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KChIP3 fosters neuroinflammation and synaptic dysfunction in the 5XFAD mouse model of Alzheimer’s disease

Arcos-Encarnación, Bolivar ; Cortes-Flores, Eladio ; Barón-Mendoza, Isabel ; Almazán, Jorge Luis ; Valle-García, David ; Díaz de León-Guerrero, Sol ; Hovan, Ladislav ; Meza-Sosa, Karla F. ; Camacho-Concha, Nohemi and Gil, Jeovanis LU orcid , et al. (2025) In Journal of Neuroinflammation 22(1).
Abstract

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 (KChIP3) as a key driver of AD pathology using the 5XFAD mouse model. 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,... (More)

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 (KChIP3) as a key driver of AD pathology using the 5XFAD mouse model. 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
5XFAD mice, Aging, Alzheimer’s disease, KChIP3, Learning, LTP, Memory, Microglia, Neuroinflammation, Synaptic plasticity
in
Journal of Neuroinflammation
volume
22
issue
1
article number
160
publisher
BioMed Central (BMC)
external identifiers
  • pmid:40537787
  • scopus:105008725295
ISSN
1742-2094
DOI
10.1186/s12974-025-03426-2
language
English
LU publication?
yes
id
100edb59-ba95-452c-ba8d-e625fb023f76
date added to LUP
2025-10-29 09:13:01
date last changed
2025-10-30 03:25:57
@article{100edb59-ba95-452c-ba8d-e625fb023f76,
  abstract     = {{<p>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 (KChIP3) as a key driver of AD pathology using the 5XFAD mouse model. 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<sup>−/−</sup>) 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.</p>}},
  author       = {{Arcos-Encarnación, Bolivar and Cortes-Flores, Eladio and Barón-Mendoza, Isabel and Almazán, Jorge Luis and Valle-García, David and Díaz de León-Guerrero, Sol and Hovan, Ladislav and Meza-Sosa, Karla F. and Camacho-Concha, Nohemi and Gil, Jeovanis and Kuijjer, Marieke Lydia and González-Arenas, Aliesha and Encarnación-Guevara, Sergio and Pedraza-Alva, Gustavo and Pérez-Martínez, Leonor}},
  issn         = {{1742-2094}},
  keywords     = {{5XFAD mice; Aging; Alzheimer’s disease; KChIP3; Learning; LTP; Memory; Microglia; Neuroinflammation; Synaptic plasticity}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Journal of Neuroinflammation}},
  title        = {{KChIP3 fosters neuroinflammation and synaptic dysfunction in the 5XFAD mouse model of Alzheimer’s disease}},
  url          = {{http://dx.doi.org/10.1186/s12974-025-03426-2}},
  doi          = {{10.1186/s12974-025-03426-2}},
  volume       = {{22}},
  year         = {{2025}},
}