Inflammatory mechanisms in neurodegeneration

Nichols, Michael R.; St‐Pierre, Marie‐Kim; Wendeln, Ann‐Christin; Makoni, Nyasha J.; Gouwens, Lisa K.; Garrad, Evan C.; Sohrabi, Mona; Neher, Jonas J.; Tremblay, Marie‐Ève; Combs, Colin K.

doi:10.1111/jnc.14674

Cited by 96 publications

(61 citation statements)

References 238 publications

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“…These observations suggest that the suppression of inflammation is important for controlling the pathogenesis of AD (67,68). In contrast, anti-inflammatory drugs failed to improve AD symptoms in a previous clinical study (64), and the surveillance in AD patients demonstrated that the loss-of-function . The results are presented as means Ϯ the SD.…”

Section: Discussionmentioning

confidence: 83%

“…We believe that GSH-mediated suppression of oxidative stress in the brain is a promising strategy for the prevention and/or early intervention of AD (61). In this regard, however, it has been reported that supplements intended to repress oxidative stresses do not improve the symptoms of AD patients (62)(63)(64). In this study, since Nrf2 suppressed both inflammation and oxidative stress in the AD mouse brain, we also focused on inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer’s Disease Model Mice

Uruno

Matsumaru

Ryoke

et al. 2020

Molecular and Cellular Biology

108

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Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether Nrf2 prevents Alzheimer’s disease (AD), AD model AppNL-G-F/NL-G-F knock-in (AppNLGF) mice were studied in combination with genetic Nrf2 induction model Keap1FA/FA mice. While AppNLGF mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in AppNLGF::Keap1FA/FA mice. Matrix-assisted laser desorption ionization–mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in AppNLGF::Keap1FA/FA mouse brains compared to AppNLGF mouse brains. Genetic Nrf2 induction in AppNLGF mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PlsPE) level as an AD biomarker. PlsPE containing polyunsaturated fatty acids was decreased in the AppNLGF mouse brain, but Nrf2 induction attenuated this decline. To evaluate whether pharmacological induction of Nrf2 elicits beneficial effects for AD treatment, we tested the natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of AppNLGF mice in the passive-avoidance task. These results demonstrate that the induction of Nrf2 ameliorates cognitive impairment in the AD model mouse by suppressing oxidative stress and neuroinflammation, suggesting that Nrf2 is an important therapeutic target of AD.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer’s Disease Model Mice

Uruno

Matsumaru

Ryoke

et al. 2020

Molecular and Cellular Biology

108

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“…The generated damage keeps microglia in an over-activated state, thus preventing these cells from returning to their homeostatic and beneficial functions and worsening the disease. It has been shown that TREM2 is critical in regulating the balance between the homeostatic and the disease-associated microglial states (Nichols et al, 2019), stimulating phagocytosis and suppressing cytokine production and inflammation (Guerreiro et al, 2013). Genetic studies have recently identified mutations of this receptor strongly associated with the risk of AD (Guerreiro et al, 2013;Jonsson et al, 2013), supporting the idea of a causative link between inflammatory cells and neurodegeneration.…”

Section: Introductionmentioning

confidence: 98%

Targeting Microglial Population Dynamics in Alzheimer’s Disease: Are We Ready for a Potential Impact on Immune Function?

Margarida

Gómez-Nicola

2020

Front. Cell. Neurosci.

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Alzheimer's disease (AD) is the most common form of dementia, affecting two-thirds of people with dementia in the world. To date, no disease-modifying treatments are available to stop or delay the progression of AD. This chronic neurodegenerative disease is dominated by a strong innate immune response, whereby microglia plays a central role as the main resident macrophage of the brain. Recent genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) located in microglial genes and associated with a delayed onset of AD, highlighting the important role of these cells on the onset and/or progression of the disease. These findings have increased the interest in targeting microglia-associated neuroinflammation as a potentially diseasemodifying therapeutic approach for AD. In this review we provide an overview on the contribution of microglia to the pathophysiology of AD, focusing on the main regulatory pathways controlling microglial population dynamics during the neuroinflammatory response, such as the colony-stimulating factor 1 receptor (CSF1R), its ligands (the colony-stimulating factor 1 and interleukin 34) and the transcription factor PU.1. We also discuss the current therapeutic strategies targeting proliferation to modulate microgliaassociated neuroinflammation and their potential impact on peripheral immune cell populations in the short and long-term. Understanding the effects of immunomodulatory approaches on microglia and other immune cell types might be critical for developing specific, effective, and safe therapies for neurodegenerative diseases.

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“…It has been a highly debatable subject as to which form of aggregated amyloids exhibits the strongest seeding potency and maximum toxicity. However, an increasingly accepted hypothesis is that oligomeric forms of amyloidogenic proteins such as α-Syn, tau, amyloid-β, and many others are the most toxic intermediates causing impairment in many cellular processes [6][7][8][9][10][11][12][13][14][15]. In addition to α-Syn protein pathology, synucleinopathies also exhibit abundant tau pathology in the form of neurofibrillary tangles (NFTs), which has also been long studied in PD [16][17][18] and dementia with Lewy bodies (DLB) [19,20].…”

Section: Introductionmentioning

confidence: 99%

Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein

et al. 2020

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The pathological hallmark of synucleinopathies, including Parkinson's disease (PD), is the aggregation of α-synuclein (α-Syn) protein. Even so, tau protein pathology is abundantly found in these diseases. Both α-Syn and tau can exist as polymorphic aggregates, a phenomenon that has been widely studied, mostly in their fibrillar assemblies. We have previously discovered that in addition to α-Syn oligomers, oligomeric tau is also present in the brain tissues of patients with PD and dementia with Lewy bodies (DLB). However, the effect of interaction between polymorphic α-Syn oligomers and tau has not been scrupulously studied. Here, we have explored the structural and functional diversity of distinct α-Syn oligomers, prepared by modifying the protein with dopamine (DA) and docosahexaenoic acid (DHA). The two α-Syn oligomers differed in aggregate size, conformation, sensitivity to proteinase K digestion, tryptic digestion, and toxicity, suggesting them as distinct α-Syn oligomeric strains. We examined their internalization mechanisms in primary neurons and seeding propensity in inducing α-Syn aggregation. Using a combined approach of molecular and cellular techniques, we observed that the tau aggregates cross-seeded with the individual α-Syn oligomeric strains differed in their biochemical and biological properties, suggesting two distinct tau strains. The tau aggregate cross-seeded with the DA-modified α-Syn oligomeric strain possessed a potent intracellular tau seeding propensity. This study provides a comprehensive analysis of unique strain-specific interaction between oligomeric α-Syn and tau. Furthermore, this study allows us to speculate that distinct α-Syn-tau interactions inducing tau aggregation might be an underlying mechanism of neurodegeneration in PD.

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Inflammatory mechanisms in neurodegeneration

Cited by 96 publications

References 238 publications

Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer’s Disease Model Mice

Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer’s Disease Model Mice

Targeting Microglial Population Dynamics in Alzheimer’s Disease: Are We Ready for a Potential Impact on Immune Function?

Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein

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