Neuronal hyperexcitability in Alzheimer’s disease: what are the drivers behind this aberrant phenotype?

Translational Psychiatry, Journal Year: 2022, Volume and Issue: 12(1)

Published: June 22, 2022

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to loss of cognitive abilities and ultimately, death. With no cure available, limited treatments mostly focus on symptom management. Identifying early changes in the course may provide new therapeutic targets halt or reverse progression. Clinical studies have shown that cortical hippocampal hyperactivity are feature shared by patients stages disease, progressing hypoactivity during later neurodegeneration. The exact mechanisms causing neuronal excitability not fully characterized; however, animal cell models provided insights into some factors involved this phenotype. In review, we summarize evidence for over AD onset progression molecular underpinning these differences. Specifically, discuss contributors aberrant excitability, including abnormal levels intracellular Ca 2+ glutamate, pathological amyloid β (Aβ) tau, genetic risk factors, APOE , impaired inhibitory interneuron glial function. light recent research indicating hyperexcitability could be predictive marker dysfunction, further argue phenotype leveraged improve diagnosis treatment AD, present potential future development.

Language: Английский

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Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity

JAMA Neurology, Journal Year: 2021, Volume and Issue: 78(11), P. 1345 - 1345

Published: Sept. 27, 2021

Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).To determine the ability of antiseizure drug levetiracetam improve cognition persons AD.The Levetiracetam for Alzheimer's Disease-Associated Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial 34 adults AD that conducted at University California, San Francisco, and Minnesota, Twin Cities, between October 16, 2014, July 21, 2020. Participants were 80 years younger who had Mini-Mental State Examination score 18 points or higher and/or Clinical Dementia Rating less than 2 points. Screening included overnight video electroencephalography 1-hour resting magnetoencephalography examination.Group A received placebo twice daily 4 weeks followed by 4-week washout period, then oral levetiracetam, 125 mg, weeks. Group B treatment using reverse sequence.The primary outcome executive function (measured National Institutes Health Executive Abilities: Measures Instruments Neurobehavioral Evaluation Research [NIH-EXAMINER] composite score). Secondary outcomes Stroop Color Word Test [Stroop] interference naming subscale Disease Assessment Scale-Cognitive Subscale) disability. Exploratory performance on virtual route learning test scores functional tests among participants epileptiform activity.Of 54 assessed eligibility, 11 did not meet criteria, 9 declined participate. total (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) enrolled (17 group 17 B). Thirteen (38.2%) categorized as having activity. In total, 28 (82.4%) completed study, 10 whom (35.7%) Overall, change NIH-EXAMINER (mean difference vs placebo, 0.07 points; 95% CI, -0.18 0.32 P = .55) secondary measures. However, activity, improved (net improvement 7.4 0.2-14.7 .046) (t 2.36; Cohen f2 0.11; .02). There no discontinuations because adverse events.In this trial, well tolerated and, although it outcome, prespecified analysis, spatial memory tasks These exploratory findings warrant further assessment approaches AD.ClinicalTrials.gov Identifier: NCT02002819.

Language: Английский

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Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease

Neuron, Journal Year: 2020, Volume and Issue: 107(3), P. 417 - 435

Published: June 23, 2020

Language: Английский

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Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure

Advanced Science, Journal Year: 2021, Volume and Issue: 8(18)

Published: Aug. 2, 2021

Alzheimer's disease (AD) is a progressive neurodegenerative with no cure. Huge efforts have been made to develop anti-AD drugs in the past decades. However, all drug development programs for disease-modifying therapies failed. Possible reasons high failure rate include incomplete understanding of complex pathophysiology AD, especially sporadic AD (sAD), and species difference between humans animal models used preclinical studies. In this study, sAD modeled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Because blood-brain barrier (BBB) leakage well-known risk factor organoids are exposed serum mimic exposure consequence BBB breakdown patient brains. The serum-exposed able recapitulate AD-like pathologies, including increased amyloid beta (Aβ) aggregates phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, impaired neural network. Serum increases Aβ p-Tau levels through inducing beta-secretase 1 (BACE) glycogen synthase kinase-3 alpha / (GSK3α/β) levels, respectively. addition, single-cell transcriptomic analysis reveals that reduced function both neurons astrocytes immune response astrocytes. organoid-based model established study can provide powerful platform mechanistic therapeutic future.

Language: Английский

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Astrocytes in Alzheimer’s Disease: Pathological Significance and Molecular Pathways

Cells, Journal Year: 2021, Volume and Issue: 10(3), P. 540 - 540

Published: March 4, 2021

Astrocytes perform a wide variety of essential functions defining normal operation the nervous system and are active contributors to pathogenesis neurodegenerative disorders such as Alzheimer’s among others. Recent data provide compelling evidence that distinct astrocyte states associated with specific stages Alzheimer´s disease. The advent transcriptomics technologies enables rapid progress in characterisation pathological states. In this review, we an overview origin, main functions, molecular morphological features astrocytes physiological well conditions related We will also explore roles disease summarize transcriptional changes altered pathways observed during course

Language: Английский

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Astrocyte metabolism and signaling pathways in the CNS

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Sept. 4, 2023

Astrocytes comprise half of the cells in central nervous system and play a critical role maintaining metabolic homeostasis. Metabolic dysfunction astrocytes has been indicated as primary cause neurological diseases, such depression, Alzheimer’s disease, epilepsy. Although functionalities are well known, their relationship to disorders is poorly understood. The ways which regulate metabolism glucose, amino acids, lipids have all implicated diseases. Metabolism also exhibited significant influence on neuron functionality brain’s neuro-network. In this review, we focused processes present astrocytes, most notably glucose pathway, fatty acid amino-acid pathway. For metabolism, glycolysis pentose-phosphate oxidative phosphorylation followed oxidation, ketone body sphingolipid metabolism. summarized neurotransmitter serine kynurenine pathways. This review will provide an overview functional changes astrocyte overall perspective current treatment therapy for disorders.

Language: Английский

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Brain organoids: an ensemble of bioassays to investigate human neurodevelopment and disease

Cell Death and Differentiation, Journal Year: 2020, Volume and Issue: 28(1), P. 52 - 67

Published: June 1, 2020

Language: Английский

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Intelligent Microfluidics: The Convergence of Machine Learning and Microfluidics in Materials Science and Biomedicine

Matter, Journal Year: 2020, Volume and Issue: 3(6), P. 1893 - 1922

Published: Dec. 1, 2020

Language: Английский

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α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss

Journal of Neuroscience, Journal Year: 2021, Volume and Issue: 41(10), P. 2264 - 2273

Published: Jan. 22, 2021

Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease. Misfolded protein aggregates in the form Lewy bodies, comprised mainly α-synuclein (αSyn), associated with disease progression, have also been linked to other neurodegenerative diseases, including body dementia, Alzheimer's disease, frontotemporal dementia. However, effects αSyn its mechanism synaptic damage remain incompletely understood. Here, we show that oligomers induce Ca 2+ -dependent release glutamate from astrocytes obtained male female mice, mice overexpressing manifest increased tonic vivo . In turn, this extracellular activates receptors, extrasynaptic NMDARs (eNMDARs), on neurons both culture hippocampal slices αSyn-overexpressing mice. Additionally, patch-clamp recording outside-out patches, found oligomerized can directly activate eNMDARs. organotypic slices, oligomeric induces eNMDAR-mediated loss, which be reversed by drug NitroSynapsin. When expose human induced pluripotent stem cell-derived cerebrocortical αSyn, find similar effects. Importantly, improved NMDAR antagonist NitroSynapsin, selectively inhibits over physiological activity, protects synapses αSyn-induced our model systems, thus meriting further study for therapeutic potential. SIGNIFICANCE STATEMENT Loss function ensuing progression (PD), dementia (LBD), diseases. remains α-Synuclein (αSyn) misfolds PD/LBD, forming bodies contributing pathogenesis. misfolded/oligomeric releases excessive astrocytic glutamate, turn activating NMDA receptors thereby damage. eNMDARs, While FDA-approved memantine has reported offer some benefit PD/LBD (Hershey Coleman-Jackson, 2019), eNMDAR NitroSynapsin ameliorates spine providing potential disease-modifying intervention PD/LBD.

Language: Английский

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Applications of brain organoids in neurodevelopment and neurological diseases

Journal of Biomedical Science, Journal Year: 2021, Volume and Issue: 28(1)

Published: April 22, 2021

Abstract A brain organoid is a self-organizing three-dimensional tissue derived from human embryonic stem cells or pluripotent and able to simulate the architecture functionality of brain. Brain generation methods are abundant continue improve, now, an in vivo vascularized has been encouragingly reported. The combination organoids with immune-staining single-cell sequencing technology facilitates our understanding organoids, including structural organization diversity cell types. Recent publications have reported that can mimic dynamic spatiotemporal process early development, model various disorders, serve as effective preclinical platform test guide personalized treatment. In this review, we introduce current state differentiation strategies, summarize progress applications medical domain, discuss challenges prospects promising technology.

Language: Английский

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