Regulation of glial homeostasis in brain health and Alzheimer’s disease

The brain is a powerhouse, consuming over 20% of the body’s glucose and oxygen to fuel neuronal activity required for information processing and cognitive functions1. However, this immense energy demand produces metabolic  waste products, including acid, which must be rapidly cleared to maintain a stable microenvironment. To achieve this, the brain relies on robust homeostatic mechanisms that regulate ionic and metabolic balance, ensuring optimal conditions for neural function. 

In Alzheimer’s disease (AD), these critical homeostatic processes are disrupted. Declines in cellular glucose metabolism and accumulation of metabolic acid are hallmark features of the disease, contributing to neurodegeneration2,3.  

Astrocytes, a type of glial cell, play a vital role in maintaining the brain’s homeostasis. By regulating ions, metabolites, and other key factors, they ensure proper neuronal function and cognitive health4,5,6,7 . Disruptions in astrocytic homeostasis, particularly those affecting intracellular ion signalling and protein quality control systems (ubiquitin-proteasome pathway (UPS) and autophagy), may contribute to the metabolic stress observed in AD 8,9. Despite this, our understanding of how these mechanisms are altered in AD, and their role in disease progression is limited. 

This PhD project will explore the fundamental processes by which astrocytes regulate ion homeostasis and proteostasis under normal conditions and how these are impacted in AD. The overarching goal is to uncover novel insights into astrocytic dysfunction and identify potential novel therapeutic targets to mitigate disease progression and enhance cognitive function. 

Research Highlights 

As part of this exciting project, you will: 

• Investigate how astrocytic mechanisms controlling ion homeostasis and signaling (eg. Ca2+) are altered in AD. 

• Study the regulation of protein quality control systems, including the UPS pathway and autophagy, in astrocytes. 

• Examine the response of astrocytes to metabolic stress and their implications for disease pathology. 

• Explore strategies targeting astrocytic pathways to improve brain health and cognition in AD models. 

Techniques and Training 

You will gain hands-on experience with a variety of advanced techniques, including: 

• High-resolution live-cell fluorescence imaging to monitor intracellular signaling and metabolic changes in astrocytes.
• Adeno-Associated Viruses (AAVs) for Astrocyte-Specific Gene Expression and Deletion
• Biochemical and molecular approaches to characterize changes in astrocytic function in response to AD-associated proteins using invitro ( primary cell and tissue culture) and invivo (mouse models) systems
• State-of-the-art iPSC-derived human astrocyte models and AD mouse models in collaboration with leading institutions.

As the primary supervisor, Dr Shefeeq Theparambil will guide the investigation into astrocyte biology, focusing on the interplay between metabolic stress and neurodegenerative processes. Supervision from Dr Ed Parkin will provide expertise in the biochemical evaluation of metabolic stress on Aβ and APP processing, while Dr Nick Robinson’s guidance will support the structure and biochemistry of proteasomes and ubiquitin-proteasomes degradation pathways.  

Collaborations 

Collaboration with Prof. Tao Wang (Manchester University) will provide access to iPSC-derived human astrocytes from AD patients. Within the department at Lancaster University, Dr. Cheryl Hawkes and Dr. Neil Dawson will facilitate access to AD mouse models and 2DG-based brain imaging. Additionally, you will have the opportunity to train at University College London (UCL) with Prof. Alexander Gourine, specializing in advanced optical imaging and viral targeting of astrocytes in vivo. 

Join Us 

This PhD position offers an opportunity to be at the forefront of cutting-edge research on Alzheimer’s disease and astrocyte biology. You will be part of the Defying Dementia (DD) Research Network at Lancaster University, offering training and networking opportunities in dementia and neurodegeneration If you are passionate about neuroscience and keen to explore innovative solutions for tackling neurodegeneration, we encourage you to apply. 

What We Are Looking For: 

We seek candidates with a strong background in neurobiology, cell biology, or physiology. Ideal applicants should have experience in cell biology and biochemical techniques, including immunostaining and western blotting. Additionally, expertise in microscopy, brain slice preparation, cell culture, and/or in vivo animal handling would be a big plus 

How to Apply: 

This opportunity is currently open only to UK-based home students.  

To apply, please submit your 2 page- CV and a cover letter explaining your academic background, research interests, experience, and how they align with the proposed project to s.theparambil@lancaster.ac.uk 

Prospective applicants are strongly encouraged to arrange a meeting with Dr Shefeeq Theparambil (s.theparambil@lancaster.ac.uk)  before submitting a full application, to get a detailed information about the project and its scope.