levels were significantly elevated in the hippocampus of 5XFAD mice, correlating with β-amyloid burden and neuroinflammation.
KChIP3 is identified as a key driver of Alzheimer's disease pathology in the .
Genetic deletion of KChIP3 resulted in reduced β-amyloid plaque deposition and lower levels of pro-inflammatory cytokines.
Restoration of synaptic markers was observed following KChIP3 deletion, indicating improved neuronal function.
KChIP3 may sustain neuroinflammation by increasing pro-inflammatory gene expression.
Deletion of KChIP3 was associated with enhanced dendritic complexity, synaptic plasticity, and cognitive performance.
Simplified
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by β-amyloid (βA) accumulation, neuroinflammation, excessive synaptic pruning, and cognitive decline. Despite extensive research, effective treatments remain elusive. Here, we identify potassium channel-interacting protein 3 () as a key driver of AD pathology using the . KChIP3 levels were significantly elevated in the hippocampus of 5XFAD mice, correlating with βA burden and neuroinflammation. This upregulation was triggered by inflammatory signaling via the NLRP3 inflammasome and Caspase-1 activation. Notably, genetic deletion of KChIP3 (5XFAD/KChIP3) markedly reduced βA plaque deposition, pro-inflammatory cytokines, reactive gliosis, and expression of inflammation-related proteins (APO, CLU, MDK). Transcriptomic and proteomic analyses revealed restored synaptic markers (CD47, CD200, CACNB4, GDA) and a shift of the disease-associated microglial (DAM-1) phenotype. Mechanistically, we propose that KChIP3 amplifies AD pathology through two key mechanisms: (1) sustaining neuroinflammation by upregulating pro-inflammatory genes and (2) impairing synaptic integrity by repressing genes critical for neuronal function. Consistently, KChIP3 deletion enhanced dendritic complexity, synaptic plasticity, and cognitive performance in 5XFAD mice. These findings position KChIP3 as a potential therapeutic target for mitigating neuroinflammation and synaptic dysfunction in AD and highlight its potential as a biomarker for disease progression. -/-
Key numbers
5 of 10
Decrease in β-amyloid plaques
Percentage of plaques in 5XFAD/ mice compared to 5XFAD mice
0.62
Increase in cognitive performance
Exploration index in the novel object recognition test for 5XFAD/ mice
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Declarations. Ethics approval and consent to participate: The Institutional Bioethical Committee approved all animal experiments described in this study. Competing interests: The authors declare no competing interests.
