c-Jun N-terminal Kinase Pathway in Alzheimer's Disease Mechanisms

The c-Jun N-terminal kinases (JNKs) comprise a subfamily of stress-activated mitogen-activated protein kinases that respond to a variety of cellular insults including oxidative stress, inflammatory cytokines and protein misfolding. In the context of Alzheimer’s disease, JNK activation has emerged as a pivotal mediator linking amyloid-β accumulation, tau hyperphosphorylation and synaptic dysfunction. Upon activation by upstream kinases such as MKK4 and MKK7, JNK phosphorylates transcription factors, cytoskeletal proteins and components of the apoptotic machinery. In neuronal circuits, excessive JNK signalling disrupts postsynaptic density integrity, impairs long-term potentiation and accelerates dendritic spine loss, thereby contributing to early cognitive deficits. Simultaneously, JNK promotes the production and aggregation of amyloid-β peptides via modulation of amyloid precursor protein processing, and fosters tau misfolding through direct phosphorylation, driving neurofibrillary tangle formation. Given its convergence on multiple pathogenic axes, the JNK pathway is under intense investigation as both a biomarker of disease progression and a therapeutic target to arrest synaptic failure and neurodegeneration.

Research from Nature Portfolio

Recent studies have explored the dual inhibition of ferroptosis and JNK signalling as a novel therapeutic avenue. In a murine model of aluminium-induced neurodegeneration, iron chelation by ciclopirox olamine combined with a selective JNK inhibitor produced marked improvements in learning and memory tasks. Biochemical analyses revealed reductions in amyloid-β and phosphorylated tau burden alongside attenuated lipid peroxidation, nitric oxide formation and JNK activation. These findings underscore the potential of targeting intersecting cell-death pathways to confer neuroprotection in early and mid-stage Alzheimer’s pathology.

c-Jun N-terminal Kinase Pathway in Alzheimer's Disease Mechanisms publication trend

The graph below shows the total number of articles in c-jun n-terminal kinase pathway in alzheimer's disease mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

c-Jun N-terminal Kinase (JNK): A subgroup of mitogen-activated protein kinases activated by stress stimuli, with JNK3 predominantly expressed in neurons.

Ferroptosis: A form of regulated cell death driven by iron-dependent lipid peroxidation, implicated in neurodegeneration.

Amyloid-β Oligomers: Soluble aggregates of amyloid-β peptides that disrupt synaptic function and trigger neuroinflammation.

Tau Hyperphosphorylation: Excessive addition of phosphate groups to tau protein, leading to microtubule destabilisation and neurofibrillary tangle formation.

Postsynaptic Density (PSD): A specialised protein network beneath the postsynaptic membrane critical for receptor anchoring and synaptic signalling.

References

1. JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model. Cells (2023).
2. JNK inhibitor and ferroptosis modulator as possible therapeutic modalities in Alzheimer disease (AD). Scientific Reports (2024).
3. JNK Activation in Alzheimer’s Disease Is Driven by Amyloid β and Is Associated with Tau Pathology. ACS Chemical Neuroscience (2023).
4. c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo. Cell Death & Disease (2014).
5. c-Jun N-terminal Kinase Regulates Soluble Aβ Oligomers and Cognitive Impairment in AD Mouse Model*. Journal of Biological Chemistry (2011).