Evidence for astrocytosis in ALS demonstrated by [11C](l)-deprenyl-D2 PET

Johansson, Anders; Engler, Henry; Blomquist, Gunnar; Scott, Berit; Wall, Anders; Aquilonius, Sten–Magnus; Långström, Bengt; Askmark, Håkan

doi:10.1016/j.jns.2007.01.057

Cited by 120 publications

(92 citation statements)

References 43 publications

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“…Recent PET studies reported significant increase in DED binding in patients with moderate to severe AD compared with healthy control subjects [1]. Similar results were reported in other neurodegenerative disorders such as ALS [26] and Creutzfeldt-Jakob disease [27]. These findings suggest that in vivo imaging of activated astrocytes is a promising additional tool useful to assess prognosis and monitoring disease activity and treatment.…”

Section: Monoamine Oxidasesupporting

confidence: 66%

Imaging of neuroinflammation

Ciarmiello

2011

Eur J Nucl Med Mol Imaging

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Section: Monoamine Oxidasesupporting

confidence: 66%

Imaging of neuroinflammation

Ciarmiello

2011

Eur J Nucl Med Mol Imaging

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“…During disease progression in humans and in mouse models of the disease, death of motor neurons is not accompanied by astrocyte loss. On the contrary, astrocytosis (46) and proliferation of reactive astrocytes (47) have been reported in the spinal cord of both humans and ALS mice (46,47). Caspase-3 proteolytic cleavage of EAAT2 presumably occurs through a controlled activation of caspase-3 in astrocytes, since we observed that the cleaved EAAT2 fragment accumulates during the disease, thus negating astrocyte death.…”

Section: Discussionmentioning

confidence: 46%

A Caspase-3-cleaved Fragment of the Glial Glutamate Transporter EAAT2 Is Sumoylated and Targeted to Promyelocytic Leukemia Nuclear Bodies in Mutant SOD1-linked Amyotrophic Lateral Sclerosis

Gibb

Boston-Howes

Lavina³

et al. 2007

Journal of Biological Chemistry

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EAAT2 (excitatory amino acid transporter 2) is a high affinity, Na؉ -dependent glutamate transporter of glial origin that is essential for the clearance of synaptically released glutamate and prevention of excitotoxicity. During the course of human amyotrophic lateral sclerosis (ALS) and in a transgenic mutant SOD1 mouse model of the disease, expression and activity of EAAT2 is remarkably reduced. We previously showed that some of the mutant SOD1 proteins exposed to oxidative stress inhibit EAAT2 by triggering caspase-3 cleavage of EAAT2 at a single defined locus. This gives rise to two fragments that we termed truncated EAAT2 and COOH terminus of EAAT2 (CTE). In this study, we report that analysis of spinal cord homogenates prepared from mutant G93A-SOD1 mice reveals CTE to be of a higher molecular weight than expected because it is conjugated with SUMO-1. The sumoylated CTE fragment (CTE-SUMO-1) accumulates in the spinal cord of these mice as early as presymptomatic stage (70 days of age) and not in other central nervous system areas unaffected by the disease. The presence and accumulation of CTE-SUMO-1 is specific to ALS mice, since it does not occur in the R6/2 mouse model for Huntington disease. Furthermore, using an astroglial cell line, primary culture of astrocytes, and tissue samples from G93A-SOD1 mice, we show that CTE-SUMO-1 is targeted to promyelocytic leukemia nuclear bodies. Since one of the proposed functions of promyelocytic leukemia nuclear bodies is regulation of gene transcription, we suggest a possible novel mechanism by which the glial glutamate transporter EAAT2 could contribute to the pathology of ALS. Amyotrophic lateral sclerosis (ALS)4 is a fatal neurodegenerative disease, resulting from a progressive death of cortical and spinal motor neurons. About 90% of ALS cases are sporadic, whereas the remaining 10% are inherited in a dominant manner (familial ALS). Transgenic expression of high levels of human mutant SOD1 (mutSOD1) proteins in mice and rats leads to a progressive motor neuron disease that shares most of the clinical features of ALS (1, 2). Astrocytes are essential partners of motorneurons, providing them with trophic support (3) and mediating rapid clearance of synaptic glutamate mainly through the action of glial glutamate transporters. The EAAT2 (excitatory amino acid transporter 2) glial isoform of glutamate transporters accounts for ϳ95% of total glutamate uptake activity in the brain (4). Studies in mutSOD1 mice and in in vitro models of ALS affirmed a role for astroglial involvement in motorneuron death and suggested that motorneuron loss is also the result of toxic contributions of nonneuronal cells of the spinal cord (5-8). Reactive astrocytes surrounding motorneurons contain protein inclusions; express inflammatory markers, such as the inducible forms of nitric oxide synthase and cycloxygenase-2; and display increased neural growth factor synthesis (9), nitrotyrosine immunoreactivity, and down-regulation of EAAT2. Excitotoxicity caused by consistent reduction in expres...

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“…Because this was a clinical study, it was not considered feasible to obtain arterial blood samples as an input function for the 11 C-DED modeling. As such, a modified reference-Patlak model was adopted for kinetic analysis (14).…”

Section: C-ded Modelingmentioning

confidence: 99%

“…The PET tracer 11 C-deuterium-L-deprenyl ( 11 C-DED) has high affinity and specificity for MAO-B (11); a previous PET study with 11 C-DED has shown that MAO-B increases in most brain regions in healthy older individuals (12). Thus far, studies using 11 C-DED PET have been performed in chronic diseases such as epilepsy, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease (13)(14)(15)(16). These studies revealed changes in 11 C-DED binding related to the epileptic lobe; increased 11 C-DED binding in the white matter and pons (amyotrophic lateral sclerosis); and increased 11 C-DED binding in the frontal, parietal, and occipital cortices (Creutzfeldt-Jakob disease).…”

mentioning

confidence: 99%