Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer's disease mouse model

Baik, Sung-Hoon; Kang, Seok Seon; Son, Sungmin; Mook‐Jung, Inhee

doi:10.1002/glia.23074

Cited by 181 publications

(144 citation statements)

References 62 publications

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…Similarly, a two‐photon in vivo study indicated that microglial uptake of aggregated Aβ, followed by microglial death and release of residual Aβ, could lead to the spreading of amyloid deposition (Baik et al . ).…”

Section: The Relationship Of Microglia and Aβ Plaque Depositionmentioning

confidence: 97%

Inflammatory mechanisms in neurodegeneration

Nichols

St‐Pierre

Wendeln

et al. 2019

Journal of Neurochemistry

106

View full text Add to dashboard Cite

This review discusses the profound connection between microglia, neuroinflammation, and Alzheimer's disease (AD).Theories have been postulated, tested, and modified over several decades. The findings have further bolstered the belief that microglia-mediated inflammation is both a product and contributor to AD pathology and progression. Distinct microglia phenotypes and their function, microglial recognition and response to protein aggregates in AD, and the overall role of microglia in AD are areas that have received considerable research attention and yielded significant results. The following article provides a historical perspective of microglia, a detailed discussion of multiple microglia phenotypes including dark microglia, and a review of a number of areas where microglia intersect with AD and other pathological neurological processes. The overall breadth of important discoveries achieved in these areas significantly strengthens the hypothesis that neuroinflammation plays a key role in AD. Future determination of the exact mechanisms by which microglia respond to, and attempt to mitigate, protein aggregation in AD may lead to new therapeutic strategies.

show abstract

Section: The Relationship Of Microglia and Aβ Plaque Depositionmentioning

confidence: 97%

Inflammatory mechanisms in neurodegeneration

Nichols

St‐Pierre

Wendeln

et al. 2019

Journal of Neurochemistry

106

View full text Add to dashboard Cite

show abstract

“…To overcome the limitations of these markers, lineage tracing mouse models have been generated using the microglial expression of the fractalkine receptor, Cx3cr1 (Jung et al, ). One study crossbred the Cx3cr1 GFP/GFP mice with the 5xFAD mouse model of AD and found that dying GFP positive cells contributed to Aβ plaque growth by releasing previously phagocytosed Aβ into the extracellular space (Baik, Kang, Son, & Mook Jung, ). However, macrophages can also express Cx3cr1, thus the contribution of peripheral monocyte‐derived macrophages cannot be ruled out.…”

Section: Introductionmentioning

confidence: 99%

CD11a expression distinguishes infiltrating myeloid cells from plaque‐associated microglia in Alzheimer's disease

Shukla

McIntyre

Marsh

et al. 2018

Glia

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the leading cause of age-related neurodegeneration and is characterized neuropathologically by the accumulation of insoluble beta-amyloid (Aβ) peptides. In AD brains, plaque-associated myeloid (PAM) cells cluster around Aβ plaques but fail to effectively clear Aβ by phagocytosis. PAM cells were originally thought to be brain-resident microglia. However, several studies have also suggested that Aβ-induced inflammation causes peripheral monocytes to enter the otherwise immune-privileged brain. The relationship between AD progression and inflammation in the brain remains ambiguous because microglia and monocyte-derived macrophages are extremely difficult to distinguish from one another in an inflamed brain. Whether PAM cells are microglia, peripheral macrophages, or a mixture of both remains unclear. CD11a is a component of the β2 integrin LFA1. We have determined that CD11a is highly expressed on peripheral immune cells, including macrophages, but is not expressed by mouse microglia. These expression patterns remain consistent in LPS-treated inflamed mice, as well as in two mouse models of AD. Thus, CD11a can be used as a marker to distinguish murine microglia from infiltrating peripheral immune cells. Using CD11a, we show that PAM cells in AD transgenic brains are comprised entirely of microglia. We also demonstrate a novel fluorescence-assisted quantification technique (FAQT), which reveals a significant increase in T lymphocytes, especially in the brains of female AD mice. Our findings support the notion that microglia are the lead myeloid players in AD and that rejuvenating their phagocytic potential may be an important therapeutic strategy. K E Y W O R D SAlzheimer's disease, CD11a, microglia, peripheral immune cells, plaque-associated myeloid cells

show abstract

“…Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular deposits of amyloid‐β (Aβ) peptides, intracellular neurofibrillary tangles, and chronic neuroinflammation resulting in a progressive loss of memory and cognitive function (Prinz & Priller, ). While Aβ can be cleared by resident microglia and astrocytes (Baik et al, ; Ries & Sastre, ), these cells become unable to clear Aβ pathology as animals age. The peripheral immune system is clearly implicated in AD pathogenesis (Heneka et al, ; Prinz & Priller, ).…”

Section: Introductionmentioning

confidence: 99%

Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

Latta-Mahieu

Elmer²,

Bretteville

et al. 2017

Glia

View full text Add to dashboard Cite

Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death-1 (PD1) checkpoint inhibition produces an IFN-γ-dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., (): Nature Medicine, 22:135-137). Immune checkpoint inhibition was therefore suggested as potential treatment for neurodegenerative disorders when activation of the immune system is appropriate. Because a xenogeneic rat antibody (mAb) was used in the study, whether the effect was specific to PD1 target engagement was uncertain. In the present study we examined whether PD1 immunotherapy can lower amyloid-β pathology in a range of different amyloid transgenic models performed at three pharmaceutical companies with the exact same anti-PD1 isotype and two mouse chimeric variants. Although PD1 immunotherapy stimulated systemic activation of the peripheral immune system, monocyte-derived macrophage infiltration into the brain was not detected, and progression of brain amyloid pathology was not altered. Similar negative results of the effect of PD1 immunotherapy on amyloid brain pathology were obtained in two additional models in two separate institutions. These results show that inhibition of PD1 checkpoint signaling by itself is not sufficient to reduce amyloid pathology and that additional factors might have contributed to previously published results (Baruch et al., (): Nature Medicine, 22:135-137). Until such factors are elucidated, animal model data do not support further evaluation of PD1 checkpoint inhibition as a therapeutic modality for Alzheimer's disease.

show abstract

Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer's disease mouse model

Cited by 181 publications

References 62 publications

Inflammatory mechanisms in neurodegeneration

Inflammatory mechanisms in neurodegeneration

CD11a expression distinguishes infiltrating myeloid cells from plaque‐associated microglia in Alzheimer's disease

Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

Contact Info

Product

Resources

About