Research interests
My major research interests are in the fields of neurodegeneration, brain injury and cerebrovascular disease. I am particularly interested in underlying disease mechanisms and how genetic variation influences disease processes in the brain.
Current projects:
i) The effects of Aβ immunisation on the brain in Alzheimer's disease
After promising experimental studies, the first human trial of Aβ immunisation in Alzheimer's disease was undertaken by Elan Pharmaceuticals and recruited patients from across southern Britain, including Southampton. As a consequence we had the opportunity to be the first to observe, and attempt to understand, the effects of Aβ immunisation on the brain in Alzheimer's disease (Nicoll et al, Nature Medicine, 2003, 9, 448; , Nicoll et al, Brain, 2019, 142, 2113). The findings are remarkable in that this approach can modify the underlying neurodegenerative process, specifically by removing the plaques from the cerebral cortex. In collaboration with our colleagues in other centres across southern Britain we have performed a long term clinical and neuropathological follow-up of patients who were recruited to this study (Holmes et al, Lancet, 2008, 372, 216). These studies confirm that removal of Aβ plaques can occur following Aβ immunisation, sometimes almost completely, but that this does not seem to be sufficient to halt the progressive neurodegeneration. Current work attempts to understand the complex sequence of changes in the Alzheimer brain that is provoked by immunotherapy which includes alterations in the associated tau pathology (Boche et al, Acta Neuropathol, 2010, 120, 13), the cerebral vasculature (Boche et al, Brain, 2008, 131, 3299; Sakai et al Acta Neuropathol, 2014, 128, 777), the microglia (Zotova et al Neuropath Appl Neurobiol, 2011, 37, 513; Brain, 2013, 136, 2677) and soluble Aβ (Maarouf et al Mol Neurodegeneration, 2010, 2, 39). Understanding the pathophysiological responses (Boche et al, Acta Neuropathol. 2010, 120, 369) may help to guide and understand the results from the many current clinical trials of Aβ immunotherapy for this common, distressing and costly disease. This work has been funded by Alzheimer's Research UK and the MRC.
ii) Neuroinflammation in Alzheimer's disease
The hypothesis being explored in these studies is that Aβ protein which accumulates as the plaques in Alzheimer's disease causes cognitive dysfunction indirectly by provoking an inflammatory reaction, activating microglia, which in turn causes tau accumulation, resulting in damage to the neurons (Perry et al, Nature Reviews Neurology, 2010, 6, 193; Boche & Nicoll, Neuropathol Appl Neurobiol, 2013, 39, 3). This follows previous work suggesting that specific polymorphisms in the genes encoding the cytokine IL-1 are over-represented in Alzheimer's disease (Nicoll et al, Ann Neurol, 2000, 47, 365-8) and more recent GWAS data implicating inflammatory processes. Recent projects include a collaboration with the Cognitive Function in Ageing Study (Ince, Sheffield and Brayne, Cambridge; Minett et al, J Neuroinflam, 2016), funded by the MRC, assessment of the role of systemic inflammation on microglial activation (Rakic et al, Acta Neuropathol Comm, 2018) and microglial motility (Franco-Bocanegra et al, Acta Neuropathol Comm, 2019), funded by Alzheimer's Research UK. Mediation of neurodegeneration in Alzheimer's disease by microglial activation has considerable implications in terms of in vivo imaging and therapy.
iii) The role of vascular changes in ageing and Alzheimer's disease
Changes in the blood vessels are a ubiquitous feature of the ageing brain and play an important, but poorly understood, role in cognitive dysfunction. The Weller perivascular drainage hypothesis (Weller et al, Acta Neuropathologica, 2009, 118, 87) states that extracellular fluid in the brain drains out of the brain, analogous to the lymphatics in other organs, along the walls of blood vessels. Impairment of drainage due to vessel ageing causes accumulation of Aβ in the walls of cerebral vessels (cerebral amyloid angiopathy) and may have detrimental effects on brain homeostasis, contributing to cognitive dysfunction. I collaborate with colleagues (Carare and Hawkes) who are pursuing this concept in human and animal studies (Carare et al, Neuropath Appl Neurobiol, 2008, 34, 13; Hawkes et al, Acta Neuropathologica, 2011, 121, 431; Hawkes et al, 2012, PloS One, 7, e41636; Keable et al, Biochim Biophys Acta, 2016, 1862, 1047).
iv) Neuroinflammation in traumatic brain injury
There is a microglial response in the brain after head injury which may persist for a prolonged period (Smith et al Neuropathol Appl Neurobiol 2013, 39, 654) and affect neuronal function. We have found evidence that cytokine gene polymorphisms, notably TNFα, influence clinical outcome (Waters et al, J Neurotrauma, 2013, 30, 1710). Manipulating the neuroinflammatory response after traumatic brain injury may be a therapeutic option.
v) The role of APOE in neurological disease
APOE is important in transporting cholesterol and lipids to neurons for maintenance and repair and in accumulation of Aβ in the brain. The APOE gene polymorphism is the major genetic risk factor for Alzheimer's disease, correlating strongly with the neuropathological features (Nicoll et al, Neuropath Appl Neurobiol, 2011, 37, 285); plays a role in outcome from traumatic brain injury (Nicoll et al Nature Medicine, 1995, 1, 135; Teasdale et al, 1997, Lancet, 350, 1069; Teasdale et al, Brain 2005, 128, 2556); and is a risk factor for stroke due to CAA-related haemorrhage (Nicoll et al, Ann Neurol, 1997, 41, 716).
vi) Brain Archive Information Network (BRAIN UK)
BRAIN UK is a virtual Brain Bank which facilitates the use for research of brain tissue stored in the archives of NHS Neuropathology departments throughout the UK. This project is an extended collaborative venture with many colleagues, supported by the British Neuropathological Society and funded by the MRC and Brain Tumour Research.
Research group
Clinical and Experimental Sciences
Affiliate research group
Clinical Neuroscience Research group