The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment

Bibliographic Details
Main Author:	Jay, Taylor Reagan
Language:	English
Published:	Case Western Reserve University School of Graduate Studies / OhioLINK 2019
Subjects:	Neurosciences Glia microglia astrocytes Alzheimers disease synaptic pruning synapse development
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=case1560181547156823

id	ndltd-OhioLink-oai-etd.ohiolink.edu-case1560181547156823
record_format	oai_dc
spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-case15601815471568232021-09-02T05:10:38Z The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment Jay, Taylor Reagan Neurosciences Glia microglia astrocytes Alzheimers disease synaptic pruning synapse development It has been known for over a century that microglia change their phenotype and function in neurodegenerative diseases, but it has remained an open question whether cells actively modulate the disease process. This question was resolved when variants in the gene TREM2, which encodes a microglia-specific receptor, were identified as risk factors for Alzheimer’s disease. Our work has focused on understanding TREM2’s function in order to gain insight into how microglia contribute to neurodegeneration and normal brain function. When we looked at when and where TREM2 was expressed in the context of Alzheimer’s disease, we were surprised to find that cells with the highest levels of TREM2 also expressed markers of peripherally derived immune cells, rather than brain-resident microglia. This finding suggested the provocative possibility that peripheral immune cells play an essential role in Alzheimer’s disease pathology. In order to determine the functional role of TREM2 on those cells, we examined how microglia and peripheral immune cell function was altered in Alzheimer’s disease mouse models lacking TREM2 expression. We found that, without TREM2, peripherally-derived immune cells were virtually absent from the brain, and resident microglia failed to respond to amyloid pathology. Interestingly, this also prevented astrocytes from responding to amyloid deposition. TREM2 deficient mice exhibited altered pathogenesis and progression of amyloid pathology and plaque-associated neuritic dystrophy. In addition to these disease-related functions, we also identified an important role for TREM2 in normal brain development. Mice lacking TREM2 expression were found to have reduced synapse number. Because microglia play a role in synaptic elimination during circuit refinement, we thought that perhaps overactive synaptic pruning by microglia would be responsible for this synaptic loss. However, we instead found fewer synapses engulfed by TREM2 deficient microglia. Rather, this synapse loss was due to enhanced engulfment of synapses by astrocytes. This was due to a decrease in the population of microglia in TREM2 deficient mice, which resulted in reduced microglial-derived signals that normally serve to limit astrocytic synaptic uptake. This demonstrates that TREM2 is important for normal microglial development, and when dysfunctional, has consequences for both astrocyte and neuronal function. 2019 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1560181547156823 http://rave.ohiolink.edu/etdc/view?acc_num=case1560181547156823 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Neurosciences Glia microglia astrocytes Alzheimers disease synaptic pruning synapse development
spellingShingle	Neurosciences Glia microglia astrocytes Alzheimers disease synaptic pruning synapse development Jay, Taylor Reagan The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment
author	Jay, Taylor Reagan
author_facet	Jay, Taylor Reagan
author_sort	Jay, Taylor Reagan
title	The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment
title_short	The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment
title_full	The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment
title_fullStr	The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment
title_full_unstemmed	The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment
title_sort	trem2 receptor directs microglial activity in neurodegeneration and neurodevelopment
publisher	Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate	2019
url	http://rave.ohiolink.edu/etdc/view?acc_num=case1560181547156823
work_keys_str_mv	AT jaytaylorreagan thetrem2receptordirectsmicroglialactivityinneurodegenerationandneurodevelopment AT jaytaylorreagan trem2receptordirectsmicroglialactivityinneurodegenerationandneurodevelopment
_version_	1719474088799371264

The TREM2 Receptor Directs Microglial Activity in Neurodegeneration and Neurodevelopment

Similar Items