PhD project comes with a Fee Waiver Scholarship that includes:

• Coverage of tuition fees for the PhD programme for a duration of three years (totalling €13,500). The successful candidate is expected to cover the tuition fees for each additional academic year (€1,500 per year).

The scholarship is subject to annual renewal based on the recipient’s satisfactory academic progress, with maximum renewal period of three years.

Requirements and Qualifications:

• Eligible Candidates should hold (or hold by the time that the programme is expected to commence i.e. October 2024) a recognised degree (BSc or a degree equivalent for entry to a Master’s Degree) and a Master’s degree (MSc) in the field(s) of Molecular Biology, or a Doctor of Medicine degree (e.g. MBBS or MD degree).
• Expertise in a variety of laboratory (e.g. immunohistochemistry and immunofluorescence in paraffin fixed mouse brain samples) and specific molecular biology methods (e.g. Western blotting, in vitro experiments with different cell lines) is a prerequisite for carrying out the experiments of the PhD project.

Application for the PhD Scholarship:

Candidates should submit an online application through the ‘Request Information’ form and upload the following supporting documents:

• A cover letter clearly stating that they apply for the PhD Scholarship in the field of Pathology of Neurodegenerative Diseases for the PhD Research Project ‘PHD-2023-4: Investigating the possible association of NRG1 and tau, in the development of Alzheimer’s Disease (AD)’.
• Copies of the applicant’s qualifications/degree(s) – the application can be assessed with scanned copies, but certified true copies must be provided if the candidate is successful and prior to enrolment on the PhD programme.
• Copies of the applicant’s transcript(s) – the application can be assessed with scanned copies, but certified true copies must be provided if the candidate is successful and prior to enrolment on the PhD programme.
• Proof of English language proficiency such as IELTS with a score of 7 overall and with a minimum score of 7 in writing or TOEFL iBT with a score of 94 overall and a minimum score of 27 in Writing. Other internationally recognized English language qualifications might be considered upon review. Students from the UK, Ireland USA, Canada (from English speaking provinces), Australia and New Zealand are exempt from the English language requirement.
• Two reference letters, of which at least one should be from an academic.
• A full Curriculum Vitae (CV)
• Once you complete your application please send an email to [email protected] expressing officially your interest in the PhD Research Project ‘PHD-2023-4: Investigating the possible association of NRG1 and tau, in the development of Alzheimer’s Disease (AD)’ and also attaching all the required documents.

Applications should be submitted by Friday, 10^th May, 2024 at 5pm. Only fully completed applications, containing all necessary supporting documents will be reviewed.

Only candidates who are shortlisted will be contacted and invited to an interview.