UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

The cellular functions of TREM2 in microglia in relation to Alzheimer's disease

Liu, Wenfei; (2017) The cellular functions of TREM2 in microglia in relation to Alzheimer's disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

[img]
Preview
Text
PhD Thesis_Wenfei Liu_UCL_final.pdf

Download (119MB) | Preview

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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The cellular functions of TREM2 in microglia in relation to Alzheimer's disease
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10037571
Downloads since deposit
106Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item