Nanoscale metallomics and mineralization: advanced spectro-microscopy determination of the role of iron and calcium in Alzheimer's disease

The most common form of dementia is Alzheimer's disease, a neurodegenerative disorder that reportedly affects 30 million people worldwide, yet for which there is no cure and only limited opportunities for accurate diagnosis and treatment. The disease is characterised by pathological hallmarks in the brain including dense amyloid protein aggregates (plaques) that are deposited outside cells in the grey matter of the brain, together with significant damage internally in neurons due to 'tangles' of abnormal tau protein. These plaques and tangles are understood to contribute to the death of neurons and the progressive degeneration of the brain. Exactly how this degeneration is mediated by these protein deposits is not yet properly understood. However, oxidative stress damage to neurons, catalysed by highly reactive chemical species known as free radicals, is understood to play a significant role. In addition, substantial evidence now suggests that the dysregulation of iron resulting in a harmful excess of reactive (ferrous) iron in the brain, is a contributing factor in the disease, and may be implicated in the processes leading to oxidative stress.

Interactions between aberrant protein deposits and iron, as well as other metals, are common features of neurodegenerative disorders. In Alzheimer's disease, metal-protein interactions are hypothesized to contribute to the formation of deposits containing reactive (harmful) iron observed post-mortem in diseased brain tissue. In addition, unusual calcium bio-mineralisation has been observed within areas of aberrant protein deposition suggesting that calcium could also play a significant role in the disease. Identifying these mineral products is an important first step in describing this aspect of Alzheimer's disease. However in order to make progress in diagnosing and treating the disease, it is necessary to understand how the metal-protein interactions contribute to the disease process at a level facilitating therapeutic intervention, and the extent to which resulting iron and calcium mineralization in the protein deposits can serve as an early-stage marker of the disease.

We aim to explore the chemical and mineral state of iron and calcium in Alzheimer's disease brain tissue using sensitive and specific analytical methods, as well performing experiments to investigate how metal-protein interactions can lead to the initiation and evolution (both chemical and structural) of the protein deposits. Further, we will assess how the metal-protein aggregates formed in human brain tissue, as well as those created artificially, respond to treatments with the metal chelating agents that are currently being developed as potential drug therapies for Alzheimer's and other neurodegenerative conditions.

To ensure the success of this project we have assembled a unique interdisciplinary research team, with a strong international track record, to build upon our successful preliminary work in this area, applying a combination of advanced synchrotron x-ray microscopy and mass spectrometry techniques to probe nanoscale variations in the bio-inorganic chemistry occurring in Alzheimer's tissue. An important aspect of the project is that in all cases we will support our evaluation using these specialist techniques, with conventional imaging and histology. From this we will build a comprehensive description of this fundamental process in Alzheimer's disease, addressing key outstanding questions about the metal-protein interactions and how they may be modified. The parallels between aberrant protein deposition and altered handling of iron and other metals in related disorders, will allow the approach developed in this project to be readily translated, enabling equivalent impact for other forms of neurodegenerative disease. With clinical advances in chelation therapy and improved scope to track brain iron status non-invasively by clinical MRI, this project is not just timely but also urgent.

There can be little doubt that dementia is a growing challenge in our society. Although cancer is the leading cause of death in the UK with an annual health and economic cost ~£12bn, the equivalent estimated cost for dementia is >£23bn, and the number of people diagnosed with dementia is predicted to double by 2050. The Department of Health 2013 'Dementia Challenge' report prioritizes Health and Care, and Improving Research. This aligns strongly with strategy from the Alzheimer's Society, which has stated research priorities as Cause, Cure, Care, and Prevention. The breadth of these priorities is motivating but also deeply concerning. Even taking into account the under-resourcing of dementia research compared to high-incidence diseases such as cancer, it is surprising just how much significant effort is still required on all fronts.

Arguably the complexity of Alzheimer's disease is the stumbling block to progress. Hundreds of perspectives on the disorder have been explored through core disciplines such as life sciences and psychiatry, but with limited success. The shift to support interdisciplinary research is an opportunity to direct effort at prominent disease features that must be fully explained if they are to be exploited for patient benefits. The overarching impact from this proposed project will therefore be delivered by targeting the complex mechanisms of the disease using non-traditional approaches, exploiting advanced synchrotron and mass spectrometry techniques. This will generate new knowledge which, combined with networking activities embedded in the research programme, will stimulate cross-linking activities between academic, clinical, and pharmaceutical sectors, enhancing our understanding of the origin and progression of Alzheimer's disease. Ultimately this will create new opportunities to improve diagnosis and treatments for a spectrum of disease involving metal ion dysregulation.

The project will train early-career Physical Sciences researchers with cross-disciplinary analytical expertise bridging into the biomedical sciences, creating opportunity for innovation. This will benefit the researchers directly, providing them with more diverse opportunities for future research, and benefit the wider community by motivating these highly trained individuals to bring new methods and expertise from the physical sciences to biomedical and clinical research. In particular, fresh lines of research enquiry into the role of metals in pathogenesis will help focus future clinical trials, impacting not only the academic community but ultimately benefiting workers in clinical and pharmaceutical research and development, and in turn supporting healthcare providers to improve patient care.

To evaluate long-term opportunities to deliver impact from the project, the team will engage with the UK and European community at a level where we keep abreast of policy and initiatives. The economic and societal costs, and present constraints on what industry and healthcare providers can achieve (in part reflected in the significant number of abandoned clinical trials in Alzheimer's disease), make understanding and targeting the toxic bio-inorganic chemical processes in the disease both advantageous and urgent. By contributing to impetus for the development of new treatments and diagnostic procedures the project has scope to stimulate economic growth through catalysing new research and development in pharmaceuticals. This is particularly relevant to the UK given its international reputation for research and development leadership in this sector (TSB - Nanoscale Technologies Strategy 2009-12). Earlier clinical screening and diagnosis with techniques such as Magnetic Resonance Imaging bring new costs, but these are offset by the tremendous costs of untreated dementia, and early diagnosis will be a prerequisite if effective clinical trials are to be conducted of future treatments that can delay or protect against neurodegeneration.