Suppression of Cyclin-Dependent Kinase 5 Activation by Amyloid Precursor Protein: A Novel Excitoprotective Mechanism Involving Modulation of Tau Phosphorylation

Han, Ping; Dou, Fei; Feng, Li; Zhang, Xue; Zhang, Yunwu; Zheng, Hui; Lipton, Stuart A.; Xu, Huaxi; Liao, Francesca‐Fang

doi:10.1523/jneurosci.3831-05.2005

Cited by 80 publications

(76 citation statements)

References 71 publications

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“…In addition to a possible direct influence on CDK5 activation, ATRA may inhibit CDK5 through stabilizing APP. Because APP has been shown to reciprocally regulate CDK5 activity (Han et al, 2005), ATRA-induced inhibition of APP processing observed in APP/PS1 mice may cause an enhanced stability of APP, thereby resulting in indirect inhibition of CDK5 activity and attenuation of tau phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Ding¹,

et al. 2008

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Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to ␤-amyloid (A␤) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain A␤ deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/ PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.

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Section: Discussionmentioning

confidence: 99%

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Ding¹,

et al. 2008

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“…However, a study by Han et al demonstrated that defects in neurite outgrowth and branching seen in the primary neuronal cultures isolated from APP knockout (APP KO) mice were restored by sAPPα (Han et al, 2005). This neurotrophic effect of sAPPα was suggested to be due to its inhibitory effect on cyclin-dependent kinase 5 (CDK5), as addition of the CDK5 inhibitor roscovitine was reported to increase neuritic outgrowth on glutamate-treated primary neuronal cultures from APP KO mice (Han et al, 2005). While there is no direct evidence linking the effects of sAPPα on CDK5 to neuronal hypertrophy, they may be explored in future studies.…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein increases cortical neuron size in transgenic mice

Savonenko

King

et al. 2009

Neurobiology of Aging

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The amyloid precursor protein (APP) is the source of β-amyloid, a pivotal peptide in the pathogenesis of Alzheimer's disease (AD). This study examines the possible effect of APP transgene expression on neuronal size by measuring the volumes of cortical neurons (μm 3 ) in transgenic mouse models with familial AD Swedish mutation (APPswe), with or without mutated presenilin1 (PS1dE9), as well as in mice carrying wild-type APP (APPwt). Overexpression of APPswe and APPwt protein, but not of PS1dE9 alone, resulted in a greater percentage of medium-sized neurons and a proportionate decrease in the percentage of small-sized neurons. Our observations indicate that the overexpression of mutant (APPswe) or wild-type APP in transgenic mice is necessary and sufficient for hypertrophy of cortical neurons. This is highly suggestive of a neurotrophic effect and also raises the possibility that the lack of neuronal loss in transgenic mouse models of AD may be attributed to overexpression of APP.

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“…After 7 days, cells were infected independently or co-infected with empty vector (EV), the constructs of p5, p25, p35, wild-type Cdk5, and dominant negative Cdk5 (changing Lys 33 to Thr 33 ) using the adenoviral vector (pAdTrack-CMV) packaging system as described above. After 48 h, cells were treated with roscovitine (20 M) for 1 h and/or for 6 h with 10 M A␤(1-42) (incubated at 37°C for 7 days before use).…”

Section: Methodsmentioning

confidence: 99%

“…It reduces Tau hyperphosphorylation and protects transfected HEK cells and neurons from apoptosis induced by Cdk5-p25 (23,27,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). To produce a smaller and more effective inhibitory peptide of Cdk5-p25 for potential therapeutic use, we designed and constructed five short peptides in GST vectors, as shown in Fig.…”

Section: Identification Of Cdk5-inhibitory Peptides Derived From P35-mentioning

confidence: 99%

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

Zheng

Amin

et al. 2010

Journal of Biological Chemistry

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The activity of Cdk5-p35 is tightly regulated in the developing and mature nervous system. Stress-induced cleavage of the activator p35 to p25 and a p10 N-terminal domain induces deregulated Cdk5 hyperactivity and perikaryal aggregations of hyperphosphorylated Tau and neurofilaments, pathogenic hallmarks in neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis, respectively. Previously, we identified a 125-residue truncated fragment of p35 called CIP that effectively and specifically inhibited Cdk5-p25 activity and Tau hyperphosphorylation induced by A␤ peptides in vitro, in HEK293 cells, and in neuronal cells. Although these results offer a possible therapeutic approach to those neurodegenerative diseases assumed to derive from Cdk5-p25 hyperactivity and/or A␤ induced pathology, CIP is too large for successful therapeutic regimens. To identify a smaller, more effective peptide, in this study we prepared a 24-residue peptide, p5, spanning CIP residues Lys 245 -Ala 277 . p5 more effectively inhibited Cdk5-p25 activity than did CIP in vitro. In neuron cells, p5 inhibited deregulated Cdk5-p25 activity but had no effect on the activity of endogenous Cdk5-p35 or on any related endogenous cyclin-dependent kinases in HEK293 cells. Specificity of p5 inhibition in cortical neurons may depend on the p10 domain in p35, which is absent in p25. Furthermore, we have demonstrated that p5 reduced A␤(1-42)-induced Tau hyperphosphorylation and apoptosis in cortical neurons. These results suggest that p5 peptide may be a unique and useful candidate for therapeutic studies of certain neurodegenerative diseases.The activity of Cdk5, a multifunctional serine/threonine kinase, is critical for neuronal development and synaptic activity; it sustains neurite outgrowth, neuronal migration, cortical lamination, and survival (1-9). Its activity depends on the binding of its neuron-specific, cyclin-related activators, p35 and p39 (10, 11). Cdk5 has also been implicated as a key player in learning and memory (12-15).Normally, Cdk5 activity is tightly regulated, but under conditions of neuronal stress, it is deregulated, leading to hyperactivity, neuronal pathology, and cell death. Accordingly, Cdk5 has been implicated in certain neurodegenerative disorders, such as AD.2 A model of the role of Cdk5 in neurodegeneration suggests that a stress-induced influx of calcium ions into neurons activates calpain, a Ca 2ϩ -activated protease, which cleaves p35 into p25 and a p10 fragment. p25, in turn, forms a more stable Cdk5-p25 hyperactive complex, which hyperphosphorylates Tau and induces cell death (16 -21). Indeed, increased levels of p25 and Cdk5 activity have been reported in AD brains. The finding that p25 may be toxic comes from studies of cortical neurons treated with ␤-amyloid (A␤), a key marker of AD pathology, where p35 is converted to p25 accompanied by activated Cdk5, Tau hyperphosphorylation, and apoptosis (22,23).Expression of the Cdk5-p25 complex seems to be primarily responsible for the Tau pathology ...

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Suppression of Cyclin-Dependent Kinase 5 Activation by Amyloid Precursor Protein: A Novel Excitoprotective Mechanism Involving Modulation of Tau Phosphorylation

Cited by 80 publications

References 71 publications

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Amyloid precursor protein increases cortical neuron size in transgenic mice

A 24-Residue Peptide (p5), Derived from p35, the Cdk5 Neuronal Activator, Specifically Inhibits Cdk5-p25 Hyperactivity and Tau Hyperphosphorylation

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