Dataset Information

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

ABSTRACT: Alzheimer's disease (AD) is a multifactorial disorder with serious social, health, and economic implications, affecting over 30 million individuals worldwide, and this number may triple by the year 2050. To date, there are no accurate biomarkers for early diagnosis nor effective treatments to delay the progression of the disease. AD is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, microglia activation, synapse loss, and inflammation leading to neuronal degeneration and cognitive decline. However, the molecular mechanisms underlying this inflammatory process are not fully understood. In this sense, increased levels of KChIP3 in the brains of postmortem AD patients and AD mouse models have been reported. Here, we propose that KChIP3 participates in AD development by maintaining an inflammatory state that negatively impacts cognitive functions. To test this hypothesis, we knock out the expression of KChIP3 in the AD mouse model 5XFAD (5XFAD/KChIP3-/-). We discovered that the absence of KChIP3 reduces the learning and memory capacity of the 5XFAD mice, reduces hippocampal inflammatory molecules and beta-amyloid plaque deposition, and rescued the reduced number and length of hippocampal dendrites and LTP in the 5XFAD mice. Transcriptomic and quantitative proteomic approaches revealed decreased levels of inflammatory mediators and enrichment of molecules related to synaptic transmission, LTP, and learning and memory in the hippocampus of 5XFAD/KChIP3-/-. Our data point out KChIP3 as a therapeutic target to restore the central nervous system's immune suppressive status, favoring the protective effect of the innate immune response in Alzheimer´s disease.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease 1,Alzheimer's Disease 4,Alzheimer's Disease 3

SUBMITTER: Magdalena Hernandez Ortiz

LAB HEAD: Leonor Pérez Martínez

PROVIDER: PXD054699 | Pride | 2025-06-30

REPOSITORIES: Pride

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

Arcos-Encarnación Bolivar B Cortes-Flores Eladio E Barón-Mendoza Isabel I Almazán Jorge Luis JL Valle-García David D Díaz de León-Guerrero Sol S Hovan Ladislav L Meza-Sosa Karla F KF Camacho-Concha Nohemi N Gil Jeovanis J Kuijjer Marieke Lydia ML González-Arenas Aliesha A Encarnación-Guevara Sergio S Pedraza-Alva Gustavo G Pérez-Martínez Leonor L

Journal of neuroinflammation 20250619 1

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. Thi ...[more]

PMID: 40537787

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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.

Project description:Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-y) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipids profile, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-B (AB) deposition and tau pathology was treated with the TZD pioglitazone (PIO- Actos) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal AB deposits, and enhanced short- and long-term plasticity. Baseline electrophysiological membrane properties and blood glucose levels were unchanged by PIO treatment. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes, and decreases in glutamatergic and ketone metabolic/ cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain. Keywords : Hippocampus; LTP; Microarray analysis; Avoidance learning; Aging; PPAR; Synaptic hyperpolarization; T2DM We used the 3xTg-AD mouse model of Alzheimer's disease and monitored the effects of pioglitazone (PIO-Actos a TZD) on behavioral, electrophysiological, and molecular variables. Emphasis was placed on identifying hippocampal PIO-sensitive genes that were also associated with learning and memory processes. Starting at 10 months of age, female mice were treated for approximately 14 weeks with either a control diet or a PIO-containing diet. PIO was incorporated into the diet to yield a final dose of approximately 18 mg/kg body weight/day.

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