Recent advances of small molecule JNK3 inhibitors for Alzheimer’s disease

Qin, Pengxia; Ran, Yingying; Liu, Yujing; Wei, Chao; Luan, Xiaoyi; Niu, Haoqian; Peng, Jie; Sun, Jie; Wu, Jingde

doi:10.1016/j.bioorg.2022.106090

Cited by 13 publications

(5 citation statements)

References 96 publications

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“…One possibility is that APPβf/Aβ induces phosphorylation of TAU through c-JUN N-terminal kinase (JNK) signaling 95 . Since JNK can be phosphorylated and activated both pro-apoptotic protein c-JUN and TAU at (Ser 202 / Thr 205 ), this kinase has become a potential therapeutic target 96 .…”

Section: Discussionmentioning

confidence: 99%

Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology

Gomez-Sequeda,

Mendivil-Perez,

Jimenez-Del-Rio

et al. 2023

Sci Rep

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Familial Alzheimer’s disease (FAD) is a complex neurodegenerative disorder for which there are no therapeutics to date. Several mutations in presenilin 1 (PSEN 1), which is the catalytic component of γ-secretase complex, are causal of FAD. Recently, the p.Ile416Thr (I416T) PSEN 1 mutation has been reported in large kindred in Colombia. However, cell and molecular information from I416T mutation is scarce. Here, we demonstrate that menstrual stromal cells (MenSCs)-derived planar (2D) PSEN 1 I416T cholinergic-like cells (ChLNS) and (3D) cerebral spheroids (CSs) reproduce the typical neuropathological markers of FAD in 4 post-transdifferentiating or 11 days of transdifferentiating, respectively. The models produce intracellular aggregation of APPβ fragments (at day 4 and 11) and phosphorylated protein TAU at residue Ser202/Thr205 (at day 11) suggesting that iAPPβ fragments precede p-TAU. Mutant ChLNs and CSs displayed DJ-1 Cys106-SO3 (sulfonic acid), failure of mitochondria membrane potential (ΔΨm), and activation of transcription factor c-JUN and p53, expression of pro-apoptotic protein PUMA, and activation of executer protein caspase 3 (CASP3), all markers of cell death by apoptosis. Moreover, we found that both mutant ChLNs and CSs produced high amounts of extracellular eAβ42. The I416T ChLNs and CSs were irresponsive to acetylcholine induced Ca2+ influx compared to WT. The I416T PSEN 1 mutation might work as dominant-negative PSEN1 mutation. These findings might help to understanding the recurring failures of clinical trials of anti-eAβ42, and support the view that FAD is triggered by the accumulation of other intracellular AβPP metabolites, rather than eAβ42.

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Section: Discussionmentioning

confidence: 99%

Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology

Gomez-Sequeda,

Mendivil-Perez,

Jimenez-Del-Rio

et al. 2023

Sci Rep

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“…In safety assessments, CC-930, a potent and selective JNK inhibitor, exhibited no in vitro toxicity, did not inhibit CYP450 enzymes, and was well-tolerated in healthy male volunteers. However, its phase II clinical trial for idiopathic pulmonary fibrosis was terminated due to cardiac adverse effects [ 53 ]. AGI-1067, inhibiting TLR4 ligand-induced activation of ASK1 and downstream p38 and JNK MAP kinases, has been assessed for safety and efficacy in treating vascular inflammation and atherosclerosis in cardiovascular events [ 54 ].…”

Section: The Development Of Jnk3 Inhibitorsmentioning

confidence: 99%

JNK3 inhibitors as promising pharmaceuticals with neuroprotective properties

Wu,

Zhao,

Guan

et al. 2024

Cell Adhesion & Migration

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The intensive study and investigation of neuroprotective therapy for central nervous system (CNS) diseases is ongoing. Due to shared mechanisms of neurodegeneration, a neuroprotective approach might offer benefits across multiple neurological disorders, despite variations in symptoms or injuries. C-Jun N-terminal Kinase 3 (JNK3) is found primarily in the CNS and is involved in physiological processes such as brain development, synapse formation, and memory formation. The potential of JNK3 as a target for pharmacological development holds promise for advancing neuroprotective therapies. Developing small molecule JNK3 inhibitors into drugs with neuroprotective qualities could facilitate neuronal restoration and self-repair. This review focuses on elucidating key neuroprotective mechanisms, exploring the interplay between neurodegenerative diseases and neuroprotection, and discussing advancements in JNK3 inhibitor drug development.

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“…Finally, JNK signalling is involved in forming and aggregating neurofibrillary tangles (NFTs) 40 . Recent evidence suggests that inhibitors of JNK3 could be beneficial in AD 41 . Here, we show that WNT-5A/ROR2 is important for JNK signalling in cortical neurons.…”

Section: Wnt/pcp/jnk Signalling In Admentioning

confidence: 99%

Amyloid-β can activate JNK signalling via WNT-5A/ROR2 to reduce synapse formation in Alzheimer’s disease

Fang,

Pishva,

Piers

et al. 2024

Preprint

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Wnt signalling is an essential signalling system in neurogenesis, and recent studies have highlighted the critical role of this signalling network in regulating synaptic plasticity, neuronal survival, and neurogenesis, processes that are disrupted in Alzheimer’s disease (AD). From the Wnt network, the Wnt/β-catenin pathway has been studied for its neuroprotective role, and this is suppressed in AD. However, the involvement of the non-canonical pathway, which operates independently of β-catenin and involves the planar cell polarity (PCP), remains to be determined in AD.In this work, we analyse the function of the orphan receptor tyrosine kinase ROR2, an essential co-receptor of the Wnt/PCP signalling pathway. We find that activation of WNT-5A/ROR2 signalling activates JNK signalling, reducing pre- and postsynaptic clusters on neurites in mature SH-SY5Y neurons. This observation is similar to SH-SY5Y neurons treated with the Amyloid-β peptide Aβ1-42or DKK1, which are both increased in AD. Surprisingly, the effect of Aβ1-42and DKK1 signalling on synaptogenesis can be mitigated by blocking ROR2 and JNK signalling, suggesting that Aβ and DKK1 signalling depends on ROR2/JNK signalling. Finally, we find an increase of WNT-5A/ROR2 clusters on neurites of iPSC-derived cortical neurons carrying the PSEN1 A75V mutation, known to enhance the pathological Aβ42/40ratio. Simultaneously, the number of pre- and post-synaptic clusters decreased in the mutant line. Inhibition of ROR2/JNK signalling in PSEN1A75Vcortical neurons partially rescues the reduction in synaptogenesis, suggesting that ROR2 signalling may act in a positive feedback loop with Aβ1-42and DKK1 signalling to augment JNK signalling as seen in AD.

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Recent advances of small molecule JNK3 inhibitors for Alzheimer’s disease

Cited by 13 publications

References 96 publications

Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology

Cholinergic-like neurons and cerebral spheroids bearing the PSEN1 p.Ile416Thr variant mirror Alzheimer's disease neuropathology

JNK3 inhibitors as promising pharmaceuticals with neuroprotective properties

Amyloid-β can activate JNK signalling via WNT-5A/ROR2 to reduce synapse formation in Alzheimer’s disease

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