Imperial College London Featured PhD Programmes
University of Bristol Featured PhD Programmes
University of Reading Featured PhD Programmes

Developing chronic implants for the treatment of Alzheimer’s disease in pre-clinical models.


   Neuroscience Institute

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Dr Jason Berwick, Prof Ivan Minev, Dr C Howarth  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

Sheffield United Kingdom Bioinformatics Biomedical Engineering Biophysics Computer Science Software Engineering

About the Project

Background:

Neurovascular coupling (NVC) is the mechanism responsible for regulating the supply of oxygen and glucose to active regions of the brain. Although our understanding of NVC mechanisms remains incomplete, investigations of NVC have taken on added importance. Accumulating evidence suggests that impaired NVC may be a significant causal component of age-related neurodegenerative disease especially Alzheimer’s Disease (AD) (Iadecola, 2013; Zlokovic, 2010, 2011). Professor Zlokovic proposed that a breakdown of the neurovascular unit may be a causal factor in neurodegenerative disease (Zlokovic, 2010). However, thus far there have been few formal measurements of NVC function as disease pathology develops. In 2014, Alzheimer’s Research UK funded Dr Berwick’s laboratory to study early AD-associated changes in NVC. Using chronic imaging capability, we characterised the breakdown of neurovascular function at specific time points during the development of AD in a mouse model (J20-AD). Surprisingly, and contrary to previous reports of significant impairments in the J20-AD model(Shabir et al., 2020; Sharp et al., 2019), we found that the typical hemodynamic response to sensory stimulation was largely unaltered in J20-AD mice. These observations suggest that the disease state in the J20-AD model may be rather more nuanced than suggested previously. We have started work on a more severe mouse model of Alzheimer’s disease (APP/PS1) and have been performing a majority of experiments in the awake condition to avoid any confounds of anaesthesia. Traditionally, most research has used a pharmacological approach to treat AD aimed at reducing the amount of Beta-Amyloid plaques in the brain. However, no disease altering therapy has been developed yet, despite 40+ years of research. Other potential therapies need to be considered and developed. A key focus of our group is to develop new methods to treat AD. The first approach is to enhance baseline blood flow using optogenetics. AD patients suffer from chronic hypoperfusion, which is also present in the mouse models of AD we use. We have recently published results (Lee et al., 2019) whereby baseline blood flow could be increased by using an optogenetic approach to selectively activate cortical interneurons. However, we need an implantable system in order to deliver this light stimulation on a daily basis. The second approach will be to investigate the effect of selective thermal cooling of the brain on disease progression. Our laboratory has previously used thermal cooling to reduce the effects of focal cortical epilepsy, and it has recently been shown that cooling could have a marked effect on AD. It is hypothesised that repeated cooling of the animal increases its thermoregulatory response (Peretti et al., 2015; Tournissac et al., 2019), which then provides neuroprotection against neurodegeneration. To date there has been no research to assess if focal brain cooling could have a similar effect. Again, we need an implantable system that can deliver thermal cooling on a regular daily basis. Professor Minev is developing devices that can be implanted into the rodent brain and can deliver both thermal cooling and optogenetic stimulation. These devices will be transparent, allowing simultaneous imaging of the brain surface during cooling/stimulation. This project will focus on developing these implants for use in APP/PS1 mice in order to assess whether cooling/stimulation of interneurons has a therapeutic effect.

The hypothesis/aims:

1.      Progress of disease of APP/PS1 AD mice can be slowed either by optogenetic stimulation of interneurons to increase baseline blood flow or focal cooling to provide neuroprotection from the disease.

2.      To fully design and build an implantable device suitable for mouse studies and all of the control systems that run it.

3.      To assess how the treatments work in terms of cells most effected by the intervention using post-mortem immunohistochemistry.

4.      To provide cellular targets for treatments targeted for therapy in humans. 

Dr Berwick’s and Howarth’s Laboratories have an international reputation in the fields of Neurovascular coupling. All technologies including the 2-photon microscope are already in place and used routinely. Both mouse models (optogenetic and APP/PS1) are currently maintained in the laboratory and available for the project.

Professor Minev’s laboratory has expertise in the design and fabrication of multi-modal bioelectronic systems including neural implants (Afanasenkau et al., 2020; Athanasiadis et al., 2020)and is housed in a newly refurbished space housing state-of-art 3D printing equipment dedicated to implant fabrication. The group is equipped for testing and characterisation of implantable devices.

The student will receive expert training in all aspects needed for successful completion of the project. There will be a formal monthly meeting with all three supervisors to check on progress and discuss any issues arising. Separate Journal and Writing clubs occur on a monthly basis in which relevant areas of the literature will be discussed, tasks will be set and monitored at subsequent meetings. Funds will be set aside for one national and one international conference during the PhD and the student will be encouraged to apply for separate travel bursaries to present at more conferences.

Applications are open to students from the UK and overseas, though we note that due to funding constraints the availability of positions for students with overseas fee status will be more limited. We anticipate competition for these studentships to be very intense. We would expect applicants to have an excellent undergraduate degree in a relevant discipline. We would also expect applicants to have completed or be undertaking a relevant master’s degree to a similar very high standard (or have equivalent research experience).

Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgradapplication/, state the prospective main supervisor in the respective box and select ‘Neuroscience’ as department.

After the application closing date, we will shortlist applicants for an online interview. We expect to carry out interviews (each lasting approximately 30 minutes) on Tuesday 27th April (am, GMT) and Tuesday 4th May (pm, GMT). If you are shortlisted for interview, we will aim to inform you of this no later than the end of Friday 23rd April. If you are unable to attend at the specified times, please let us know if we confirm that we would like to interview you.


Funding Notes

EPSRC FUNDED
• 3.5 years PhD studentship commencing October 2021
• UKRI equivalent home stipend rate per annum for 3.5 years
• Tuition fees for 3.5 years
• EPSRC studentships come with a £4,500 Research Training Support Grant over the course of the award.

References

Afanasenkau, D., Kalinina, D., Lyakhovetskii, V., Tondera, C., Gorsky, O., Moosavi, S., Pavlova, N., Merkulyeva, N., Kalueff, A. V., Minev, I. R., & Musienko, P. (2020, Oct). Rapid prototyping of soft bioelectronic implants for use as neuromuscular interfaces. Nat Biomed Eng, 4(10), 1010-1022. https://doi.org/10.1038/s41551-020-00615-7
Athanasiadis, M., Afanasenkau, D., Derks, W., Tondera, C., Murganti, F., Busskamp, V., Bergmann, O., & Minev, I. R. (2020, 2020/07/16). Printed elastic membranes for multimodal pacing and recording of human stem-cell-derived cardiomyocytes. npj Flexible Electronics, 4(1), 16. https://doi.org/10.1038/s41528-020-0075-z
Iadecola, C. (2013, Nov 20). The pathobiology of vascular dementia. Neuron, 80(4), 844-866. https://doi.org/10.1016/j.neuron.2013.10.008
Lee, L., Boorman, L., Glendenning, E., Christmas, C., Sharp, P., Redgrave, P., Shabir, O., Bracci, E., Berwick, J., & Howarth, C. (2019, Nov 20). Key Aspects of Neurovascular Control Mediated by Specific Populations of Inhibitory Cortical Interneurons. Cereb Cortex. https://doi.org/10.1093/cercor/bhz251
Peretti, D., Bastide, A., Radford, H., Verity, N., Molloy, C., Martin, M. G., Moreno, J. A., Steinert, J. R., Smith, T., Dinsdale, D., Willis, A. E., & Mallucci, G. R. (2015, Feb 12). RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature, 518(7538), 236-239. https://doi.org/10.1038/nature14142
Shabir, O., Sharp, P., Rebollar, M. A., Boorman, L., Howarth, C., Wharton, S. B., Francis, S. E., & Berwick, J. (2020, May 5). Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer's Disease. Sci Rep, 10(1), 7518. https://doi.org/10.1038/s41598-020-64334-4
Sharp, P. S., Ameen-Ali, K. E., Boorman, L., Harris, S., Wharton, S., Howarth, C., Shabir, O., Redgrave, P., & Berwick, J. (2019, Nov 23). Neurovascular coupling preserved in a chronic mouse model of Alzheimer's disease: Methodology is critical. J Cereb Blood Flow Metab, 271678X19890830. https://doi.org/10.1177/0271678X19890830
Tournissac, M., Bourassa, P., Martinez-Cano, R. D., Vu, T. M., Hebert, S. S., Planel, E., & Calon, F. (2019, Apr). Repeated cold exposures protect a mouse model of Alzheimer's disease against cold-induced tau phosphorylation. Mol Metab, 22, 110-120. https://doi.org/10.1016/j.molmet.2019.01.008
Zlokovic, B. V. (2010, Dec). Neurodegeneration and the neurovascular unit. Nat Med, 16(12), 1370-1371. https://doi.org/10.1038/nm1210-1370
Zlokovic, B. V. (2011, Dec). Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci, 12(12), 723-738. https://doi.org/10.1038/nrn3114