Structure- and ligand-based drug design of novel p38-alpha MAPK inhibitors in the fight against the Alzheimer’s disease

Pinsetta, Flávio Roberto; Taft, Carlton A.; Silva, Carlos Henrique Tomich de Paula da

doi:10.1080/07391102.2013.803441

Cited by 23 publications

(13 citation statements)

References 58 publications

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“…Recently, MAPK signaling was shown to promote NMNAT2 turnover, and inhibiting this signaling cascade increased NMNAT2 levels in Drosophila and mammalian motoneurons46. Interestingly, p38 MAPK activity has been associated with the hallmarks of AD and tau hyperphosphorylation47. Inhibitors of p38- α-MAPK have been shown to attenuate the inflammatory response and synaptic dysfunction seen in AD mouse models through unknown mechanisms48.…”

Section: Discussionmentioning

confidence: 99%

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Ali

Bradley

2017

Sci Rep

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Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

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Section: Discussionmentioning

confidence: 99%

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Ali

Bradley

2017

Sci Rep

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“…Based on the early observation of aberrant MAPK signaling (e.g., ERK, p38) in human AD brains and AD mouse models (Dineley et al, 2001; Dineley et al, 2002; Hensley et al, 1999; Hyman, Elvhage, & Reiter, 1994; Savage, Lin, Ciallella, Flood, & Scott, 2002; Zhu et al, 2000), aberrant MAPK activity has long been thought to be a significant contributor to AD. Furthermore, the age-dependent induction of CNS p38α activity that drives stress signals to promote neuroinflammation and cognitive impairment in AD and the converse outcome of acute inhibition of p38α activity that improved spatial memory in AD mouse models (Ashabi, Alamdary, Ramin, & Khodagholi, 2013; Ashabi et al, 2012) has driven recent pursuits of p38α inhibitors as a therapeutic strategy (Bachstetter & Van Eldik, 2010; Munoz & Ammit, 2010; Pinsetta et al, 2014). …”

Section: 0 Discussionmentioning

confidence: 99%

“…It is not surprising then that p38α MAPK represents an actively pursued therapeutic target for age-dependent cell senescence, neuroinflammation, and AD (Bachstetter & Van Eldik, 2010; Munoz & Ammit, 2010; Pinsetta, Taft, & de Paula da Silva, 2014). In the present study, we evaluated aged DN-p38α AF/+ and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline.…”

Section: 0 Introductionmentioning

confidence: 99%

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning

Cortez

Bulavin

et al. 2017

Behavioural Brain Research

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A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38αAF/+ ) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38αAF/+) and kinase activity. As a result, aged DN-p38αAF/+ mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer’s disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual’s relative risk. In the present study, we evaluated aged DN-p38αAF/+ and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38αAF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38αAF/+ exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38αAF/+, we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38αAF/+ mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD.

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“…Small molecule inhibitors of GSK-3β might be potent to reduce Aβ-induced tau hyperphosphorylation (Noh et al, 2013; Ye et al, 2013). Given the contribution of other kinases to tau hyperphosphorylation, effective treatment may require multiple kinase targeting (Mazanetz and Fischer, 2007; Tell and Hilgeroth, 2013; Pinsetta et al, 2014). …”

Section: Phosphorylation As a Target For Therapeutic Interventionmentioning

confidence: 99%

Protein phosphorylation in neurodegeneration: friend or foe?

Tenreiro¹,

Eckermann

Outeiro

2014

Front. Mol. Neurosci.

219

197

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Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD). In these disorders, the misfolding and aggregation of specific proteins occurs alongside neuronal degeneration in somewhat specific brain areas, depending on the disorder and the stage of the disease. However, we still do not fully understand the mechanisms governing protein aggregation, and whether this constitutes a protective or detrimental process. In PD, alpha-synuclein (aSyn) forms protein aggregates, known as Lewy bodies, and is phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but the significance of phosphorylation in the biology and pathophysiology of the protein is still controversial. In AD and in FTD, hyperphosphorylation of tau protein causes its misfolding and aggregation. Again, our understanding of the precise consequences of tau phosphorylation in the biology and pathophysiology of the protein is still limited. Through the use of a variety of model organisms and technical approaches, we are now gaining stronger insight into the effects of phosphorylation in the behavior of these proteins. In this review, we cover recent findings in the field and discuss how targeting phosphorylation events might be used for therapeutic intervention in these devastating diseases of the nervous system.

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Structure- and ligand-based drug design of novel p38-alpha MAPK inhibitors in the fight against the Alzheimer’s disease

Cited by 23 publications

References 58 publications

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning

Protein phosphorylation in neurodegeneration: friend or foe?

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