Neuroinflammation in frontotemporal dementia

Bright, Fiona; Werry, Eryn L.; Dobson‐Stone, Carol; Piguet, Olivier; Ittner, Lars M.; Halliday, Glenda M.; Hodges, John R.; Kiernan, Matthew C.; Loy, Clement T.; Kassiou, Michael; Kril, Jillian J.

doi:10.1038/s41582-019-0231-z

Cited by 190 publications

(162 citation statements)

References 230 publications

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“…Taken together, all these data highlight the crucial role of innate immune responses both in ALS and FTD, whose activation is initially aimed at restoring tissue homeostasis, but ultimately generate a vicious circle by promoting proinflammatory toxic phenomena [147,[158][159][160].…”

Section: Amyotrophic Lateral Sclerosis and Frontotemporal Dementiamentioning

confidence: 91%

“…Although the cause of ALS and FTD is still unknown, the impact of the innate immune response has been suggested as being important for both the initiation and the progression of these diseases [146][147][148].…”

Section: Amyotrophic Lateral Sclerosis and Frontotemporal Dementiamentioning

confidence: 99%

“…Therefore, C9orf72 likely has a different effect on different cell types: proinflammatory in microglia, and protein aggregate toxicity in neurons. These combined effects may lead to neurodegeneration in ALS/FTD [147,168,175].…”

Section: Amyotrophic Lateral Sclerosis and Frontotemporal Dementiamentioning

confidence: 99%

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Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases

Novellino

Saccà

Donato

et al. 2020

IJMS

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The intricate relationships between innate immunity and brain diseases raise increased interest across the wide spectrum of neurodegenerative and neuropsychiatric disorders. Barriers, such as the blood–brain barrier, and innate immunity cells such as microglia, astrocytes, macrophages, and mast cells are involved in triggering disease events in these groups, through the action of many different cytokines. Chronic inflammation can lead to dysfunctions in large-scale brain networks. Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are associated with a substrate of dysregulated immune responses that impair the central nervous system balance. Recent evidence suggests that similar phenomena are involved in psychiatric diseases, such as depression, schizophrenia, autism spectrum disorders, and post-traumatic stress disorder. The present review summarizes and discusses the main evidence linking the innate immunological response in neurodegenerative and psychiatric diseases, thus providing insights into how the responses of innate immunity represent a common denominator between diseases belonging to the neurological and psychiatric sphere. Improved knowledge of such immunological aspects could provide the framework for the future development of new diagnostic and therapeutic approaches.

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Section: Amyotrophic Lateral Sclerosis and Frontotemporal Dementiamentioning

confidence: 91%

Section: Amyotrophic Lateral Sclerosis and Frontotemporal Dementiamentioning

confidence: 99%

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Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases

Novellino

Saccà

Donato

et al. 2020

IJMS

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“…Several lines of evidence indicate an important role for neuroinflammation in the progression of FTD (Bright et al, 2019). Microglial activation and astrogliosis have been detected in the frontal and temporal cortices of FTD patients.…”

Section: Ftld-tdp Is the Most Common Neuropathologic Type Of Ftld Andmentioning

confidence: 99%

Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia

Pasetto

Grassano

Pozzi

et al. 2020

Preprint

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Frontotemporal dementia (FTD) is a common cause of early-onset dementia, characterized by frontotemporal lobar degeneration and considerable clinical, genetic and neuropathological heterogeneity. Several mouse models of FTD have been generated targeting genes with known pathogenic roles. However, each of these models recapitulates only certain aspects of the human disease. Cyclophilin A (PPIA) is a multifunctional protein abundantly expressed in the brain, with double-edged functions. Intracellularly, it is mainly protective as a foldase and molecular chaperone with scaffolding properties. Extracellularly, it behaves as a proinflammatory cytokine able to activate an aberrant inflammatory response. In a previous work, we found that PPIA governs TDP-43 functions and its deficiency exacerbates disease in a mouse model of ALS.Selective inhibition of extracellular PPIA rescued motor neurons and increased survival. To decipher PPIA's functions in the central nervous system, we planned a deep neuropathological and behavioral characterization of PPIA knock-out (PPIA-/-) mice throughout their lifespan. They develop a neurodegenerative disease that recapitulates key features of the behavioral variant of FTD associated with TDP-43 pathology. PPIA-/-mice present progressive hippocampal and cortex atrophy, with neuronal death and clear-cut TDP-43 pathology that include fragmentation, hyperphosphorylation, and cytoplasmic mislocalization/nuclear clearing. Mice exhibit increased disinhibition, defects in social behavior, but no memory and motor impairment. On a molecular level, our findings indicate that PPIA is involved in multiple genes and pathways that have a dominant protective effect in the brain, and is fundamental for TDP-43 function. Considering that an impaired interaction of TDP-43 with PPIA has been observed in ALS/FTD patients, the PPIA-/-mouse is a useful experimental model to investigate the mechanism at the basis of TDP-43 pathology and develop novel therapeutic approaches for ALS/FTD and possibly other TDP-43 proteinopathies.

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“…Neuroinflammation is a main host defense response to injury (4,8). Numerous studies have indicated that neuroinflammation is a critical pathological factor in multiple neurological disorders (4,5,9), although neuroinflammation can also produce beneficial effects under certain conditions (10). Excessive activation of microglia -the major immune cells in the brain -leads to the production of multiple pro-inflammatory factors, which play a key role in neuroinflammation (11,12).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Electron Transport Chain Inhibition Suppresses LPS-Induced Inflammatory Responses via TREM1/STAT3 Pathway in BV2 Microglia

Zhou

Zhang

Ying

2019

Preprint

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Mitochondrial damage and neuroinflammation belong to two of the most important pathological factors in multiple neurological disorders. However, the effect of mitochondrial damage of microglia on microglial activation under pathological conditions has remained unclear. In our current study, we used BV2 microglia as a cellular model to determine the effects of mitochondrial electron transport chain (ETC) inhibitors on LPS-induced inflammatory responses of microglia. We found that all of the three mitochondrial ETC inhibitors, including rotenone, sodium azide and antimycin A, significantly inhibited LPS-induced inflammatory responses of the microglia, assessed by determinations of the protein or mRNA levels of IL-1, IL-6, TNF- iNOS and COX2Nuclear translocation of NF-B p65 subunit does not appear to play an important role in the mitochondrial ETC inhibition-produced suppression of microglial activation. Instead, our study found that the mitochondrial ETC inhibitors significantly attenuated not only the LPS-induced increase in the TREM1 levels -an amplifier of inflammatory process, but also the LPS-induced increase in the ratio of phosphorylated STAT3 / STAT3. In summary, our study has suggested that mitochondrial ETC inhibition of microglia can lead to suppression of LPS-induced microglial activation, which may be mediated by the inhibitory effects of mitochondrial ETC inhibition on the LPS-induced increases in the level of TREM1 and the ratio of p-STAT3 / STAT3. These findings have provided valuable information for elucidating the relationships between mitochondrial damage and neuroinflammation in multiple neurological diseases.

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Neuroinflammation in frontotemporal dementia

Cited by 190 publications

References 230 publications

Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases

Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases

Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia

Mitochondrial Electron Transport Chain Inhibition Suppresses LPS-Induced Inflammatory Responses via TREM1/STAT3 Pathway in BV2 Microglia

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