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Title: Neurogranin-A synaptic biomarker of Alzheimer's disease
Author: Wellington, Henrietta
ISNI:       0000 0004 7228 8365
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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An important and early pathophysiological process of Alzheimer’s disease (AD) is synapse dysfunction and loss. Neurogranin (Ng), a post-synaptic protein, is elevated in the cerebrospinal (CSF) from AD patients, likely reflecting synapse degeneration. In five studies, the utility and role of Ng as a novel synaptic biomarker for AD are investigated and a number of conclusions are drawn from this work. (1) CSF samples from individuals with AD, other neurodegenerative diseases and healthy controls are analysed using a novel immunoassay for Ng. Ng differentiated AD from controls as well as non-AD diagnoses with high specificity. (2) Reasons for Ng specificity are probed by comparing CSF Ng in AD variants where pathology is focused on specific brain regions. Important differences in Ng are found between typical AD and individuals with the visual variant, posterior cortical atrophy and evidence presented that CSF Ng may relate to factors others than disease topography. (3) Protein expression is compared in post-mortem tissue in AD variants and controls across cortical regions and the hippocampus. Evidence that Ng protein is decreased in most cortical regions in AD variants compared controls is presented. (4) Regulation of Ng protein expression on dendritic spines and its release into media are investigated in primary rat hippocampal cultures. Neuronal activity is shown to regulate the number of Ng puncta at dendritic spines. It remains to be determined whether activity regulates release into media. In the fifth experiment, evidence that Ng is expressed and released into media from control and genetic AD neurons derived from human induced pluripotent stem cells is presented, which provides a more disease relevant model to better validate novel biomarkers, including Ng. Together these results provide novel data addressing important questions about both the underlying biology of Ng in AD, and its role as an AD biomarker.
Supervisor: Zetterberg, H. ; Schott, J. M. ; Fox, N. C. ; Wray, Selina Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available