Myeloid Cells in Alzheimer's Disease: Culprits, Victims or Innocent Bystanders?

Meyer‐Luehmann, Melanie; Prinz, Marco

doi:10.1016/j.tins.2015.08.011

Cited by 59 publications

(50 citation statements)

References 113 publications

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“…In this study, we evaluated the microglial response in the hippocampus of postmortem human samples classified from Braak 0 to Braak VI stages. Contrary to the expected results based on APP-transgenic models [16, 22, 33], an attenuated rather than massive microglial activation was observed in Braak V–VI samples (AD cases). More importantly, the present results also demonstrate the existence of a microglial degenerative process in the Braak V–VI hippocampus.…”

Section: Discussioncontrasting

confidence: 99%

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

et al. 2016

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The role of microglial cells in the development and progression of Alzheimer’s disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance (“microglial domain”). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1630-5) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 99%

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

et al. 2016

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“…Increasing evidence supports the hypothesis that the microglial response to AD lesions controls disease progression (Gold and El Khoury, 2015; Hong et al, 2016; Meyer-Luehmann and Prinz, 2015; Perry and Holmes, 2014; Tejera and Heneka, 2016; Wang et al, 2016; Yuan et al, 2016). Toll-like receptors and NOD-like receptors have been previously implicated in the microglia response to Aβ accumulation and shown to mediate an inflammatory response that contributes to pathology (Freeman and Ting, 2016; Heneka et al, 2015; Heneka et al, 2013).…”

Section: Discussionmentioning

confidence: 79%

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

Ulland

Song

Huang

et al. 2017

Cell

880

746

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Summary Elevated risk of developing Alzheimer’s disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth factor limitation or ER stress. Combined metabolomics and RNA-seq linked this anomalous autophagy to defective mTOR signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.

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“…Finally, we asked the question to which extent microglia may be relevant for diminished seeding activity after EE and voluntary running (Meyer‐Luehmann & Prinz, ). Recent studies showed that exposure to EE can have a pivotal role for microglia activation and maintenance of adult neurogenesis that was dependent on the presence of PS mutations (Ziv et al , ; Choi et al , ).…”

Section: Resultsmentioning

confidence: 99%

Seed‐induced Aβ deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer's disease

et al. 2017

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Alzheimer's disease (AD) is characterized by severe neuronal loss as well as the accumulation of amyloid‐β (Aβ), which ultimately leads to plaque formation. Although there is now a general agreement that the aggregation of Aβ can be initiated by prion‐like seeding, the impact and functional consequences of induced Aβ deposits (Aβ seeding) on neurons still remain open questions. Here, we find that Aβ seeding, representing early stages of plaque formation, leads to a dramatic decrease in proliferation and neurogenesis in two APP transgenic mouse models. We further demonstrate that neuronal cell death occurs primarily in the vicinity of induced Aβ deposits culminating in electrophysiological abnormalities. Notably, environmental enrichment and voluntary exercise not only revives adult neurogenesis and reverses memory deficits but, most importantly, prevents Aβ seeding by activated, phagocytic microglia cells. Our work expands the current knowledge regarding Aβ seeding and the consequences thereof and attributes microglia an important role in diminishing Aβ seeding by environmental enrichment.

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Myeloid Cells in Alzheimer's Disease: Culprits, Victims or Innocent Bystanders?

Cited by 59 publications

References 113 publications

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

Seed‐induced Aβ deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer's disease

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