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  Investigating the links between β-amyloid, osteoporosis and frailty in Alzheimer’s disease


   Institute of Dentistry

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Background:

Individuals with Alzheimer’s disease are more likely to suffer from osteoporosis (the loss of bone mass and strength) than age-matched individuals1, significantly contributing to the frailty associated with dementia. Moreover, individuals with osteoporosis are at an increased risk of cognitive impairment, emphasising a possible connection between the two conditions2. This idea is circumstantially supported by the finding that the key pathogenic marker of Alzheimer’s disease, β-amyloid peptide, is not only deposited within osteoporotic bone, with the extent of this deposition negatively correlating with bone mineral density3. Together, these data raise the possibility that the relationship between osteoporosis and Alzheimer’s is more than coincidental and that the two conditions may be directly linked.

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, with evidence implicating ionotropic glutamate transmission as a major component of these regulatory systems. Based on our preliminary data indicating NMDA receptor-dependent signalling to govern bone cell activity and an interaction with β-amyloid oligomers, alongside the evidence indicating 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.

 Research Aims:

1.      To characterise weight-bearing, cranial and mandibular bone mass, composition and architecture in the well-established 5xFAD murine model of Alzheimer’s disease and how it differs from that in young and old wild-type animals

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

Admission Requirements

Applicants are usually expected to hold a good first BSc honors degree of at least 2:1, or equivalent, to be eligible to apply for admission to research degrees. The exact entry requirements for each PhD will vary depending on the nature of the project. This project would best suit a clinician/scientist with an interest in osteoporosis/neurosciences.

If English is not your first language, the standard requirement for English is an IELTS score of 6.5 overall for non-clinical projects and 7 overall for clinical projects (or equivalent). More details about language requirements can be found here.

For more information on the project, please contact Dr Simon McArthur.

For information on the application process, please contact


Biological Sciences (4) Medicine (26)

Funding Notes

We will consider applications from prospective students with a source of funding to cover tuition fees and bench fees for three years full-time or 6 years part-time. Both self-funded and sponsored students will be considered.
UK nationals, Irish citizens and those with settled status under the EU Settlement Scheme or indefinite leave to remain in the UK might be eligible for a doctoral loan for both the cost of tuition fees and a yearly stipend over the course of the PhD programme from Student Finance England: View Website

References

1. Dengler-Crish, C. M. & Elefteriou, F. Shared mechanisms: osteoporosis and Alzheimer’s disease? Aging (Albany NY) 11, 1317–1318 (2019).
2. Zhao, Y., Chen, H., Qiu, F., He, J. & Chen, J. Cognitive impairment and risks of osteoporosis: A systematic review and meta-analysis. Arch Gerontol Geriatr 106, 104879 (2023).
3. Li, S., Liu, B., Zhang, L. & Rong, L. Amyloid beta peptide is elevated in osteoporotic bone tissues and enhances osteoclast function. Bone 61, 164–175 (2014).

Register your interest for this project


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