A unique type of GSK-3 inhibitor brings new opportunities to the clinic

Licht-Murava, Avital; Paz, Rom; Vaks, Lilach; Avrahami, Limor; Plotkin, Batya; Eisenstein, Miriam; Eldar-Finkelman, Hagit

doi:10.1126/scisignal.aah7102

Cited by 60 publications

(47 citation statements)

References 85 publications

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“…Inhibition of Wnt signaling hastened disease progression and resulted in increased numbers of CD4 + T cells in the CNS (105). Chemical modulators of Wnt signaling have been validated in vitro and in rodent models of neuroinflammation (144, 145). Translation of such therapies to clinical use could repair the damaged barrier, translating to improved clinical outcomes in AE patients by limiting influx of blood-borne immune cells, cytokines, and/or antibodies.…”

Section: Treatment Of Ae Syndromesmentioning

confidence: 99%

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

2017

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Antibodies against neuronal receptors and synaptic proteins are associated with autoimmune encephalitides (AE) that produce movement and psychiatric disorders. In order to exert their pathological effects on neural circuits, autoantibodies against central nervous system (CNS) targets must gain access to the brain and spinal cord by crossing the blood–brain barrier (BBB), a tightly regulated gateway formed by endothelial cells lining CNS blood vessels. To date, the pathogenic mechanisms that underlie autoantibody-triggered encephalitic syndromes are poorly understood, and how autoantibodies breach the barrier remains obscure for almost all AE syndromes. The relative importance of cellular versus humoral immune mechanisms for disease pathogenesis also remains largely unexplored. Here, we review the proposed triggers for various autoimmune encephalopathies and their animal models, as well as basic structural features of the BBB and how they differ among various CNS regions, a feature that likely underlies some regional aspects of autoimmune encephalitis pathogenesis. We then discuss the routes that antibodies and immune cells employ to enter the CNS and their implications for AE. Finally, we explore future therapeutic strategies that may either preserve or restore barrier function and thereby limit immune cell and autoantibody infiltration into the CNS. Recent mechanistic insights into CNS autoantibody entry indicate promising future directions for therapeutic intervention beyond current, short-lived therapies that eliminate circulating autoantibodies.

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Section: Treatment Of Ae Syndromesmentioning

confidence: 99%

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

2017

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“…Tau hyperphosphorylation could be toxic, independently if it forms toxic aggregates or could remain in soluble form (76). In this way, tau toxicity could result in an inflammatory process that could be prevented by the inhibition of tau kinases, like GSK3 (77). However, tau phosphorylation at different residues could result in different toxicity levels and even a site-specific phosphorylation of tau could inhibit amyloid toxicity, in a mouse model (78).…”

Section: Role Of Tau In Brain Inflammationmentioning

confidence: 99%

Alzheimer’s disease as an inflammatory disease

Bolós

Perea

Ávila

2017

Biomolecular Concepts

178

127

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Alzheimer's disease (AD) is a neurodegenerative condition characterized by the formation of amyloid-β plaques, aggregated and hyperphosphorylated tau protein, activated microglia and neuronal cell death, ultimately leading to progressive dementia. In this short review, we focus on neuroinflammation in AD. Specifically, we describe the participation of microglia, as well as other factors that may contribute to inflammation, in neurodegeneration.

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“…More recently, triazinones displayed i n vitro anti-GSK-3 and anti-BACE-1 activity plus neuroprotective and neurogenic effects besides good brain permeability in vivo (Prati et al, 2015), however no anti-inflammatory data are currently available. Lastly, L807mts, a highly selective GSK-3 peptide derivative inhibitor, reduced Aβ levels, reduced inflammation and enhanced autophagy in a transgenic AD mouse model (Licht-Murava et al, 2016). …”

Section: Pharmacological Approaches Towards Immunomodulation and Theimentioning

confidence: 99%

Nutritional and Pharmacological Strategies to Regulate Microglial Polarization in Cognitive Aging and Alzheimer’s Disease

Peña-Altamira

Petralla

Massenzio

et al. 2017

Front. Aging Neurosci.

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The study of microglia, the immune cells of the brain, has experienced a renaissance after the discovery of microglia polarization. In fact, the concept that activated microglia can shift into the M1 pro-inflammatory or M2 neuroprotective phenotypes, depending on brain microenvironment, has completely changed the understanding of microglia in brain aging and neurodegenerative diseases. Microglia polarization is particularly important in aging since an increased inflammatory status of body compartments, including the brain, has been reported in elderly people. In addition, inflammatory markers, mainly derived from activated microglia, are widely present in neurodegenerative diseases. Microglial inflammatory dysfunction, also linked to microglial senescence, has been extensively demonstrated and associated with cognitive impairment in neuropathological conditions related to aging. In fact, microglia polarization is known to influence cognitive function and has therefore become a main player in neurodegenerative diseases leading to dementia. As the life span of human beings increases, so does the prevalence of cognitive dysfunction. Thus, therapeutic strategies aimed to modify microglia polarization are currently being developed. Pharmacological approaches able to shift microglia from M1 pro-inflammatory to M2 neuroprotective phenotype are actually being studied, by acting on many different molecular targets, such as glycogen synthase kinase-3 (GSK3) β, AMP-activated protein kinase (AMPK), histone deacetylases (HDACs), etc. Furthermore, nutritional approaches can also modify microglia polarization and, consequently, impact cognitive function. Several bioactive compounds normally present in foods, such as polyphenols, can have anti-inflammatory effects on microglia. Both pharmacological and nutritional approaches seem to be promising, but still need further development. Here we review recent data on these approaches and propose that their combination could have a synergistic effect to counteract cognitive aging impairment and Alzheimer’s disease (AD) through immunomodulation of microglia polarization, i.e., by driving the shift of activated microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype.

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A unique type of GSK-3 inhibitor brings new opportunities to the clinic

Cited by 60 publications

References 85 publications

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

Alzheimer’s disease as an inflammatory disease

Nutritional and Pharmacological Strategies to Regulate Microglial Polarization in Cognitive Aging and Alzheimer’s Disease

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