Impaired expression of GABA transporters in the human Alzheimer’s disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus

Fuhrer, Tessa E.; Palpagama, Thulani H.; Waldvogel, Henry J.; Synek, Beth J.; Turner, Clinton; Faull, Richard L.M.; Kwakowsky, Andrea

doi:10.1016/j.neuroscience.2017.03.041

Cited by 61 publications

(61 citation statements)

References 51 publications

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“…We have previously demonstrated complex brain region‐, cell layer‐, and cell type‐specific changes in the expression of BGT‐1, GAT‐1, and GAT‐3 in postmortem human AD tissue compared with healthy controls (Fuhrer et al . ). BGT‐1 expression was increased in all layers of the hippocampal dentate gyrus, in the stratum oriens of the CA2 and CA3 regions and throughout the superior temporal gyrus (Fuhrer et al .…”

Section: Drugs Targeting Gaba Transportersmentioning

confidence: 97%

“…We have shown previously that BGT‐1 is expressed at low levels in the healthy human hippocampus and is up‐regulated on astrocytes in AD cortical and hippocampal tissue (Fuhrer et al . ). The expression of the other GATs also shows brain region‐ and layer‐specific alterations in AD (Fuhrer et al .…”

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confidence: 97%

“…), and changes in GABA transporter expression have also been observed in the human AD hippocampus (Fuhrer et al . ). Various studies have described alterations in inhibitory currents and network activity in animal models, as well as in vitro cell systems and brain sections, and possible changes in GABA levels and glutamic acid decarboxylase (GAD) activity have been described in several brain regions (Lanctôt et al .…”

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confidence: 97%

“…The expression of the other GATs also shows brain region‐ and layer‐specific alterations in AD (Fuhrer et al . ) that might buffer changes in synaptic GABA levels and regulate the disturbances in E/I balance and neuronal excitability associated with AD. However, the mechanisms behind these changes and their functional consequences have to be further investigated.…”

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confidence: 99%

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The GABAergic system as a therapeutic target for Alzheimer's disease

Guzmán

Vinnakota

Govindpani

et al. 2018

Journal of Neurochemistry

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123

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Glutamatergic and cholinergic dysfunction are well-attested features of Alzheimer's disease (AD), progressing with other pathological indices of the disorder and exacerbating neuronal and network dysfunction. However, relatively little attention has been paid to the inhibitory component of the excitatory/inhibitory (E/I) network, particularly dysfunction in the gamma-aminobutyric acid (GABA) signaling system. There is growing evidence in support of GABAergic remodeling in the AD brain, potentially beginning in early stages of disease pathogenesis, and this could thus be a valid molecular target for drug development and pharmacological therapies. Several GABAergic drugs have been tested for efficacy in attenuating or reversing various features and symptoms of AD, and this could represent a novel path by which we might address the growing need for more effective and benign therapies.

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Section: Drugs Targeting Gaba Transportersmentioning

confidence: 97%

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confidence: 97%

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confidence: 97%

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confidence: 99%

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The GABAergic system as a therapeutic target for Alzheimer's disease

Guzmán

Vinnakota

Govindpani

et al. 2018

Journal of Neurochemistry

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123

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“…Altered levels and signaling of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter, is frequently reported in depression [1, 2], anxiety disorder [3], normal ageing [4], and neurodegenerative disorders, including Alzheimer’s disease [5], and in multiple brain regions including the prefrontal cortex [6] and anterior cingulate cortex [7]. Recent studies showed that such reductions of GABA levels in the human brain are associated with cognitive impairments in an age-dependent manner [8] and are further worsened during older age [9].…”

Section: Introductionmentioning

confidence: 99%

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Prevot¹,

Vidojević

et al. 2019

Complex Psychiatry

116

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Altered gamma-aminobutyric acid (GABA) function is consistently reported in psychiatric disorders, normal aging, and neurodegenerative disorders and reduced function of GABA interneurons is associated with both mood and cognitive symptoms. Benzodiazepines (BZ) have broad anxiolytic, but also sedative, anticonvulsant and amnesic effects, due to nonspecific GABA-A receptor (GABAA-R) targeting. Varying the profile of activity of BZs at GABAA-Rs is predicted to uncover additional therapeutic potential. We synthesized four novel imidazobenzodiazepine (IBZD) amide ligands and tested them for positive allosteric modulation at multiple α-GABAA-R (α-positive allosteric modulators), pharmacokinetic properties, as well as anxiolytic and antidepressant activities in adult mice. Efficacy at reversing stress-induced or age-related working memory deficits was assessed using a spontaneous alternation task. Diazepam (DZP) was used as a control. Three ligands (GL-II-73, GL-II-74, and GL-II-75) demonstrated adequate brain penetration and showed predictive anxiolytic and antidepressant efficacies. GL-II-73 and GL-II-75 significantly reversed stress-induced and age-related working memory deficits. In contrast, DZP displayed anxiolytic but no antidepressant effects or effects on working memory. We demonstrate distinct profiles of anxiolytic, antidepressant, and/or pro-cognitive activities of newly designed IBZD amide ligands, suggesting novel therapeutic potential for IBZD derivatives in depression and aging.

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Whole genome methylation sequencing in blood identifies extensive differential DNA methylation in late‐onset dementia due to Alzheimer's disease

Breen,

Papale,

Clark

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONDNA microarray‐based studies report differentially methylated positions (DMPs) in blood between late‐onset dementia due to Alzheimer's disease (AD) and cognitively unimpaired individuals, but interrogate < 4% of the genome.METHODSWe used whole genome methylation sequencing (WGMS) to quantify DNA methylation levels at 25,409,826 CpG loci in 281 blood samples from 108 AD and 173 cognitively unimpaired individuals.RESULTSWGMS identified 28,038 DMPs throughout the human methylome, including 2707 differentially methylated genes (e.g., SORCS3, GABA, and PICALM) encoding proteins in biological pathways relevant to AD such as synaptic membrane, cation channel complex, and glutamatergic synapse. One hundred seventy‐three differentially methylated blood‐specific enhancers interact with the promoters of 95 genes that are differentially expressed in blood from persons with and without AD.DISCUSSIONWGMS identifies differentially methylated CpGs in known and newly detected genes and enhancers in blood from persons with and without AD.Highlights Whole genome DNA methylation levels were quantified in blood from persons with and without Alzheimer's disease (AD). Twenty‐eight thousand thirty‐eight differentially methylated positions (DMPs) were identified. Two thousand seven hundred seven genes comprise DMPs. Forty‐eight of 75 independent genetic risk loci for AD have DMPs. One thousand five hundred sixty‐eight blood‐specific enhancers comprise DMPs, 173 of which interact with the promoters of 95 genes that are differentially expressed in blood from persons with and without AD.

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Impaired expression of GABA transporters in the human Alzheimer’s disease hippocampus, subiculum, entorhinal cortex and superior temporal gyrus

Cited by 61 publications

References 51 publications

The GABAergic system as a therapeutic target for Alzheimer's disease

The GABAergic system as a therapeutic target for Alzheimer's disease

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

Whole genome methylation sequencing in blood identifies extensive differential DNA methylation in late‐onset dementia due to Alzheimer's disease

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