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KChIP3 promotes Alzheimer's disease by impairing long-term potentiation and memory

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β -amyloid (βA) 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 βA 40 accumulation and neuroinflammation. Genetic deletion of KChIP3 in 5XFAD mice significantly reduced βA 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE275435 | GEO | 2025/06/25

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, how this metabolic interplay may be affected during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.

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KChIP3 promotes Alzheimer's disease by impairing long-term potentiation and memory

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