Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ

Ittner, Arne; Asih, Prita R.; Tan, Amanda R. P.; Prikas, Emmanuel; Bertz, Josefine; Stefanoska, Kristie; Lin, Y.; Volkerling, Alexander; Ke, Yazi D.; Delerue, Fabien; Ittner, Lars M.

doi:10.1007/s00401-020-02191-1

Cited by 28 publications

(47 citation statements)

References 67 publications

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“…This phosphorylation event results in disruption of the PSD-95-tau complex and inhibits toxic signals of Aβ (Ittner et al, 2016). Thus, this mechanism involving post-synaptic p38γ showed a novel neuroprotective function for this p38 kinase and revealed an unprecedented function of tau phosphorylation in inhibiting a pivotal toxicity mechanism of Aβ (Ittner and Ittner, 2018;Ittner et al, 2020). Interestingly, neither p38α, p38β nor p38δ were able to mediate the same neuroprotective tau phosphorylation and inhibition of Aβ toxicity as p38γ (Ittner et al, 2016), likely due to the distinct localization of p38γ in neurons at post-synapses (Sabio et al, 2005;Ittner et al, 2016).…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 96%

Functions of p38 MAP Kinases in the Central Nervous System

Asih

Prikas

Stefanoska

et al. 2020

Front. Mol. Neurosci.

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111

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Mitogen-activated protein (MAP) kinases are a central component in signaling networks in a multitude of mammalian cell types. This review covers recent advances on specific functions of p38 MAP kinases in cells of the central nervous system. Unique and specific functions of the four mammalian p38 kinases are found in all major cell types in the brain. Mechanisms of p38 activation and downstream phosphorylation substrates in these different contexts are outlined and how they contribute to functions of p38 in physiological and under disease conditions. Results in different model organisms demonstrated that p38 kinases are involved in cognitive functions, including functions related to anxiety, addiction behavior, neurotoxicity, neurodegeneration, and decision making. Finally, the role of p38 kinases in psychiatric and neurological conditions and the current progress on therapeutic inhibitors targeting p38 kinases are covered and implicate p38 kinases in a multitude of CNS-related physiological and disease states.

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Section: Alzheimer's Disease (Ad)mentioning

confidence: 96%

Functions of p38 MAP Kinases in the Central Nervous System

Asih

Prikas

Stefanoska

et al. 2020

Front. Mol. Neurosci.

Self Cite

111

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“…Interestingly, and in contrast to p38α (and p38β), p38g has a protective effect in AD mice [ 316 ]. This protective effect involves phosphorylation of Tau by p38γ at Ser205 which results in disruption of postsynaptic excitotoxic protein signaling complexes activated by Aβ [ 316 , 317 ]. Neuronal deletion of p38γ in AD mice results in exacerbation of neural circuitry degeneration and cognitive defects as well as premature lethality, demonstrating a protective role for p38γ in AD [ 316 ].…”

Section: The Enzymesmentioning

confidence: 99%

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

D’Mello¹

2021

IJMS

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Alzheimer’s disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington’s disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.

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“…In fact, anisomycin administration produced a time-dependent decline in field excitatory post-synaptic potentials (fEPSPs) amplitude in acute brain slices of V1, and this decline could be rescued by the application of SB203580 [42]. However, SB203580 is proposed as a multi-target kinase inhibitor, which makes its use in support of a specific p38MAPK biological role more questionable [43].…”

Section: P38 Mapk and Synaptic Functionmentioning

confidence: 99%

“…An opposite role in neurodegeneration emerged for p38γ MAPK. This isoform mediates phosphorylation on tau at Threonine-205 (T205), a site-specific phosphorylation that improved memory deficits in APP transgenic mice [43], in particular interfering with the synaptic action of Aβ on glutamatergic neurotransmission [74,75].…”

Section: P38 Mapk Ad Neurodegeneration and Synaptic Dysfunctionmentioning

confidence: 99%

Involvement of p38 MAPK in Synaptic Function and Dysfunction

Falcicchia

Tozzi

Arancio

et al. 2020

IJMS

135

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Many studies have revealed a central role of p38 MAPK in neuronal plasticity and the regulation of long-term changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). However, p38 MAPK is classically known as a responsive element to stress stimuli, including neuroinflammation. Specific to the pathophysiology of Alzheimer’s disease (AD), several studies have shown that the p38 MAPK cascade is activated either in response to the Aβ peptide or in the presence of tauopathies. Here, we describe the role of p38 MAPK in the regulation of synaptic plasticity and its implication in an animal model of neurodegeneration. In particular, recent evidence suggests the p38 MAPK α isoform as a potential neurotherapeutic target, and specific inhibitors have been developed and have proven to be effective in ameliorating synaptic and memory deficits in AD mouse models.

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Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ

Cited by 28 publications

References 67 publications

Functions of p38 MAP Kinases in the Central Nervous System

Functions of p38 MAP Kinases in the Central Nervous System

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

Involvement of p38 MAPK in Synaptic Function and Dysfunction

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