Targeting protein kinases for the treatment of Alzheimer's disease: Recent progress and future perspectives

Li, Zhijia; Yin, Bo; Zhang, Shuangqian; Lan, Zhigang; Zhang, Lan

doi:10.1016/j.ejmech.2023.115817

Cited by 12 publications

(3 citation statements)

References 172 publications

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“…The complexity relies on gene expression up/downregulation; furthermore, the regulation is also influenced by posttranslational modifications of several proteins, such as reversible phosphorylation. Many recent studies have shown the involvement of protein phosphorylation and dephosphorylation not only in neuronal differentiation but also in many neurodegenerative disorders such as Parkinson's or Alzheimer's disease [31][32][33]. These findings presenting the importance of protein phosphatases were expected, as the brain expresses the highest levels of protein kinases and phosphatases of all mammalian tissues [34].…”

Section: Discussionmentioning

confidence: 93%

TIMAP, a Regulatory Subunit of Protein Phosphatase 1, Inhibits In Vitro Neuronal Differentiation

Fonódi,

Thalwieser,

Csortos

et al. 2023

IJMS

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TIMAP (TGF-β-inhibited membrane associated protein) is abundant in endothelial cells, and it has been regarded as a member of the myosin phosphatase targeting protein (MYPT) family. Our workgroup previously identified several interacting protein partners of TIMAP and proved its regulatory subunit role for protein phosphatase 1 catalytic subunit (PP1c). TIMAP is also expressed in neuronal cells, but details of its function have not been studied yet. Therefore, we aimed to explore the role of TIMAP in neuronal cells, especially during differentiation. Expression of TIMAP was proved both at mRNA and protein levels in SH-SY5Y human neuroblastoma cells. Differentiation of SH-SY5Y cells was optimized and proved by the detection of neuronal differentiation markers, such as β3-tubulin, nestin and inhibitor of differentiation 1 (ID1) using qPCR and Western blot. We found downregulation of TIMAP during differentiation. In accordance with this, overexpression of recombinant TIMAP attenuated the differentiation of neuronal cells. Moreover, the subcellular localization of TIMAP has changed during differentiation as it translocated from the plasma membrane into the nucleus. The nuclear interactome of TIMAP revealed more than 50 proteins, offering the possibility to further investigate the role of TIMAP in several key physiological pathways of neuronal cells.

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Section: Discussionmentioning

confidence: 93%

TIMAP, a Regulatory Subunit of Protein Phosphatase 1, Inhibits In Vitro Neuronal Differentiation

Fonódi,

Thalwieser,

Csortos

et al. 2023

IJMS

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show abstract

“…Protein kinases are valuable therapeutic targets for the intervention of AD, not only due to the direct participation of dysregulated kinases in various AD pathologies, but also because of the vast number of chemicals and strategies available for drug development [ 227 ]. Compounds targeting GSK-3β, CDK5, p38 MAPK, ERK1/2, JNK3 or several tyrosine kinases have been evaluated in AD mouse models, and some of them have reached clinical trials [ 228 ].…”

Section: Dapk1 As a Target For Disease-modifying Treatment Of Admentioning

confidence: 99%

“…Tideglusib, another GSK-3β inhibitor that has been evaluated in a 26-week, multicenter phase II clinical trial, also demonstrated positive effects on cognitive performance in patients with mild AD [ 231 ]. Other kinase inhibitors such as Neflamapimod for p38 MAPK and NE3107 for ERK1/2 are being analyzed in AD patients and have shown promising results in phase II clinical trials [ 227 ]. However, CDK5 or JNK3 inhibitors are less investigated in clinical trials although these kinases play a pivotal role in the pathogenesis of AD.…”

Section: Dapk1 As a Target For Disease-modifying Treatment Of Admentioning

confidence: 99%

Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease

Zhang,

Kim,

Lee

2024

Transl Neurodegener

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Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly and represents a major clinical challenge in the ageing society. Neuropathological hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau, senile plaques derived from the deposition of amyloid-β (Aβ) peptides, brain atrophy induced by neuronal loss, and synaptic dysfunctions. Death-associated protein kinase 1 (DAPK1) is ubiquitously expressed in the central nervous system. Dysregulation of DAPK1 has been shown to contribute to various neurological diseases including AD, ischemic stroke and Parkinson’s disease (PD). We have established an upstream effect of DAPK1 on Aβ and tau pathologies and neuronal apoptosis through kinase-mediated protein phosphorylation, supporting a causal role of DAPK1 in the pathophysiology of AD. In this review, we summarize current knowledge about how DAPK1 is involved in various AD pathological changes including tau hyperphosphorylation, Aβ deposition, neuronal cell death and synaptic degeneration. The underlying molecular mechanisms of DAPK1 dysregulation in AD are discussed. We also review the recent progress regarding the development of novel DAPK1 modulators and their potential applications in AD intervention. These findings substantiate DAPK1 as a novel therapeutic target for the development of multifunctional disease-modifying treatments for AD and other neurological disorders.

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Protein Kinases – High Yield Targets for Cancer and Dementia Drug Discovery

Shroff,

Goetzl

2024

The American Journal of Medicine

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Targeting protein kinases for the treatment of Alzheimer's disease: Recent progress and future perspectives

Cited by 12 publications

References 172 publications

TIMAP, a Regulatory Subunit of Protein Phosphatase 1, Inhibits In Vitro Neuronal Differentiation

TIMAP, a Regulatory Subunit of Protein Phosphatase 1, Inhibits In Vitro Neuronal Differentiation

Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease

Protein Kinases – High Yield Targets for Cancer and Dementia Drug Discovery

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