ArticleBrain : a journal of neurology2018
Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer's disease: preclinical proof of concept.
Article in Brain : a journal of neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 131 citations in OpenAlex.
- KArchiv der Pharmazie · 2026Article
- Selective Kv1.3 inhibition promotes M2 microglial polarization, accelerates hematoma resolution, and improves neurological recovery following collagenase-induced spontaneous intracerebral hemorrhage in mice.Veterinary world · 2026Article
- A Blood-Brain Barrier-Penetrant Ag(III) Corrole Compound Rescues Alzheimer's Disease Pathology by Targeting Aβ42-Induced Oxidative Stress.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Neuroimmune Interactions in Neurodegeneration: The Role of Microglia in Alzheimer's and Parkinson's Disease Pathogenesis.Brain sciences · 2026Review
- Kv1.3 as an upstream regulator of oxidative stress-mediated neuroinflammation following organic dust exposure in murineFrontiers in toxicology · 2026Article
- l-Fucose is a candidate monosaccharide neuromodulator and mitigates Alzheimer's synaptic deficits.Science advances · 2025Article
- Activation of Hippocampal ACE2 Prevents the Dysbiosis-induced Depression-like Behavior in Mice by Enhanced Neurogenesis and Neuroprotection via Mas Receptor.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Article
- Depression exacerbates AD pathology through lactate-dependent activation of microglial Kv1.3 to promote Aβ-containing exosome spreading.Journal of neuroinflammation · 2025Article
- Role of Ion Channels in Alzheimer's Disease Pathophysiology.The Journal of membrane biology · 2025Review
- Unique N-glycosylation signatures in human iPSC derived microglia activated by Aβ oligomer and lipopolysaccharide.Scientific reports · 2025Article
- ShK-modified UCMSCs Inhibit M1-Like Macrophage Polarization and Alleviate Osteoarthritis Progression via PI3K/Akt Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer's Disease Therapeutics.Biomedicines · 2025Review
- Dulaglutide Alleviates Alzheimer's Disease by Regulating Microglial Polarization and Neurogenic Activity.Combinatorial chemistry & high throughput screening · 2025Article
- The impact of mild episodic ketosis on microglia and hippocampal long-term depression in 5xFAD mice.FASEB bioAdvances · 2024Article
- Nitroxyl Hybrids with Curcumin and Stilbene Scaffolds Display Potent Antioxidant Activity, Remodel the Amyloid Beta Oligomer, and Reverse Amyloid Beta-Induced Cytotoxicity.Antioxidants (Basel, Switzerland) · 2024Article
- Unraveling neuroprotection with Kv1.3 potassium channel blockade by a scorpion venom peptide.Scientific reports · 2024Article
- Therapeutic potential of adipose-derived stem cell extracellular vesicles: from inflammation regulation to tissue repair.Stem cell research & therapy · 2024Review
- Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer's mouse model and stimulates synaptic plasticity pathway enzymes.Communications biology · 2024Article
- Therapeutic role of voltage-gated potassium channels in age-related neurodegenerative diseases.Frontiers in cellular neuroscience · 2024Review
- Structure of the voltage-gated potassium channel KChannels (Austin, Tex.) · 2023Review
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Microglia significantly contribute to the pathophysiology of Alzheimer's disease but an effective microglia-targeted therapeutic approach is not yet available clinically. The potassium channels Kv1.3 and Kir2.1 play important roles in regulating immune cell functions and have been implicated by in vitro studies in the 'M1-like pro-inflammatory' or 'M2-like anti-inflammatory' state of microglia, respectively. We here found that amyloid-β oligomer-induced expression of Kv1.3 and Kir2.1 in cultured primary microglia. Likewise, ex vivo microglia acutely isolated from the Alzheimer's model 5xFAD mice co-expressed Kv1.3 and Kir2.1 as well as markers traditionally associated with M1 and M2 activation suggesting that amyloid-β oligomer induces a microglial activation state that is more complex than previously thought. Using the orally available, brain penetrant small molecule Kv1.3 blocker PAP-1 as a tool, we showed that pro-inflammatory and neurotoxic microglial responses induced by amyloid-β oligomer required Kv1.3 activity in vitro and in hippocampal slices. Since we further observed that Kv1.3 was highly expressed in microglia of transgenic Alzheimer's mouse models and human Alzheimer's disease brains, we hypothesized that pharmacological Kv1.3 inhibition could mitigate the pathology induced by amyloid-β aggregates. Indeed, treating APP/PS1 transgenic mice with a 5-month oral regimen of PAP-1, starting at 9 months of age, when the animals already manifest cognitive deficits and amyloid pathology, reduced neuroinflammation, decreased cerebral amyloid load, enhanced hippocampal neuronal plasticity, and improved behavioural deficits. The observed decrease in cerebral amyloid deposition was consistent with the in vitro finding that PAP-1 enhanced amyloid-β uptake by microglia. Collectively, these results provide proof-of-concept data to advance Kv1.3 blockers to Alzheimer's disease clinical trials.
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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 OpenQuestion graph.