ArticleBrain : a journal of neurology2023
Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations.
Article in Brain : a journal of neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 27 citations in OpenAlex.
- Differential isoform-specific control of KCC2 function in developing and mature cortical neurons.EMBO reports · 2026Article
- Cross-sectional Associations of Serum Sodium, Potassium, and Chloride with Cognition in Patients on Hemodialysis: The Osaka Dialysis Complication Study (ODCS).Kidney medicine · 2026Article
- Enhancing KCC2 function reduces interictal activity and prevents seizures in temporal lobe epilepsy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The alpha7 nicotinic acetylcholine receptor mediates network dysfunction in a mouse model of local amyloid pathology.Molecular psychiatry · 2026Article
- Chronic optogenetic activation of hippocampal CA1 neurons triggers Alzheimer's disease-like proteomic remodeling.iScience · 2025Article
- KCC2 enhancers normalize reflex responses and improve locomotor function after chronic spinal cord injury.The Journal of physiology · 2025Article
- Chloride Homeostasis in Neuronal Disorders: Bridging Measurement to Therapy.Life (Basel, Switzerland) · 2025Review
- Intracellular accumulation of amyloid-ß is a marker of selective neuronal vulnerability in Alzheimer's disease.Nature communications · 2025Article
- The Bidirectional Relationship Between Epilepsy and Alzheimer's Disease.Current neurology and neuroscience reports · 2025Review
- Targeting ApoE-KCC2 Signaling Rescues GABAergic Synaptic Dysfunction and Depression-like Behaviors in Mice.Research (Washington, D.C.) · 2025Article
- Altered GABAergic signaling and chloride homeostasis in eye movement circuits during late neurodevelopment: implications for Alzheimer's disease therapy.Frontiers in pharmacology · 2025Review
- Midbrain KCC2 downregulation: Implications for stress-related and substance use behaviors.Current opinion in neurobiology · 2024Review
- Regulation of Neuronal Chloride Homeostasis by Pro- and Mature Brain-Derived Neurotrophic Factor (BDNF) via KCC2 Cation-Chloride Cotransporters in Rat Cortical Neurons.International journal of molecular sciences · 2024Article
- Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease and 5XFAD mice.Brain : a journal of neurology · 2024Article
- Bidirectional Regulation of GABALife (Basel, Switzerland) · 2024Review
- Development of KCC2 therapeutics to treat neurological disorders.Frontiers in molecular neuroscience · 2024Article
- Unraveling the socio-cognitive consequences of KCC2 disruption in zebrafish: implications for neurodevelopmental disorders and therapeutic interventions.Frontiers in molecular neuroscience · 2024Article
- Daphnetin Ameliorates the Amyloid β-Induced Alzheimer Disease via Restoring Potassium-Chloride Co-Transporter 2 (KCC2) Ion Channel Functions in Mice.Iranian journal of pharmaceutical research : IJPRArticle
- The biogenesis of potassium transporters: implications of disease-associated mutations.Critical reviews in biochemistry and molecular biologyReview
Corrections and comments
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
Abstract
Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-β 42 (Aβ42). Acute administration of Aβ42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline; they confirm target engagement, where the therapeutic intervention takes place, and its effectiveness.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.