Regulation of microglial survival and proliferation in health and diseases

Ulland, Tyler K.; Wang, Yaming; Colonna, Marco

doi:10.1016/j.smim.2016.03.011

Cited by 39 publications

(31 citation statements)

References 72 publications

(116 reference statements)

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“…Analysis of the correlation between single-nucleotide polymorphisms and disease or specific endophenotypes of the disease led to the identification of several susceptibility loci, many of them related to immune functions (e.g., APOE, CR1, BIN1, CD33, TREM2, PICALM) (see 76 for review). Among them, preclinical and clinical studies indicate a strong association between reduced TREM2 and increased CD33 expression with increased Aβ accumulation (78). These data agree with several lines of evidence indicating that microglia hyperactivation is intimately associated with formation of amyloid plaques and AD progression.…”

Section: Targeting Neuroinflammationsupporting

confidence: 86%

Update on Alzheimer's Disease Therapy and Prevention Strategies

2017

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Alzheimer's disease (AD) is the primary cause of age-related dementia. Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology. Significant investments in therapeutic drug discovery programs over the past two decades have yielded some important insights but no blockbuster drugs to alter the course of disease. Because significant memory loss and cognitive decline are associated with neuron death and loss of gray matter, especially in the frontal cortex and hippocampus, some focus in drug development has shifted to early prevention of cellular pathology. Although clinical trial design is challenging, due in part to a lack of robust biomarkers with predictive value, some optimism has come from the identification and study of inherited forms of early-onset AD and genetic risk factors that provide insights about molecular pathophysiology and potential drug targets. In addition, better understanding of the Aβ amyloid pathway and the tau pathway-leading to amyloid plaques and neurofibrillary tangles, respectively, which are histopathological hallmarks of AD-continues to drive significant drug research and development programs. The main focus of this review is to summarize the most recent basic biology, biochemistry, and pharmacology that serve as a foundation for more than 50 active advanced-phase clinical trials for AD prevention and therapy.

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Section: Targeting Neuroinflammationsupporting

confidence: 86%

Update on Alzheimer's Disease Therapy and Prevention Strategies

2017

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“…The implication of microglial cells in the development of neurodegenerative disorders is generally accepted [16, 19, 59]. However, microglial dysfunction in AD has been primarily associated with over-activation and cytotoxicity of these cells [19, 59].…”

Section: Discussionmentioning

confidence: 99%

“…However, microglial dysfunction in AD has been primarily associated with over-activation and cytotoxicity of these cells [19, 59]. Microglial activation has been undoubtedly observed in cerebral regions with the early and abundant extracellular Abeta deposits [15, 36, 49, 50].…”

Section: Discussionmentioning

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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“…Microglia receive signals for survival and proliferation following stimulation of the CSF1 receptor (CSF1R) with CSF1 or IL-34 (142). At the transcriptional level, the CEBP/α/PU.1 pathway is involved in the regulation of monopoiesis and granulopoiesis (143,144) and serves as a candidate for regulating proliferation in microglia.…”

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E N mentioning

confidence: 99%