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Published on: February 13, 2014
c-Jun N-terminal Kinase 1 ablation protects against metabolic-induced hippocampal cognitive impairments
Oriol Busquets1,2,3,4, Miren Ettcheto1,2,3,4, Àuria Eritja1
1Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII 27/31, 08028, Barcelona, Spain.
Abstract:
The development of metabolic alterations like insulin resistance has been associated with dysfunctions in mitochondrial oxidative capacity, induction of neuroinflammatory responses, and the appearance of cognitive impairments in the brain. The c-Jun N-terminal Kinase 1 (JNK1) is a potential key modulator of these mechanisms. The current study identifies a protective effect of whole-body JNK1 knockout in the presence of a high-fat diet (HFD). Specifically, the data suggest that mice missing JNK1 show increased insulin sensitivity and mitochondrial activity, as well as reduced body weight, and astrocyte and microglial reactivity. Finally, these animals are also protected against HFD-induced cognitive impairments as assessed through novel object recognition test, the observation of dendritic spines, and the levels of BDNF or other proteins like spinophilin and ARC. Thus, modulation of JNK1 activity seems like a promising approach for the design of therapies aimed at treating metabolic-induced cognitive impairments. KEY MESSAGES: JNK1 is a link between obesity/type 2 diabetes and cognitive loss Inhibition of JNK1 is neuroprotective JNK1 constitutes a therapeutic strategy for cognitive loss.
Insights
Mice lacking c-Jun N-terminal Kinase 1 (JNK1) show improved insulin sensitivity and cognitive function when fed a high-fat diet. Inhibiting JNK1 may offer a therapeutic strategy for metabolic-induced cognitive impairments.
Area of Science:
- Neuroscience
- Metabolic Research
- Molecular Biology
Background:
- Metabolic alterations, such as insulin resistance, are linked to mitochondrial dysfunction, neuroinflammation, and cognitive deficits.
- c-Jun N-terminal Kinase 1 (JNK1) is implicated as a key regulator in these processes.
Purpose of the Study:
- To investigate the protective role of whole-body JNK1 knockout against high-fat diet (HFD)-induced metabolic and cognitive impairments.
- To explore JNK1 as a potential therapeutic target for cognitive dysfunction associated with metabolic disorders.
Main Methods:
- Utilized whole-body JNK1 knockout mice and a high-fat diet (HFD) model.
- Assessed metabolic parameters, including insulin sensitivity and body weight.
- Evaluated mitochondrial oxidative capacity and markers of neuroinflammation (astrocyte and microglial reactivity).
- Quantified cognitive performance using the novel object recognition test and analyzed synaptic plasticity markers (dendritic spines, BDNF, spinophilin, ARC).
Main Results:
- JNK1 knockout mice exhibited enhanced insulin sensitivity, increased mitochondrial activity, and reduced body weight under HFD.
- These mice showed significantly reduced astrocyte and microglial reactivity, indicating decreased neuroinflammation.
- Protection against HFD-induced cognitive impairments was observed, evidenced by improved novel object recognition, preserved dendritic spine morphology, and normalized levels of synaptic proteins.
Conclusions:
- Whole-body JNK1 knockout confers protection against HFD-induced metabolic dysfunction and cognitive impairments.
- JNK1 inhibition emerges as a promising therapeutic strategy for treating cognitive deficits linked to obesity and type 2 diabetes.
- Modulating JNK1 activity represents a viable approach for developing novel therapies for metabolic-related cognitive decline.
