The inante immune receptor CD14 mediates microglial activation in Alzheimer's disease

The inante immune receptor CD14 mediates microglial activation in Alzheimer's disease

Bibliographic Details
Main Author: Reed-Geaghan, Erin Grace
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2010
Subjects:
Cellular Biology
Immunology
Neurology
Alzheimer's disease
CD14
A&946
Toll like receptor
microglia
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1266602303
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case12666023032021-08-03T05:33:33Z The inante immune receptor CD14 mediates microglial activation in Alzheimer's disease Reed-Geaghan, Erin Grace Cellular Biology Immunology Neurology Alzheimer's disease CD14 A&946 Toll like receptor microglia Alzheimer’s disease (AD) is characterized by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles, and is accompanied by a robust inflammatory response mediated by microglia, the brain’s immune cells. Microglia are intimately associated with the plaques and interact with fibrillar Aβ (fAβ) through an ensemble of surface receptors including the α6β1 integrin, CD36, CD47, and the class A scavenger receptor. These receptors act in concert to initiate intracellular signaling cascades and phenotypic activation of these cells. However, it is unclear how engagement of this receptor complex is linked to the induction of an activated microglial phenotype. We found this response requires the participation of Toll like receptors (TLRs) and the co-receptor CD14. The response of microglia to fAβ is reliant upon CD14, which acts together with TLR4 and TLR2 to bind fAβ and to activate intracellular signaling. Microglia lacking these receptors could not initiate a Src-Vav-Rac signaling cascade for reactive oxygen species (ROS) production and phagocytosis. The fAβ-mediated activation of p38 MAPK also required CD14, TLR4, and TLR2. Inhibition of p38 abrogated fAβ-induced ROS production and attenuated the induction of phagocytosis. Microglia lacking CD14, TLR4, and TLR2 showed no induction of phosphorylated IκBα following fAβ. These data indicate these innate immune receptors function as members of the microglial fAβ receptor complex and identify the signaling mechanisms whereby they contribute to microglial activation. We extended these studies on the innate immune system in the inflammatory component of AD by crossing CD14-knockout mice to the APPswe/PSEN1dE9 AD mouse model. CD14 deletion reduced insoluble but not soluble levels of Aβ in the brain, corresponding to decreased plaque load resulting from decreased number and size of Thioflavin S-positive plaques. Moreover, APPswe/PSEN1dE9 CD14-/- mice had increased levels of the pro-inflammatory cytokine genes Tnfα and Ifnγ, decreased levels of the alternative activation markers Fizz1 and Ym1, and increased expression of Il-10, reflective of their conversion into an alternative M2b activation state. These changes in inflammatory cytokines alter the expression of various Aβ degrading enzymes or Aβ clearance proteins. These data suggest that CD14 is a critical regulator of the microglial inflammatory response to plaques and that this inflammatory response can modulate Aβ deposition. 2010-07-30 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1266602303 http://rave.ohiolink.edu/etdc/view?acc_num=case1266602303 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 Cellular Biology
Immunology
Neurology
Alzheimer's disease
CD14
A&946
Toll like receptor
microglia
spellingShingle Cellular Biology
Immunology
Neurology
Alzheimer's disease
CD14
A&946
Toll like receptor
microglia
Reed-Geaghan, Erin Grace
The inante immune receptor CD14 mediates microglial activation in Alzheimer's disease
author Reed-Geaghan, Erin Grace
author_facet Reed-Geaghan, Erin Grace
author_sort Reed-Geaghan, Erin Grace
title The inante immune receptor CD14 mediates microglial activation in Alzheimer's disease
title_short The inante immune receptor CD14 mediates microglial activation in Alzheimer's disease
title_full The inante immune receptor CD14 mediates microglial activation in Alzheimer's disease
title_fullStr The inante immune receptor CD14 mediates microglial activation in Alzheimer's disease
title_full_unstemmed The inante immune receptor CD14 mediates microglial activation in Alzheimer's disease
title_sort inante immune receptor cd14 mediates microglial activation in alzheimer's disease
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2010
url http://rave.ohiolink.edu/etdc/view?acc_num=case1266602303
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