Pharmacological relevance of CDK inhibitors in Alzheimer's disease

Malhotra, Nishtha; Gupta, Rohan; Kumar, Pravir

doi:10.1016/j.neuint.2021.105115

Cited by 36 publications

(28 citation statements)

References 261 publications

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“…Memantine, which is a phosphatase modifier that enhances PP2A (Protein phosphatase 2) activity, improves cognition, and reduces tau pathology in model mice (Chohan et al, 2006 ). Kinase inhibitors, such as CDK5 inhibitors, attenuated pathology, and neurodegeneration in tauopathy mice (Malhotra et al, 2021 ). An acetyltransferase inhibitor was shown to rescue tau-induced memory deficits and to prevent hippocampal atrophy in PS19 mice (Min et al, 2015 ).…”

Section: Preclinical Analyses Of Potential Ad Therapies Using Model Micementioning

confidence: 99%

Mouse Models of Alzheimer’s Disease

Yokoyama

Kobayashi

Tatsumi

et al. 2022

Front. Mol. Neurosci.

105

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, eventually leading to dementia. The pathological hallmarks of AD are senile plaques and neurofibrillary tangles, which comprise abnormally aggregated β-amyloid peptide (Aβ) and hyperphosphorylated tau protein. To develop preventive, diagnostic, and therapeutic strategies for AD, it is essential to establish animal models that recapitulate the pathophysiological process of AD. In this review, we will summarize the advantages and limitations of various mouse models of AD, including transgenic, knock-in, and injection models based on Aβ and tau. We will also discuss other mouse models based on neuroinflammation because recent genetic studies have suggested that microglia are crucial in the pathogenesis of AD. Although each mouse model has its advantages and disadvantages, further research on AD pathobiology will lead to the establishment of more accurate mouse models, and accelerate the development of innovative therapeutics.

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Section: Preclinical Analyses Of Potential Ad Therapies Using Model Micementioning

confidence: 99%

Mouse Models of Alzheimer’s Disease

Yokoyama

Kobayashi

Tatsumi

et al. 2022

Front. Mol. Neurosci.

105

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“…Various studies have reported the overexpression of cell cycle protein regulators, such as CDKs, in the vicinity of NFTs and senile plaques in the post-mortem brains of AD patients [68,90], indicating that the overexpression of the regulators of the cell cycle may be a characteristic feature of AD. Consistently, the administration of CDKIs (inhibitors of CDK1, 2, 4, 5, 7, 9) ameliorated AD symptoms in animal models [91][92][93][94][95][96], corroborating that the cell cycle and mitosis play an important role in AD development and could become important targets of drug research. In this sense, CDKIs have been suggested to be of potential relevance in the treatment of AD [93].…”

Section: Cell Cycle and Admentioning

confidence: 64%

“…Consistently, the administration of CDKIs (inhibitors of CDK1, 2, 4, 5, 7, 9) ameliorated AD symptoms in animal models [91][92][93][94][95][96], corroborating that the cell cycle and mitosis play an important role in AD development and could become important targets of drug research. In this sense, CDKIs have been suggested to be of potential relevance in the treatment of AD [93].…”

Section: Cell Cycle and Admentioning

confidence: 64%

“…However, although several CDKIs have been reported in the literature to treat other diseases, such as cancer, few studies have been conducted to investigate their effects against neurodegeneration. Not only that but also various side effects may arise due to the non-specificity of CDKIs, which may affect several CDKs, leading to controversial opinions towards its use [93]. Therefore, achieving a higher selectivity might be considered to be one of the most important aspects in the field of CDKI development.…”

Section: Discussionmentioning

confidence: 99%

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p27, The Cell Cycle and Alzheimer´s Disease

García‐Osta

Dong

Moreno-Aliaga

et al. 2022

IJMS

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The cell cycle consists of successive events that lead to the generation of new cells. The cell cycle is regulated by different cyclins, cyclin-dependent kinases (CDKs) and their inhibitors, such as p27Kip1. At the nuclear level, p27Kip1 has the ability to control the evolution of different phases of the cell cycle and oppose cell cycle progression by binding to CDKs. In the cytoplasm, diverse functions have been described for p27Kip1, including microtubule remodeling, axonal transport and phagocytosis. In Alzheimer’s disease (AD), alterations to cycle events and a purported increase in neurogenesis have been described in the early disease process before significant pathological changes could be detected. However, most neurons cannot progress to complete their cell division and undergo apoptotic cell death. Increased levels of both the p27Kip1 levels and phosphorylation status have been described in AD. Increased levels of Ab42, tau hyperphosphorylation or even altered insulin signals could lead to alterations in p27Kip1 post-transcriptional modifications, causing a disbalance between the levels and functions of p27Kip1 in the cytoplasm and nucleus, thus inducing an aberrant cell cycle re-entry and alteration of extra cell cycle functions. Further studies are needed to completely understand the role of p27Kip1 in AD and the therapeutic opportunities associated with the modulation of this target.

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“…Moreover, in previous years, CDK5 action was also proved to be associated with dopaminergic signaling, neurotransmitter release, and membrane cycling [ 122 ]. Concerning its mechanism of action, the aforementioned protein was suggested as a new therapeutic target for cancer [ 123 , 124 , 125 ], along with CNS diseases including AD, HD, stroke, and PD [ 126 , 127 , 128 , 129 ]. Increased activity of CDK5 is suggested as one of the causes of AD development.…”

Section: 5-ht 6 R/cdk5 As Possible Dual Target App...mentioning

confidence: 99%

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

Czarnota-Łydka

Kucwaj-Brysz

Pyka

et al. 2022

IJMS

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In view of the unsatisfactory treatment of cognitive disorders, in particular Alzheimer’s disease (AD), the aim of this review was to perform a computer-aided analysis of the state of the art that will help in the search for innovative polypharmacology-based therapeutic approaches to fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, the hope of effectively treating Alzheimer’s disease has been placed on serotonin 5-HT6 receptor (5-HT6R), due to its proven, both for agonists and antagonists, beneficial procognitive effects in animal models; however, research into this treatment has so far not been successfully translated to human patients. Recent lines of evidence strongly emphasize the role of kinases, in particular microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein kinase I/II (ROCKI/II) and cyclin-dependent kinase 5 (CDK5) in the etiology of AD, pointing to the therapeutic potential of their inhibitors not only against the symptoms, but also the causes of this disease. Thus, finding a drug that acts simultaneously on both 5-HT6R and one of those kinases will provide a potential breakthrough in AD treatment. The pharmacophore- and docking-based comprehensive literature analysis performed herein serves to answer the question of whether the design of these kind of dual agents is possible, and the conclusions turned out to be highly promising.

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Pharmacological relevance of CDK inhibitors in Alzheimer's disease

Cited by 36 publications

References 261 publications

Mouse Models of Alzheimer’s Disease

Mouse Models of Alzheimer’s Disease

p27, The Cell Cycle and Alzheimer´s Disease

Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer’s Disease: Can It Work from a Molecular Point of View?

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