Ameliorating Alzheimer’s-like Pathology by Minocycline via Inhibiting
Cdk5/p25 Signaling

Zhang, Yu; Wang, Chuanling; He, Wenbo; Cai, Zhiyou

doi:10.2174/1570159x19666211202124925

Cited by 9 publications

(4 citation statements)

References 43 publications

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“…Therefore, the results of Co‐IP (Figure 3B) demonstrated that activation of CB1R cause the formation of p‐Cdk5/p25 complex after oxycodone withdrawal. In line with our study, previous studies showed that abnormal activity of Cdk5/p25 can lead to neurological dysfunction and a variety of neurodegenerative diseases 30,31 …”

Section: Discussionsupporting

confidence: 92%

“…In line with our study, previous studies showed that abnormal activity of Cdk5/p25 can lead to neurological dysfunction and a variety of neurodegenerative diseases. 30,31 The interest in tau rose sharply when tau was identified as a pathological hallmark in the patient with AD. 32 The association between opioid exposure and Alzheimer's disease has gained more attention, 33,34 but the alterations in tau phosphorylation site induced by oxycodone remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

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Blockade of endocannabinoid system by oxytocin attenuates memory deficits in oxycodone‐treated rats

et al. 2022

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Oxycodone is a highly prescribed opioid and its abuse has been rampant. Accumulating evidence shows that the cannabinoid CB1 receptor (CB1R) plays a key role in mediating rewarding effects to opioids. However, the downstream signalling of CB1R induced by oxycodone remains unclear. The neuropeptide oxytocin is well known as a potential remedy for drug addiction. Thus, our study aims to explore the mechanism of oxycodone-induced learning and memory deficits underlying the endocannabinoid system (ECS) and the effect of oxytocin. Rats were intraperitoneally injected with oxycodone once a day for eight consecutive day. Novel object recognition, resident-intruder and Morris Water Maze tests were employed to assess the cognitive, social and spatial memory of the rats after oxycodone withdrawal. The (co-)expression of CB1R, cyclin-dependent kinase 5 (Cdk5), regulatory protein p25, tau and phosphorylated tau was measured 1 day after the last behavioural test. The histopathological staining and synaptic density in the hippocampus were observed as well. We found that oxycodone upregulated the expression of p-GSK3β, co-expression of p-Cdk5 and p25 through CB1R. This finding was accompanied by elevation of pSer396, pSer404 in the tau, and reduction of the number of neurons, dendritic spines and synaptic density in the hippocampus. Furthermore, i.c.v. treatment with oxytocin ameliorates memory deficits in oxycodone-treated rats through inhibition of the ECS. We propose further studies on the clinical use of this neuropeptide, which may potentially cure drug addiction.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Blockade of endocannabinoid system by oxytocin attenuates memory deficits in oxycodone‐treated rats

et al. 2022

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“…Tau, as an important substrate of CDK5, can be phosphorylated by CDK5, then separates from microtubules and self-aggregates, and finally forms PHFs and insoluble NFTs in neurons [68] . Knockdown of CDK5 in triple transgenic (3xTg) AD mice, as well as inhibition of CDK5 with CDK5 inhibitory peptide in vitro, has been shown to reduce tau hyperphosphorylation and NFT formation [69] . Minocycline alleviates AD-like pathology and improves cognitive impairment by inhibiting the CDK5/p25 signaling pathway [70] .…”

Section: Tau Phosphorylation Inhibitorsmentioning

confidence: 99%

Tau-targeting therapy in Alzheimer’s disease: critical advances and future opportunities

Guo¹,

Li²,

Zeng³

et al. 2022

Ageing Neur Dis

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by two pathological hallmark lesions: extracellular plaques composed of β-amyloid (Aβ) peptide and intracellular neurofibrillary tangles made up of highly phosphorylated tau protein. Over the past two decades, most disease-modifying therapies against AD have been developed mainly on the basis of the amyloid cascade hypothesis with a focus on Aβ. However, these agents yielded only limited benefits against disease progression, which prompts us to revitalize the long-neglected tau hypothesis. Tau protein is a microtubule-associated protein, which can stabilize microtubules, regulate microtubule assembly, and affect the morphology and growth of neuronal axons. Much more importantly, the degree of tau pathology is more closely related to cognitive decline in AD patients than that of Aβ pathology. Therefore, tau-targeting therapy seems to be a promising approach to combat AD. This review describes the research progress of tau-targeting therapy in AD, with an emphasis on immunotherapy. The current challenges and future perspectives in this field are also discussed.

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“…Transgenic expression of Cdk5 inhibitory peptide before and after the insult of p25 could both suppress hippocampal tau phosphorylation and neuronal death, improve the cognitive dysfunction of model mice ( Xu et al, 2019 ; Huang et al, 2020 ). Inhibition of Cdk5/p25 complex also reduced hippocampal Aβ production and tau hyperphosphorylation, improved learning and memory abilities of AD model mice ( Zhao et al, 2021 ).…”

Section: Cyclin-dependent Kinases 5: a Culprit In Neurological Disordersmentioning

confidence: 99%

Focusing on cyclin-dependent kinases 5: A potential target for neurological disorders

Zhang

Bao

Wang

et al. 2022

Front. Mol. Neurosci.

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Cyclin-dependent kinases 5 (Cdk5) is a special member of proline-directed serine threonine kinase family. Unlike other Cdks, Cdk5 is not directly involved in cell cycle regulation but plays important roles in nervous system functions. Under physiological conditions, the activity of Cdk5 is tightly controlled by p35 or p39, which are specific activators of Cdk5 and highly expressed in post-mitotic neurons. However, they will be cleaved into the corresponding truncated forms namely p25 and p29 under pathological conditions, such as neurodegenerative diseases and neurotoxic insults. The binding to truncated co-activators results in aberrant Cdk5 activity and contributes to the initiation and progression of multiple neurological disorders through affecting the down-stream targets. Although Cdk5 kinase activity is mainly regulated through combining with co-activators, it is not the only way. Post-translational modifications of Cdk5 including phosphorylation, S-nitrosylation, sumoylation, and acetylation can also affect its kinase activity and then participate in physiological and pathological processes of nervous system. In this review, we focus on the regulatory mechanisms of Cdk5 and its roles in a series of common neurological disorders such as neurodegenerative diseases, stroke, anxiety/depression, pathological pain and epilepsy.

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Ameliorating Alzheimer’s-like Pathology by Minocycline via Inhibiting Cdk5/p25 Signaling

Cited by 9 publications

References 43 publications

Blockade of endocannabinoid system by oxytocin attenuates memory deficits in oxycodone‐treated rats

Blockade of endocannabinoid system by oxytocin attenuates memory deficits in oxycodone‐treated rats

Tau-targeting therapy in Alzheimer’s disease: critical advances and future opportunities

Focusing on cyclin-dependent kinases 5: A potential target for neurological disorders

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