Alterations in Expression of Glutamatergic Transporters and Receptors in Sporadic Alzheimer's Disease

Jacob, Christian; Koutsilieri, Eleni; Bartl, Jasmin; Neuen-Jacob, Eva; Arzberger, Thomas; Zander, Nicole E.; Ravid, Rivka; Roggendorf, Wolfgang; Riederer, Peter; Grünblatt, Edna

doi:10.3233/jad-2007-11113

Cited by 262 publications

(205 citation statements)

References 40 publications

Supporting

Mentioning

190

Contrasting

Order By: Relevance

“…Evidence of dysfunction of astrocytes in the LC region in individuals with MDD include reduced expression of SLC1A3, SLC1A2 and GFAP; lower GFAP protein levels; and reduced density of GFAP-positive astrocytes. Altered expression of glutamate transporter genes has been reported previously in a number of studies of neurodegenerative and psychiatric diseases, [32][33][34] including MDD. 20,35 The present study provides direct evidence of astrocyte pathology in the cell body region of a monoamine neurotransmitter, indicating that glia cell abnormalities reported in more superior/rostral brain regions in MDD 16,19 extend to the brainstem and may contribute to pathology of mono amine systems.…”

Section: Discussionmentioning

confidence: 99%

Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder

Chandley

Szebeni

et al. 2013

J Psychiatry Neurosci

View full text Add to dashboard Cite

IntroductionMajor depressive disorder (MDD) has a lifetime prevalence of 16% in the United States.1 Antidepressant drugs are the most used intervention for those with a diagnosis of depressive disorders, but the road to remission is long and uncertain, with 40% of patients never reaching full remission and at least 15% not experiencing any symptomatic improvements.2 Elucidating the biological bases of MDD is likely to provide novel targets for the development of more effective drugs, or at the very least, adjunctive treatments for existing antidepressants that increase the chance of remission.Speculation that norepinephrine plays a role in depressive disorders dates back to the early 1950s, and research since then increasingly supports this. The locus coeruleus (LC) in the pontine brainstem contains the cell bodies of the major source of norepinephrine in the brain and has been the subject of numerous investigations regarding the neuropathology of MDD.3 The human LC is an area with very high densities of radioligand binding of antidepressant drugs to monoamine oxidase, 4 the norepinephrine transporter 5 and the serotonin transporter.6 Numerous postmortem studies demonstrate abnormal neurochemistry of the noradrenergic LC in people with MDD and in people who died by suicide. A role of Background: Norepinephrine and glutamate are among several neurotransmitters implicated in the neuropathology of major depressive disorder (MDD). Glia deficits have also been demonstrated in people with MDD, and glia are critical modulators of central glutamatergic transmission. We studied glia in men with MDD in the region of the brain (locus coeruleus; LC) where noradrenergic neuronal cell bodies reside and receive glutamatergic input. Methods: The expression of 3 glutamate-related genes (SLC1A3, SLC1A2, GLUL) concentrated in glia and a glia gene (GFAP) were measured in postmortem tissues from men with MDD and from paired psychiatrically healthy controls. Initial gene expression analysis of RNA isolated from homogenized tissue (n = 9-10 pairs) containing the LC were followed by detailed analysis of gene expressions in astrocytes and oligodendrocytes (n = 6-7 pairs) laser captured from the LC region. We assessed protein changes in GFAP using immunohistochemistry and immunoblotting (n = 7-14 pairs). Results: Astrocytes, but not oligodendrocytes, demonstrated robust reductions in the expression of SLC1A3 and SLC1A2, whereas GLUL expression was unchanged. GFAP expression was lower in astrocytes, and we confirmed reduced GFAP protein in the LC using immunostaining methods. Limitations: Reduced expression of protein products of SLC1A3 and SLC1A2 could not be confirmed because of insufficient amounts of LC tissue for these assays. Whether gene expression abnormalities were associated with only MDD and not with suicide could not be confirmed because most of the decedents who had MDD died by suicide. Conclusion: Major depressive disorder is associated with unhealthy astrocytes in the noradrenergic LC, characterized here by a reduction in a...

show abstract

Section: Discussionmentioning

confidence: 99%

Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder

Chandley

Szebeni

et al. 2013

J Psychiatry Neurosci

View full text Add to dashboard Cite

show abstract

“…A significant reduction of GLT-1 activity has been reported to occur in an early stage of AD and correlates well with synaptic loss and cognitive decline in patients (Masliah et al, 1996). In addition, GLT-1 gene expression and protein levels are altered in the hippocampus of AD patients (Jacob et al, 2007). Recent studies further support the involvement of GLT-1 in AD by showing that the heterozygous knockdown of GLT-1 in an AD mouse model exacerbates cognitive decline without affecting Ab pathology and that astrocytic GLT-1 dysfunction plays an important role in human AD pathogenesis (Mookherjee et al, 2011;Woltjer et al, 2010).…”

Section: Introductionmentioning

confidence: 92%

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

Zumkehr

Rodriguez‐Ortiz

Cheng

et al. 2015

Neurobiology of Aging

130

106

View full text Add to dashboard Cite

TauAmyloid b a b s t r a c t Glial glutamate transporter, GLT-1, is the major Na þ -driven glutamate transporter to control glutamate levels in synapses and prevent glutamate-induced excitotoxicity implicated in neurodegenerative disorders including Alzheimer's disease (AD). Significant functional loss of GLT-1 has been reported to correlate well with synaptic degeneration and severity of cognitive impairment among AD patients, yet the underlying molecular mechanism and its pathological consequence in AD are not well understood.Here, we find the temporal decrease in GLT-1 levels in the hippocampus of the 3xTg-AD mouse model and that the pharmacological upregulation of GLT-1 significantly ameliorates the age-dependent pathological tau accumulation, restores synaptic proteins, and rescues cognitive decline with minimal effects on Ab pathology. In primary neuron and astrocyte coculture, naturally secreted Ab species significantly downregulate GLT-1 steady-state and expression levels. Taken together, our data strongly suggest that GLT-1 restoration is neuroprotective and Ab-induced astrocyte dysfunction represented by a functional loss of GLT-1 may serve as one of the major pathological links between Ab and tau pathology.

show abstract

“…Moreover, treatment of rat organotypic slices containing pyramidal neurons with Aβ oligomers decreased dendritic spine density and reduced NMDAR-mediated Ca 2+ influx (Shankar et al, 2007). In humans, Jacob and colleagues reported a downregulation of GluN1 subunit in brains of AD patients in various stages of the disease (Jacob et al, 2007).…”

Section: Synaptic and Extrasynaptic Localization And Activation Of Nmmentioning

confidence: 99%

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Mota¹,

Ferreira²,

Rego³

2014

Neuropharmacology

170

100

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly.Alterations capable of causing brain circuitry dysfunctions in AD may take several years to develop. Oligomeric amyloid-beta peptide (Aβ) plays a complex role in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in this devastating disease. Moreover, N-methyl-D-aspartate (NMDA) receptors (NMDARs) activation has been recently implicated in AD-related synaptic dysfunction. Thus, in this review we focus on glutamatergic neurotransmission impairment and the changes in NMDAR regulation in AD, following the description on the role and location of NMDARs at pre-and post-synaptic sites under physiological conditions. In addition, considering that there is currently no effective ways to cure AD or stop its progression, we further discuss the relevance of NMDARs antagonists to prevent AD symptomatology. This review posits additional information on the role played by Aβ in AD and the importance of targeting the tripartite glutamatergic synapse in early asymptomatic and possible reversible stages of the disease through preventive and/or disease-modifying therapeutic strategies.

show abstract

Alterations in Expression of Glutamatergic Transporters and Receptors in Sporadic Alzheimer's Disease

Cited by 262 publications

References 40 publications

Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder

Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder

Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Contact Info

Product

Resources

About