GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

Xu, Yilan; Zhao, Man-Na; Han, Yong Chol; Zhang, Heng

doi:10.3389/fnins.2020.00660

Cited by 140 publications

(134 citation statements)

References 273 publications

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“…In addition, there has been found Aβ injection impaired synaptic plasticity in association with mTOR signaling, confirming the mediating role of this protein complex in Aβ-mediated synaptic dysfunction [ 381 ]. Another neurotransmitter homeostasis is also altered in AD pathogenesis: Aβ has shown to conduct dysfunction and loss of GABAergic inhibitory interneurons [ 386 , 387 ], although more studies are needed to unravel the molecular mechanisms underlying this alteration.…”

Section: The Relation Between T2dm and Ad: A Molecular Approachmentioning

confidence: 99%

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Burillo

Marqués

Jiménez

et al. 2021

Cells

100

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Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

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Section: The Relation Between T2dm and Ad: A Molecular Approachmentioning

confidence: 99%

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Burillo

Marqués

Jiménez

et al. 2021

Cells

100

View full text Add to dashboard Cite

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“…The n5 sub-cluster includes layer I, II, and VI VIP+ interneurons, which have not been shown to be impaired in AD [52]. We found multiple glycolysis metabolites as different between AD and control conditions (Fig.…”

Section: Neuron Subtype-specific Analysis Reveals Unique Metabolic Expression Changes In Admentioning

confidence: 66%

Identifying neuron subtype-specific metabolic network changes in single cell transcriptomics of Alzheimer’s Disease using perturb-Met

Wang

2021

Preprint

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Metabolic aberrations are a prominent feature of Alzheimer’s Disease (AD). Different neuronal subtypes have selective vulnerability in AD. Despite the recent advance of single cell and single nucleus RNA-seq of AD brains, genome-scale metabolic network changes in neuronal subtypes have not been systematically studied with detail. To bridge this knowledge gap, I developed a computational method called perturb-Met that can uncover transcriptional dysregulation centered at hundreds of metabolites in a metabolic network. perturb-Met successfully recapitulated known glycolysis, cholesterol, and other metabolic defects in APOE4-neurons and microglia, many of which are missed by current methods. Applying perturb-Met on AD snRNA-seq data, I revealed that the four neuronal subtypes in the entorhinal cortex shows subtype-specific metabolic changes, namely mitochondrial complex I metabolism, ganglioside metabolism, galactose and heparan sulfate metabolism, as well as glucose and lipid metabolism, respectively. perturb-Met also revealed significant changes in protein glycosylation in the neuron subtype specifically found in AD brains. These subtype-specific metabolic changes may potentially underlie their selective vulnerability in AD. perturb-Met is a valuable tool to discover potential metabolic network changes in many other single cell or bulk transcriptomic studies.

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“…In addition to increases in excitatory synaptic transmission, disruption of inhibitory synaptic transmission in the LEC is thought to contribute to excitotoxicity ( Xu et al, 2020 ). In a knock-in mouse model of AD expressing a mutant form of human Aβ precursor protein, cells in LEC show loss of parvalbumin containing interneurons that regulate excitability, leading to hyperexcitability of principle neuron and increases in EPSPs, and the disruption of parvalbumin neurons was observed earliest in the LEC ( Petrache et al, 2019 ).…”

Section: Loss Of Modulatory Transmitters In the Ecmentioning

confidence: 99%

Molecular mechanisms of neurodegeneration in the entorhinal cortex that underlie its selective vulnerability during the pathogenesis of Alzheimer's disease

2021

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The entorhinal cortex (EC) is a vital component of the medial temporal lobe, and its contributions to cognitive processes and memory formation are supported through its extensive interconnections with the hippocampal formation. During the pathogenesis of Alzheimer's disease (AD), many of the earliest degenerative changes are seen within the EC. Neurodegeneration in the EC and hippocampus during AD has been clearly linked to impairments in memory and cognitive function, and a growing body of evidence indicates that molecular and functional neurodegeneration within the EC may play a primary role in cognitive decline in the early phases of AD. Defining the mechanisms underlying molecular neurodegeneration in the EC is crucial to determining its contributions to the pathogenesis of AD. Surprisingly few studies have focused on understanding the mechanisms of molecular neurodegeneration and selective vulnerability within the EC. However, there have been advancements indicating that early dysregulation of cellular and molecular signaling pathways in the EC involve neurodegenerative cascades including oxidative stress, neuroinflammation, glia activation, stress kinases activation, and neuronal loss. Dysfunction within the EC can impact the function of the hippocampus, which relies on entorhinal inputs, and further degeneration within the hippocampus can compound this effect, leading to severe cognitive disruption. This review assesses the molecular and cellular mechanisms underlying early degeneration in the EC during AD. These mechanisms may underlie the selective vulnerability of neuronal subpopulations in this brain region to the disease development and contribute both directly and indirectly to cognitive loss.This paper has an associated Future Leader to Watch interview with the first author of the article.

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GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

Cited by 140 publications

References 273 publications

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Identifying neuron subtype-specific metabolic network changes in single cell transcriptomics of Alzheimer’s Disease using perturb-Met

Molecular mechanisms of neurodegeneration in the entorhinal cortex that underlie its selective vulnerability during the pathogenesis of Alzheimer's disease

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