T Cells—Protective or Pathogenic in Alzheimer’s Disease?

McManus, Róisín M.; Mills, Kingston H. G.; Lynch, Marina A.

doi:10.1007/s11481-015-9612-2

Cited by 45 publications

(33 citation statements)

References 167 publications

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“…Significantly, IFNc inhibits LTP (Kelly et al 2013) and synergizes with Ab to increase microglial activation (Jones et al 2015). Infiltration of T cells also occurs with age, particularly in APP/PS1 mice, and our evidence indicates that Th1 and also Th17 cells activate microglia in vitro and in vivo while their presence in the brain of APP/ PS1 mice negatively impacts hippocampal-dependent cognitive function (Browne et al 2013;McManus et al 2014McManus et al , 2015.…”

Section: Microglia In the Aged Brainmentioning

confidence: 65%

Targeting innate immunity for neurodegenerative disorders of the central nervous system

Andreasson

Bachstetter

Colonna

et al. 2016

Journal of Neurochemistry

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113

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Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer’s disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer’s disease are further contributions to this series.

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Section: Microglia In the Aged Brainmentioning

confidence: 65%

Targeting innate immunity for neurodegenerative disorders of the central nervous system

Andreasson

Bachstetter

Colonna

et al. 2016

Journal of Neurochemistry

Self Cite

113

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“…This rhythm slowing was specific because chronic exposures to IFN-α (type I IFN) or IL-17 (Th17 response) did not affect the properties of gamma oscillations (SI Appendix, Fig. S3) (36,37).…”

Section: Resultsmentioning

confidence: 99%

“…Such a general mechanism might apply to a variety of (chronic) clinical situations that are associated with elevated IFN-γ levels, bloodbrain barrier leakage and/or T cell infiltration (SI Appendix, SI Discussion). Prominent examples are aging, (post) stroke, multiple sclerosis, and, perhaps, Alzheimer's disease (2,9,10,23,37,62).…”

Section: Discussionmentioning

confidence: 99%

Priming of microglia with IFN-γ slows neuronal gamma oscillations in situ

Dikmen

Schilling

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

105

101

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Type II IFN (IFN-γ) is a proinflammatory T lymphocyte cytokine that serves in priming of microglia-resident CNS macrophagesduring the complex microglial activation process under pathological conditions. Priming generally permits an exaggerated microglial response to a secondary inflammatory stimulus. The impact of primed microglia on physiological neuronal function in intact cortical tissue (in situ) is widely unknown, however. We explored the effects of chronic IFN-γ exposure on microglia in hippocampal slice cultures, i.e., postnatal parenchyma lacking leukocyte infiltration (adaptive immunity). We focused on fast neuronal network waves in the gamma-band (30-70 Hz). Such gamma oscillations are fundamental to higher brain functions, such as perception, attention, and memory, and are exquisitely sensitive to metabolic and oxidative stress. IFN-γ induced substantial morphological changes and cell population expansion in microglia as well as moderate upregulation of activation markers, MHC-II, CD86, IL-6, and inducible nitric oxide synthase (iNOS), but not TNF-α. Cytoarchitecture and morphology of pyramidal neurons and parvalbumin-positive inhibitory interneurons were well-preserved. Notably, gamma oscillations showed a specific decline in frequency of up to 8 Hz, which was not mimicked by IFN-α or IL-17 exposure. The rhythm disturbance was caused by moderate microglial nitric oxide (NO) release demonstrated by pharmacological microglia depletion and iNOS inhibition. In conclusion, IFN-γ priming induces substantial proliferation and moderate activation of microglia that is capable of slowing neural information processing. This mechanism might contribute to cognitive impairment in chronic brain disease featuring elevated IFN-γ levels, blood-brain barrier leakage, and/or T cell infiltration, well before neurodegeneration occurs.interferon-gamma | microglia | neuroinflammation | neuronal electrical activity | nitric oxide synthase

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“…Importantly, it is indisputable that many specific viral, bacterial, and fungal infections are associated with AD development, although whether these pathogens are a direct cause of dementia or instead are advantageous, infiltrating microorganisms that exacerbate the neuroinflammation already ongoing in these individuals remains to be confirmed. Importantly, the BBB of AD patients is significantly leakier than in healthy subjects, which facilitates infiltration of peripheral immune cells [100] and possibly these infectious pathogens (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Role of neuroinflammation in neurodegeneration: new insights

2017

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Previously, the contribution of peripheral infection to cognitive decline was largely overlooked however, the past 15 years have established a key role for infectious pathogens in the progression of age-related neurodegeneration. It is now accepted that the immune privilege of the brain is not absolute, and that cells of the central nervous system are sensitive to both the inflammatory events occurring in the periphery and to the infiltration of peripheral immune cells. This is particularly relevant for the progression of Alzheimer’s disease, in which it has been demonstrated that patients are more vulnerable to infection-related cognitive changes. This can occur from typical infectious challenges such as respiratory tract infections, although a number of specific viral, bacterial, and fungal pathogens have also been associated with the development of the disease. To date, it is not clear whether these microorganisms are directly related to Alzheimer’s disease progression or if they are opportune pathogens that easily colonize those with dementia and exacerbate the ongoing inflammation observed in these individuals. This review will discuss the impact of each of these challenges, and examine the changes known to occur with age in the peripheral immune system, which may contribute to the age-related vulnerability to infection-induced cognitive decline.

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T Cells—Protective or Pathogenic in Alzheimer’s Disease?

Cited by 45 publications

References 167 publications

Targeting innate immunity for neurodegenerative disorders of the central nervous system

Targeting innate immunity for neurodegenerative disorders of the central nervous system

Priming of microglia with IFN-γ slows neuronal gamma oscillations in situ

Role of neuroinflammation in neurodegeneration: new insights

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