Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.747010
Title: The cellular functions of TREM2 in microglia in relation to Alzheimer's disease
Author: Liu, Wenfei
ISNI:       0000 0004 7227 8829
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Abstract:
Alzheimer’s disease (AD) is the most common cause of dementia. Neuroinflammation is one of the key pathological features of AD, suggesting microglia, the major immune cell type in the brain, may play an important role in AD development. Furthermore, GWAS studies have found rare variants in immune-related gene TREM2 that increase AD risk by ~2-3 fold. TREM2 therefore seems critically implicated in the microglial functions in AD progression, and targeting its role may yield protective agents for AD. Although several recent studies have begun to shed light on the importance of microglia in dementia and the cellular function of TREM2, at time this thesis was started there was very little known about TREM2. To investigate microglia and TREM2 implications in AD, first I characterized the microglial response in relation to different stages of pathology development of AD via molecular biology and immunohistochemistry in brain samples of mice modeling either abnormal amyloid beta accumulation (APPSwe/PS1M146V transgenic mice) or tauopathy (TAUP301L transgenic mice). Both mouse models showed robust microglial activation, as manifested by expansion of microglial population along with pathology progression in the brain and up-regulation of microglial genes. I subsequently established an in vitro primary microglial model with acute Trem2 knock-down to study the role of TREM2 loss-of-function in microglia. Endogenous Trem2 expression in primary microglia was largely inhibited with pro-inflammatory stimulation such as LPS but up-regulated with anti-inflammatory stimuli such as Interleukin-4. Trem2 knock-down resulted in significant gene expression changes in the microglia, and also impaired anti-inflammatory responses and phagocytosis. The results suggest decreased expression and/or function of TREM2, due to accumulated inflammatory stimuli in the brain or loss-of-function variants of TREM2, may shift the transcriptional and functional balance of microglia away from anti-inflammatory and phagocytic properties towards pro-inflammatory properties, which might contribute to AD progression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.747010  DOI: Not available
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