Single cell and behavioural studies of entorhinal cortex and hippocampal function in a transgenic mouse model of Alzheimer's disease

点击翻译按钮获取中文摘要

Alzheimer's disease (AD) is the most common cause of dementia and its early detection is a priority for healthcare worldwide. AD is associated with the accumulation of two proteins, amyloid-beta and tau, and these have a toxic effect on brain cells. These proteins accumulate many years before symptom onset, and the associated brain damage is initially restricted to certain regions, known as the entorhinal cortex (EC) and the hippocampus (HC). As such, identifying changes in the function of brain cells within the EC and HC may help us detect the first evidence of impaired brain function in AD, which in turn will help us diagnose and treat AD before people develop dementia. To date, only one study (from the O'Keefe lab) has researched the effect of disease on the function of living brain cells. Given that brain cells underpin all aspects of brain function including memory, thinking and behaviour, this lack of understanding of how AD affects cell function represents a major knowledge gap, limiting early diagnosis and attempts to discover effective therapies. My work aims to address this knowledge gap. Studies conducted by Professor O'Keefe (UCL) in freely moving rodents have shown that cell activity in the EC and HC is related to spatial function, and that this underpins the role of these brain regions in spatial navigation and memory. The human hippocampus is also involved in spatial memory and Dr Chan (Cambridge) has shown that spatial memory testing is more effective for diagnosing patients with early AD than traditional memory tests. Such work demonstrates how research in animal models of AD can benefit patients.I will study transgenic mice, i.e. mice with a mutation causing AD. Electrodes implanted into the EC and HC will allow me to determine how disease affects the function of individual EC and HC cells as these mice move around a maze, and as these mice age I aim to see how single cell function alters with progression of disease. By recording cell activity as the mice explore and remember places within the maze I will determine how disease affects spatial behaviour. I will also assess how changes in brain function vary with the size and quantity of amyloid-beta proteins, measured from cerebrospinal fluid. A state of the art MRI scanner will allow measurement of the volumes of the cell fields in the EC and HC in order to establish whether the changes in function correlate with damage to these cell fields.My study questions are:1. What is the effect of AD pathology on EC and HC function, as determined by studies of single cell activity and spatial behaviour?2. Do changes in EC and HC function correspond to changes in the structure of these brain regions?Successful delivery of study objectives will have significant impact for basic science and clinical practice:1. Demonstration that AD affects single cell function in living animals provides a platform for study of the mechanisms by which the disease affects the brain, in particular looking at the functional effect of molecules believed to contribute to the disease.2. The EC and HC form a circuit with cells connected via synapses. There is now evidence that AD pathology spreads across synapses. Knowledge gained from this study about the EC-HC circuit would assist in further studies looking at the functional impact of such spread and would have considerable implications for understanding how AD affects the brain.Furthermore, the results from my behavioural work can help in the design of an analogous spatial memory tests for use in patients which would have the potential to improve accuracy of diagnosis of pre-dementia AD. These analogous tests could be used to measure treatment effect across preclinical (animal-based) and clinical (patient-based) phases of future treatment trials; at present the inability to compare measurements across these different trial phases is a major factor contributing to the failure of trials of AD disease-modifying drugs.