Glutamate transporter variants reduce glutamate uptake in Alzheimer's disease

Scott, H. L.; Gebhardt, Florian M.; Mitrovic, Ann D.; Vandenberg, Robert J.; Dodd, Peter R.

doi:10.1016/j.neurobiolaging.2010.03.008

Cited by 151 publications

(129 citation statements)

References 46 publications

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“…Here, we show the opposite, namely, failure to detect the protein that is actually present. Postmortem proteolysis (as shown here) and variable splicing (e.g., Utsunomiya-Tate et al 1997;Münch et al 2003;Rauen et al 2004;Holmseth et al 2009;Scott et al 2011) can lead to loss of the epitopes recognized by the antibodies. In these cases, the transporters are there but go undetected with the antibodies used.…”

Section: Transporter-deficient Patches In Vivomentioning

confidence: 80%

The Rates of Postmortem Proteolysis of Glutamate Transporters Differ Dramatically between Cells and between Transporter Subtypes

Zhou

Danbolt

2012

J Histochem Cytochem.

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SummaryGlutamate transporters (GLT-1, GLAST, EAAC1) limit the actions of excitatory amino acids. Because a disturbed transporter operation can cause or aggravate neurological diseases, transporters are of considerable neuropathological interest. Human samples, however, are seldom obtained fresh. Here, we used mice brains to study how fast glutamate transporters are degraded after death. Immunoblots showed that terminal GLT-1 epitopes (within residues 1-26 and 518-573) had mostly disappeared after 24 hr. GLAST termini (1-25 and 522-543) degraded slightly slower. In contrast, epitopes within central parts of GLT-1 (493-508) and the EAAC1 C-terminus (510-523) were readily detectable after 72 hr. The decline in immunoreactivity of the GLT-1 and GLAST termini was also seen in tissue sections, but proteolysis did not happen synchronously in all cells. At 24 hr, scattered cells remained strongly immunopositive, while the majority of cells were completely immunonegative. GLAST and GLT-1 co-localized in neocortical tissue, but at 12 hr, many GLAST-positive cells had lost the GLT-1 termini. The uneven disappearance of labeling was not observed with the antibodies to GLT-1 residues 493-508. The immunoreactivity to this epitope correlated better with the reported glutamate uptake activity. Thus, postmortem delay may affect epitopes differently, possibly causing erroneous conclusions about relative expression levels. (J Histochem Cytochem 60:811-821, 2012)

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Section: Transporter-deficient Patches In Vivomentioning

confidence: 80%

The Rates of Postmortem Proteolysis of Glutamate Transporters Differ Dramatically between Cells and between Transporter Subtypes

Zhou

Danbolt

2012

J Histochem Cytochem.

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“…Nevertheless, this study showed that amyloid β peptide accumulates more in VGLUT1/2-containing terminals than in non-VGLUT terminals, thus suggesting that these peptides may preferentially affect presynaptic glutamatergic terminals in the cortex of individuals with Alzheimer disease. 58 The gene expression and protein level of EAAT1 and EAAT2, on the other hand, have also been shown to be reduced in the cortex and hippocampus of individuals with Alzheimer disease, 59,60,71 suggesting that glutamate clearance from the synaptic cleft is attenuated. In one study, it has been demonstrated that reduced levels of EAAT2, produced mainly by astrocytes, inversely correlates with APP751/770 mRNA levels, thus indicating that abnormal functioning and/or processing of APP may be involved in regulating EAAT2 levels/functions.…”

Section: Neuropathological Changes In the Glutamate System In Alzheimmentioning

confidence: 99%

“…Reduced protein levels before cell loss and onset of pathology [56][57][58] GLAST/EAAT1 Reduced protein at early clinical stages 59,60 GLT-1/EAAT2 Reduced protein levels at early clinical stages 59,60 Glutamine synthetase Reduced protein levels…”

Section: Vglut2mentioning

confidence: 99%

“…135 Second, amyloid β can activate α 7 nicotinic receptors or NMDA receptors and increase Ca 2+ entry into the cell. This • Increase long-term depression 98,[108][109][110] • Decrease synaptic density and alter the morphology of dendritic spines 98,106,107,115 • Regulate glutamate uptake from the synapse 60,73,110,116,117 • Stimulate release of glutamate 117,118 • Increase endocytosis of AMPA and NMDA receptors 108,119 • Disrupt the postsynaptic density and prevent NMDA and AMPA receptors reaching the cell surface 120,121 • Increase tau phosphorylation/cell death [122][123][124][125][126] AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA = N-methyl-D-aspartate.…”

Section: Amyloid β-Mediated Neuronal Function and Glutamatementioning

confidence: 99%

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Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

Revett

Baker

Jhamandas³

et al. 2013

J Psychiatry Neurosci

256

182

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“…Neuronal excitotoxicity leading to neuronal death [34,35] Hyperphosphorylated tau Formation of neurofibrillary tangles [36,37] Inflammation Exacerbation of tau pathology [38] , induction of Aβ release from neurons [39] , attenuation of long-term potentiation [40] , retraction of synapses [41] Metal ion dyshomeostasis Promotion of Aβ aggregation [42,43] Mutations in genes for presenillin-1 and -2, and Increased Aβ levels, linked to Aβ accumulation [44][45][46] amyloid precursor protein; ApoE 4 allele genotype Neurosci Bull February 1, 2013, 29(1): 111-120 114 thologies leads to increased Aβ production [67] . This finding may well explain the sporadic AD which does not involve mutations of genes implicated in Aβ generation.…”

Section: Glutamate Increasesmentioning

confidence: 99%

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

et al. 2012

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There is no effective drug to treat Alzheimer's disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.Keywords: Alzheimer's disease; amyloid-beta; neurotrophic factors; treatment IntroductionAlzheimer's disease (AD) is an age-related, progressive and irreversible neurodegenerative disease that causes serious cognitive dysfunction. Its pathological hallmarks are extracellular deposits of amyloid-beta (Aβ) and intracellular neurofibrillary tangles, together with drastic synaptic and neuronal reduction or loss [1] . It has been estimated that AD affects 30 million people around the world [2] , and the past two decades have witnessed an explosion in research into the underlying mechanisms as well as potential therapeutic strategies. Although it was first described by German psychiatrist Alois Alzheimer in 1906, there is still no cure for AD, partly because the cellular and molecular mechanisms underlying it are far from clear. The Food and Drug Administration in the United Stateshas approved a limited range of drugs to treat AD, including acetylcholinesterase inhibitors (AChEIs) and N-methyl-Daspartate receptor (NMDAR) antagonists [3] , although their effects are merely symptomatic and memory-improvement occurs within a limited period. Donepezil, galantamine, rivastigmine and tacrine are AChEIs that prevent the breakdown of acetylcholine released from presynaptic terminals, increasing the residence time of the neurotransmitter within the synapse and thereby prolonging the duration of its interaction with postsynaptic receptors [4] . Memantine, an NMDAR antagonist, has been approved for the treatment of moderate and severe AD; it works by preventing the excitatory neurotoxicity induced by excessive glutamate [5] .Currently, no available pharmacological agents cure or reverse the progression of this devastating neurological disorder. It is therefore urgent to improve our understanding of its pathogenesis, and then develop an effective treatment strategy. This review aimed to provide insights Neurosci Bull February 1, 2013, 29(1): 111-120 112 into the design of potentially effective pharmaceutical treatments for AD by targeting two seemingly separate but tightly connected components, Aβ and neurotrophic factors (NTFs). Aβ as a Promising Target for AD TreatmentAβ is a peptide of 36-43 amino-acids produced from amyloid precursor protein (APP) through aberrant cleavage by...

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Glutamate transporter variants reduce glutamate uptake in Alzheimer's disease

Cited by 151 publications

References 46 publications

The Rates of Postmortem Proteolysis of Glutamate Transporters Differ Dramatically between Cells and between Transporter Subtypes

The Rates of Postmortem Proteolysis of Glutamate Transporters Differ Dramatically between Cells and between Transporter Subtypes

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

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