KChIP3 promotes Alzheimer's disease by impairing long-term potentiation and memory
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by ß -amyloid (ßA) peptide accumulation, neuroinflammation, increased synaptic pruning, and cognitive decline. Effective treatments for AD are still lacking. This study investigates the role of potassium channel interacting protein 3 (KChIP3) in AD using the 5XFAD murine model. We found increased KChIP3 levels in the hippocampus of 5XFAD mice, correlating with ßA 40 accumulation and neuroinflammation. Genetic deletion of KChIP3 in 5XFAD mice significantly reduced ßA plaque formation, proinflammatory cytokine levels, and reactive gliosis in the hippocampus. Transcriptomic and proteomic analyses revealed restored synaptic markers and reduced microglial DAM1 phenotype in 5XFAD/KChIP3 -/- mice. KChIP3 deficiency improved dendritic tree complexity and synaptic plasticity, enhancing learning and memory in 5XFAD mice. Mechanistically, KChIP3 deletion restores immune response balance by modulating microglial phenotype upregulating CD47, CD200, and C1q levels. Our findings, along with recent computational studies using human data, suggest KChIP3 as a potential therapeutic target in AD, addressing neuroinflammation and synaptic dysfunction. Further research is needed to explore its potential as a diagnostic and prognostic biomarker. Overall design: RNA-seq from hippocampus samples derived from control (WT) 5xFAD, Kcnip3 KO and 5xFAD/Kcnip3 KO adult animals