Investigating phenotypic, proteomic and functional changes in microglia in a preclinical model for sporadic Alzheimer’s disease research (Manchester-Melbourne Dual Award) at The University of Manchester on FindAPhD.com

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Dr M Harte, Dr A Tirella No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

About the Project

Current treatments for Alzheimer’s disease (AD) are symptomatic and do little to slow down the progression of the disease. This has led to an array of research investigating hallmark pathologies in the search for novel therapeutic strategies. One such process is neuroinflammation – a chronic form of which is seen in AD.

Microglia, the resident brain immune cell, fulfil a number of key roles in the brain including maintaining homeostasis, phagocytosis, synaptic pruning and they are key players in the immune response. Recent insights into the characterisation of microglia have revealed an extensive array of distinct, though overlapping phenotypes with corresponding functions. Recent morphological, functional, transcriptomic and GWAS studies have all highlighted the potential role of microglia in disease progression in AD and as such point towards this cell population as a potentially interesting target for treatment.

Transgenic rodent models for AD have undoubtedly advanced our understanding of the disease but come with the caveat that in humans these models correspond to Familial / Early Onset AD that account for 3-5% of the cases seen. The majority of cases (~95%) are sporadic or Late Onset with little known about the exact cause. Since its first iteration (Hardy & Higgins 1992) the “amyloid cascade hypothesis” has evolved and it is now widely accepted that amyloid beta accumulation is a central event in AD pathology. We have developed an optimized method for the production of stable alginate microbeads containing amyloid beta -producing cells to enable the modelling of important aspects of sporadic AD in vivo (Almari et al. 2019).

Evidence is emerging demonstrating that microglia can play both beneficial and detrimental roles in relation to disease progression (See Review by Moore et al., 2019). We will utilise a novel model for sporadic AD to investigate phenotypic, proteomic and functional markers of microglia and determine how these change in relation to cognitive dysfunction and disease progression.

See https://www.manchester.ac.uk/study/postgraduate-research/golden/melbourne/

Funding Notes

This project is available to UK/EU candidates. Funding covers fees and stipend for 3.5 years. Candidates will be required to split their time between Manchester and Melbourne.

Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Dr Michael Harte

Almari, B, Harte, M, Brough, D & Tirella, A (2019), 'Fabrication of Amyloid-β-Secreting Alginate Microbeads for Use in Modelling Alzheimer's Disease', Journal of Visualized Experiments.

Sellers, KJ, Elliott, C, Jackson, J, Ghosh, A, Ribe, E, Rojo, AI, Jarosz-Griffiths, HH, Watson, IA, Xia, W, Semenov, M, Morin, P, Hooper, NM, Porter, R, Preston, J, Al-Shawi, R, Baillie, G, Lovestone, S, Cuadrado, A, Harte, M, Simons, P, Srivastava, DP & Killick, R (2018), 'Amyloid β synaptotoxicity is Wnt-PCP dependent and blocked by fasudil', Alzheimer's & dementia : the journal of the Alzheimer's Association.

Watremez, W, Jackson, J, Almari, B, McLean, SL, Grayson, B, Neill, JC, Fischer, N, Allouche, A, Koziel, V, Pillot, T & Harte, MK (2018), 'Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat', Journal of Alzheimer's disease : JAD, vol. 62, no. 1, pp. 213-226.

Daniels, MJD, Rivers-Auty, J, Schilling, T, Spencer, NG, Watremez, W, Fasolino, V, Booth, SJ, White, CS, Baldwin, AG, Freeman, S, Wong, R, Latta, C, Yu, S, Jackson, J, Fischer, N, Koziel, V, Pillot, T, Bagnall, J, Allan, SM, Paszek, P, Galea, J, Harte, MK, Eder, C, Lawrence, CB & Brough, D (2016), 'Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models', Nature Communications, vol. 7, 12504, pp. 12504.

Dr Peter Crack

Moore Z, Taylor JM, Crack PJ (2019) The involvement of microglia in Alzheimer's disease: a new dog in the fight. Br J Pharmacol. Sep;176(18):3533-3543.

Taylor JM, Moore Z, Minter MR, Crack PJ (2018) Type-I interferon pathway in neuroinflammation and neurodegeneration: focus on Alzheimer's disease. J Neural Transm (Vienna). May;125(5):797-807.

Minter MR, Moore Z, Zhang M, Brody KM, Jones NC, Shultz SR, Taylor JM, Crack PJ (2016) Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype. Acta Neuropathol Commun. Jul 11;4(1):72.

Minter MR, Main BS, Brody KM, Zhang M, Taylor JM, Crack PJ (2015) Soluble amyloid triggers a myeloid differentiation factor 88 and interferon regulatory factor 7 dependent neuronal type-1 interferon response in vitro. J Neuroinflammation Apr 12;12:71

Investigating phenotypic, proteomic and functional changes in microglia in a preclinical model for sporadic Alzheimer’s disease research (Manchester-Melbourne Dual Award)

The University of Manchester Faculty of Biology, Medicine and Health

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

About the Project

Funding Notes

References

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