A hydrocortisone derivative binds to GAPDH and reduces the toxicity of extracellular polyglutamine-containing aggregates

Lazarev, Vladimir F.; Mikhaylova, Elena R.; Dutysheva, Elizaveta A.; Суезов, Роман В.; Guzhova, Irina V.; Margulis, Boris A.

doi:10.1016/j.bbrc.2017.04.125

Cited by 11 publications

(14 citation statements)

References 20 publications

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“…Emerging as a signi cant pathological factor in the late stages of AD, GAPDH may also be used as a promising therapeutic target. Indeed, we show here that hydrocortisone 21-hemisuccinate (RX-624), which speci cally binds GAPDH and diminishes its aggregation [36], has drastically reduced the accumulation of aggregated Aβ in hippocampi of 5XFAD mice and greatly improved their spatial memory. Earlier, our group has reported that RX-624 also reduces the cytotoxicity of the extracellular GAPDH-polyQ complexes [36].…”

Section: Discussionmentioning

confidence: 91%

“…Indeed, we show here that hydrocortisone 21-hemisuccinate (RX-624), which speci cally binds GAPDH and diminishes its aggregation [36], has drastically reduced the accumulation of aggregated Aβ in hippocampi of 5XFAD mice and greatly improved their spatial memory. Earlier, our group has reported that RX-624 also reduces the cytotoxicity of the extracellular GAPDH-polyQ complexes [36]. Thus RX-624 may be a constituent of a novel class of anti-neurodegeneration therapeutic molecules that diminish the propagation of cytotoxic heterologous protein aggregates, a hypothesis that warrants further exploration in other animal models involving larger mammals.…”

Section: Discussionmentioning

confidence: 91%

“…Previously, we have showed that a cortisol derivative (Fig. 6a), hydrocortisone 21-hemisuccinate (RX-624), speci cally binds GAPDH and reduces its aggregation [36]. To test whether RX-624 is capable of reducing aggregation of Aβ-GAPDH complexes as well, we mixed Aβ42, GAPDH and tTG in the presence of 0.3, 1.0 and 3.0 µM of RX-624 followed by ultra ltration and immunoblotting.…”

Section: Gapdh Ligand Reduces Aβ Aggregation and Ameliorates Spatial mentioning

confidence: 99%

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Extracellular GAPDH promotes Alzheimer disease progression by enhancing amyloid-β aggregation and cytotoxicity

Lazarev

Tsolaki

Mikhaylova

et al. 2020

Preprint

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Background Neuronal cell death during Alzheimer disease (AD) causes the release of cytosolic proteins, particularly glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which forms highly cytotoxic detergent-insoluble complexes with amyloid-β (Aβ) and promotes neurodegeneration. Methods We detected and quantified the complex formation between Aβ and GAPDH released from brain tissue of patients with AD using ultrafiltration, and fluorescence resonance energy transfer (FRET). To explore the biochemical and structural features of Aβ-GAPDH complexes we employed novel immunoenzyme assays and atomic force microscopy. Lentiviral infection in situ was used to elevate GAPDH in brain tissue of rat and mouse models of AD. The Morris maize water test, MRI, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and lactate dehydrogenase (LDH)-activity assays were used to characterize the effects of Aβ-GAPDH complexes in animal and cellular models of AD. Results Here we report that GAPDH forms stable aggregates with extracellular Aβ. We detected these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD. We found that GAPDH forms a covalent bond with Q15 of Aβ that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between Aβ and GAPDH and reduces Aβ-GAPDH cytotoxicity. Lentivirus-driven GAPDH overexpression in two AD animal models increased the level of apoptosis of hippocampal neurons, neuronal degeneration, and cognitive dysfunction. In contrast, in vivo knockdown of GAPDH reversed these pathogenic abnormalities suggesting a pivotal role of GAPDH in Aβ-stimulated neurodegeneration. CSF obtained from animals with enhanced GAPDH expression demonstrated increased cytotoxicity in vitro . Furthermore, RX-624, a specific GAPDH small molecular ligand reduced accumulation of Aβ aggregates and reversed memory deficit in AD transgenic mice. Conclusions Extracellular GAPDH compromises Aβ clearance and accelerates neurodegeneration, thus representing a promising pharmacological target for AD.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 91%

Section: Gapdh Ligand Reduces Aβ Aggregation and Ameliorates Spatial mentioning

confidence: 99%

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Extracellular GAPDH promotes Alzheimer disease progression by enhancing amyloid-β aggregation and cytotoxicity

Lazarev

Tsolaki

Mikhaylova

et al. 2020

Preprint

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“…The data presented in this article demonstrate that different fractions of pre-denatured GAPDH may cause apoptotic processes in neuroblastoma cells. We used the GAPDH binder RX624 to preserve cells from exogenous GAPDH [2] , [3] . This paper contains data showing the ability of RX624 to affect the apoptosis induced by exogenous GAPDH.…”

Section: Datamentioning

confidence: 99%

Hydrocortisone 21-hemisuccinate did not prevent exogenous GAPDH-induced apoptosis in human neuroblastoma cells

et al. 2018

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These data are related to our paper “GAPDH-targeted therapy – a new approach for secondary damage after traumatic brain injury on rats” (Lazarev et al., In press), in which we explore the role of exogenous GAPDH in traumatic brain injury-induced neuron death, and the therapeutic application of small molecules that bind to the enzyme. The current article demonstrates the induction of apoptosis by exogenous GAPDH and the effectiveness of the hydrocortisone derivative for suppressing the pathogenic action of the enzyme.

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“…GAPDH is a homo-tetramer and one of the cellular proteins abnormally enriched by reactive sulfhydryl groups; this explains the unusually high aggregation capacity of the S-nitrosylated or oxidized protein. Importantly, these modifications have a significant impact on a great variety of neurodegenerative processes [3,4]. The enzyme catalyzes the glycolytic reaction resulting in the creation of macroergic products and NADH, which are used further in reactions of oxidative phosphorylation [5].…”

Section: Introductionmentioning

confidence: 99%

Glyceraldehyde-3-phosphate Dehydrogenase Is a Multifaceted Therapeutic Target

2020

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme whose role in cell metabolism and homeostasis is well defined, while its function in pathologic processes needs further elucidation. Depending on the cell context, GAPDH may bind a number of physiologically important proteins, control their function and correspondingly affect the cell’s fate. These interprotein interactions and post-translational modifications of GAPDH mediate its cytotoxic or cytoprotective functions in the manner of a Janus-like molecule. In this review, we discuss the functional features of the enzyme in cellular physiology and its possible involvement in human pathologies. In the last part of the article, we describe drugs that can be employed to modulate this enzyme’s function in some pathologic states.

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A hydrocortisone derivative binds to GAPDH and reduces the toxicity of extracellular polyglutamine-containing aggregates

Cited by 11 publications

References 20 publications

Extracellular GAPDH promotes Alzheimer disease progression by enhancing amyloid-β aggregation and cytotoxicity

Extracellular GAPDH promotes Alzheimer disease progression by enhancing amyloid-β aggregation and cytotoxicity

Hydrocortisone 21-hemisuccinate did not prevent exogenous GAPDH-induced apoptosis in human neuroblastoma cells

Glyceraldehyde-3-phosphate Dehydrogenase Is a Multifaceted Therapeutic Target

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