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Investigating the links between osteoporosis & Alzheimer’s disease – effects of β-amyloid upon the mechanical set-point in bone


Project Description

Background:
Individuals with Alzheimer’s disease are more likely to suffer from osteoporosis (the loss of bone mass and strength) than age-matched individuals; significantly contributing to the frailty associated with dementia. Notably, the key pathogenic marker of Alzheimer’s disease, β-amyloid peptide, has been found within osteoporotic bone, suggesting a direct link between the two conditions.
Bone mass, regulated by exercise-related loading and resulting mechanical strain, fluctuates to maintain a target mechanical strain level; increasing in response to higher strain and reducing following a drop in mechanical demand. Implicitly, this requires a mechanism to register the extent of mechanical deformation, and a companion mechanism to respond appropriately, in a homeostatic feedback process termed ‘mechanically adaptive bone remodelling’. The principal bone cells, osteocytes, are a key component of the registration network by virtue of their position in the bone cortex and by the existence of multiple physical connections through canaliculi, with other osteocytes. Osteocytes integrate stimuli generated by mechanical loading and communicate with surface osteoblasts (bone formation) and osteoclasts (bone resorption) to regulate bone mass.
Curiously, there exist strong molecular parallels between the pathways controlling bone strength and remodelling and those known to regulate neuronal networks. Given the presence of β-amyloid deposits within the bone of Alzheimer’s patients, we hypothesise that the increased incidence of osteoporosis in this condition may be due to functional disruption of mechanically adaptive bone modelling. This project will use a combination of 3D in vitro models and ex vivo murine analysis to examine the neural network-like control systems regulating bone mass, and the consequences of β-amyloid exposure.

Aims:
1. To characterise weight-bearing and periodontal bone mass, composition and architecture in the well-established 5xFAD murine model of Alzheimer’s disease
2. To compare neuronal signalling markers in bone sections from wild type and 5xFAD mice
3. To establish a mechanically loadable 3D culture model seeded with osteocytes and surface osteoblasts, and quantify known cellular responses to mechanical strain in the presence of neuronal agonists/antagonists
4. To establish the effects of β-amyloid on the magnitude of the osteocyte/osteoblast response to strain in the 3D culture model

Person specification: Would best suit a clinician/scientist with an interest in osteoporosis/neurosciences

How to apply

For more information regarding the project, please contact Dr Simon McArthur ()

Applications should be submitted through the Queen Mary application system. Please indicate the project title and supervisor in the ‘Research Degree Programmes - Additional Questions’ section of the application.

Alongside the application form, please send the following supporting documents:
• Curriculum Vitae (CV)
• Copies of your degree certificates with transcripts
• Proof of English language ability for overseas applicants from non-English speaking countries
• A one-side A4 statement of purpose. This should set out your previous academic or other experience relevant to the proposed research; why you wish to undertake this research at QMUL; your previous research or professional training and what further training you think you will need to complete a PhD; and what ethical issues you will need to consider in undertaking this research.
• Two references. At least one reference must be from an academic referee who is in a position to comment on the standard of your academic work and suitability for postgraduate level study. Where appropriate, a second referee can provide comment on your professional experience.

Please contact Charlotte Royle () with any queries about the application process.

Funding Notes

We will consider applications from prospective students with a source of funding to cover tuition fees and bench fees. Both self-funded and sponsored students will be considered.

UK and EU nationality self-funded students might be eligible for both the cost of tuition fees and a yearly stipend over the course of the PhD programme from the Student Finance England: View Website

How good is research at Queen Mary University of London in Allied Health Professions, Dentistry, Nursing and Pharmacy?

FTE Category A staff submitted: 32.20

Research output data provided by the Research Excellence Framework (REF)

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