About the Project
Applications are invited for a PhD studentship funded by the Faculty of Medicine and Health working under the supervision of Dr Matthew Pontifex (UEA), Prof Michael Müller (UEA) and Prof Tom Wileman (Quadram Institute)
Females are at considerably greater risk of developing Alzheimer’s disease (AD), despite this they remain relatively understudied in neuroscience research. Menopause has been identified as a contributing factor in this female predisposition, however the mechanisms responsible are yet to be fully elucidated. Non-canonical functions of autophagy proteins such as LC3-associated phagocytosis (LAP) are beginning to gain recognition for their involvement in neurodegenerative conditions. Indeed, deletion of a single domain (WD), of the autophagy machinery Atg16L (critical for LAP function, but dispensable for canonical autophagy), is sufficient to drive spontaneous age-associated AD pathology recapitulating key pathological hallmarks of AD including Aβ deposition, tau hyperphosphorylation and microglial activation. This project will build upon the present research using this novel model to determine the impact of sex and menopausal status upon disease pathology. The successful candidate will utilise animal models, conducting extensive behavioural and molecular analysis in order to categorise this novel model of AD, elucidating the underlying mechanisms involved.
The project should appeal to candidates interested in neuroscience, neurodegenerative diseases, autophagy, and sexual dimorphism. The student will join the Norwich Medical School which provides a supportive research environment and access to experienced researchers. The student will receive training in behavioural tests of cognition in animals as well as molecular biology techniques. In addition to their research the student will be provided with training in scientific writing, presentation, data management, statistical analysis and will be encouraged to attend and present at national and international conferences. As such the student will gain an array of highly sort after techniques that will enhance their career prospects in neuroscience/molecular biology research.
i) Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease
Heckmann, B. L., Teubner, B. J. W., Boada-Romero, E., Tummers, B., Guy, C., Fitzgerald, P., Mayer, U., Carding, S., Zakharenko, S. S., Wileman, T. & Green, D. R., 14 Aug 2020, In: Science Advances. 6, 33, p. eabb9036 eabb9036.
ii) APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE‐TR mice
Pontifex, M. G., Martinsen, A., Saleh, R. N. M., Harden, G., Tejera, N., Müller, M., Fox, C., Vauzour, D. & Minihane, AM., May 2021, In: The FASEB Journal. 35, 5, e21583.
iii) APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer’s disease pathophysiology
Tran, T. T. T., Corsini, S., Kellingray, L., Hegarty, C., Le Gall, G., Narbad, A., Müller, M., Tejera, N., O'Toole, P. W., Minihane, A-M. & Vauzour, D., Jul 2019, In: The FASEB Journal. 33, 7, p. 8221-8231 11 p.
iv) The effect of APOE genotype on Alzheimer’s disease risk is influenced by sex and DHA status
Pontifex, M., Vauzour, D. & Minihane, A-M., Sep 2018, In: Neurobiology of Aging. 69, p. 209-220