Positive allosteric activation of glial EAAT-2 transporter protein: A novel strategy for Alzheimer’s disease

Manisha, Chennu; Ayyamperumal, Selvaraj; Selvaraj, Jubie; Nanjan, Chandrasekar Moola Joghee; Joghee, Nanjan Moola; Clement, James P.; Justin, Antony

doi:10.1016/j.mehy.2020.109794

Cited by 4 publications

(5 citation statements)

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“…Animal studies have suggested that Aβ may be responsible for decreases in EAAT2 expression (Takahashi et al, 2015 ; Huang et al, 2018 ). In addition, amyloid-beta administration has been shown to result in the mislocalization of EAAT2 (Manisha et al, 2020 ). However, it is uncertain if this is the reason behind EAAT2 alterations (both expressional and qualitative) previously documented in AD postmortem tissue (Li et al, 1997 ; Abdul et al, 2009 ; Hoshi et al, 2018 ; Yeung et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Other methods of EAAT2 modulation have also been explored. A recent medical hypothesis published by Manisha et al ( 2020 ) described increasing EAAT2 activity by promoting glutamate ligand binding through allosteric modulator GT949. Enhancement of glutamate ligand binding is effective in promoting EAAT2 activity independent of substrate pharmacokinetics (Kortagere et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…Based on early previous evidence from radiolabeling, an ∼30% reduction in [ 3 H] aspartate binding was revealed in the postmortem AD brain, signaling a significant dysfunction in glutamate uptake (Masliah et al, 1996). This is likely to play a role in AD progression, with implications such as glutamate excitotoxicity, a well-documented concept in the literature (Conway, 2020;Manisha et al, 2020). However, how this might relate to EAAT2 expression in the human AD brain is still unclear.…”

Section: Eaat Protein Expressionmentioning

confidence: 99%

“…Translational activation of EAAT2 Kong et al, 2014;Takahashi et al, 2015;Zumkehr et al, 2015;Fan et al, 2018;Hamidi et al, 2019;Manisha et al, 2020 Allosteric modulation to promote glutamate binding Manisha et al, 2020 Restore aberrant mislocalization of EAAT2 Scimemi et al, 2013 for other neurodegenerative disorders might also be useful as potential drugs for AD. Riluzole, currently approved for the management of amyotrophic lateral sclerosis, has been shown to promote activation of EAAT2 translation and reducing excitotoxic cellular injury in cultured neurons (Kong et al, 2014).…”

Section: Referencesmentioning

confidence: 99%

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EAAT2 as a therapeutic research target in Alzheimer's disease: A systematic review

et al. 2022

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Glutamate is the main excitatory neurotransmitter in the human central nervous system, responsible for a wide variety of normal physiological processes. Glutamatergic metabolism and its sequestration are tightly regulated in the normal human brain, and it has been demonstrated that dysregulation of the glutamatergic system can have wide-ranging effects both in acute brain injury and neurodegenerative diseases. The excitatory amino acid transporter 2 (EAAT2) is the dominant glutamatergic transporter in the human brain, responsible for efficient removal of glutamate from the synaptic cleft for recycling within glial cells. As such, it has a key role in maintaining excitatory-inhibitory homeostasis. Animal studies have demonstrated dysregulation or alterations of EAAT2 expression can have implications in neurodegenerative disorders. Despite extensive research into glutamatergic alterations in AD mouse models, there is a lack of studies examining the expression of EAAT2 within the AD human brain. In this systematic review, 29 articles were identified that either analyzed EAAT2 expression in the AD human brain or used a human-derived cell culture. Studies were inconclusive as to whether EAAT2 was upregulated or downregulated in AD. However, changes in localization and correlation between EAAT2 expression and symptomatology was noted. These findings implicate EAAT2 alterations as a key process in AD progression and highlight the need for further research into the characterization of EAAT2 processes in normal physiology and disease in human tissue and to identify compounds that can act as EAAT2 neuromodulators.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Eaat Protein Expressionmentioning

confidence: 99%

Section: Referencesmentioning

confidence: 99%

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EAAT2 as a therapeutic research target in Alzheimer's disease: A systematic review

et al. 2022

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“…Although both glia and neurons express EAATs, it is currently posited that glial EAATs have a much stronger capacity for transporting glutamate than that of neuronal EAATs. − In particular, the astrocytic glutamate transporter subtype EAAT2 mediates 90% of glutamate uptake in the brain. − EAAT2 is highly expressed in astrocytes within the cerebellum and hippocampus , as well as in neurons throughout the brain . Moreover, the high expression of EAAT2 in the axonal terminals of hippocampal neurons plays an important role in maintaining synaptic glutamate homeostasis and in regulating mitochondrial function. , Several recent studies have reported that abnormal functioning or expression of EAAT2 is involved in the pathogenesis of multiple psychiatric and neurological disorders, such as Parkinson’s disease (PD), , Alzheimer’s disease (AD), − Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), ,, epilepsy, , and traumatic brain injury (TBI) . In addition, EAATs are electrogenic for the transport of glutamate, − involving the cotransport of 3 Na + and 1 H + and the reverse transport of 1 K + …”

Section: Introductionmentioning

confidence: 99%

Conformationally Sensitive Proximity Between the TM3–4 Loop and Hairpin Loop 2 of the Glutamate Transporter EAAT2 Revealed by Paired-Cysteine Mutagenesis

Wang

2020

ACS Chem. Neurosci.

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Excitatory amino acid transporters (EAATs) serve to maintain extracellular neurotransmitter concentrations below neurotoxic levels by transporting glutamate from the synaptic cleft into apposed glia and neurons. Although the crystal structures of the archaeal EAAT homologue from Pyrococcus horikoshii, GltPh, and the human glutamate transporter, EAAT1cryst, have been resolved, the transport mechanism of the transmembrane 3–4 (TM3–4) loop and its structural rearrangement during transport have remained poorly understood. In order to explore the spatial position and function of the TM3–4 loop in the transport cycle, we engineered a pair of cysteine residues between the TM3–4 loop and hairpin loop 2 (HP2) in cysteine-less EAAT2 (CL-EAAT2). We observed that the oxidative cross-linking reagent Cu(II)(1,10-phenanthroline)3 (CuPh) had a significant inhibitory effect on transport in the disubstituted A167C/G437C mutant, whereas dl-dithiothreitol (DTT) reversed the effect of cross-linking A167C/G437C on transport activity, as assayed by d-[3H]-aspartate uptake. Furthermore, we found that the effect of CuPh in this mutant was due to the formation of disulfide bonds in the transporter molecule. Moreover, dl-threo-β-benzyloxyaspartic acid (TBOA) attenuated, while l-glutamate or KCl enhanced, the CuPh-mediated inhibitory effect in the A167C/G437C mutant, suggesting that the A167C and G437C cysteines were farther apart in the outward-facing configuration and closer in the inward-facing configuration. Taken together, our findings provide evidence that the TM3–4 loop and HP2 change spatial proximity during the transport cycle.

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Metabolic Regulation of Glia and Their Neuroinflammatory Role in Alzheimer's Disease

2021

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Positive allosteric activation of glial EAAT-2 transporter protein: A novel strategy for Alzheimer’s disease

Cited by 4 publications

References 69 publications

EAAT2 as a therapeutic research target in Alzheimer's disease: A systematic review

EAAT2 as a therapeutic research target in Alzheimer's disease: A systematic review

Conformationally Sensitive Proximity Between the TM3–4 Loop and Hairpin Loop 2 of the Glutamate Transporter EAAT2 Revealed by Paired-Cysteine Mutagenesis

Metabolic Regulation of Glia and Their Neuroinflammatory Role in Alzheimer's Disease

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