Cyclin‐dependent kinase‐5 in neurodegeneration

The p53 tumor suppressor protein, a critical modulator of cellular stress responses, is activated through diverse mechanisms that result in its stabilization and transcriptional activation. p53 activity is controlled by transcriptional, translational, and post-translational regulation. The major mechanisms of p53 regulation occur primarily through interactions with HDM2, an E3 ubiquitin ligase that leads to p53 nuclear export and degradation. Here, we demonstrate that hydrogen peroxide-induced oxidative stress elicits down-regulation of HDM2.

Section: P53 Stabilization Occurs Post-translationally Via Hdm2supporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Cooperative Roles of c-Abl and Cdk5 in Regulation of p53 in Response to Oxidative Stress

Lee¹,

Jeong²,

Kim

et al. 2008

“…Tau is phosphorylated at over 38 serine/threonine residues by several kinases, including ERK and Cdk5 (50). Hyperphosphorylated Tau is observed in the APP/PS1 mice brain after the onset of A␤ plaques (51).…”

Section: Cast Overexpression Blocks Tau Phosphorylation and Improves mentioning

confidence: 99%

Calpain Activation Promotes BACE1 Expression, Amyloid Precursor Protein Processing, and Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease

Liang

Duan

Zhou

et al. 2010

Abnormal activation of calpain is implicated in synaptic dysfunction and participates in neuronal death in Alzheimer disease (AD) and other neurological disorders. Pharmacological inhibition of calpain has been shown to improve memory and synaptic transmission in the mouse model of AD. However, the role and mechanism of calpain in AD progression remain elusive. Here we demonstrate a role of calpain in the neuropathology in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, an established mouse model of AD. We found that overexpression of endogenous calpain inhibitor calpastatin (CAST) under the control of the calcium/calmodulindependent protein kinase II promoter in APP/PS1 mice caused a remarkable decrease of amyloid plaque burdens and prevented Tau phosphorylation and the loss of synapses. Furthermore, CAST overexpression prevented the decrease in the phosphorylation of the memory-related molecules CREB and ERK in the brain of APP/PS1 mice and improved spatial learning and memory. Interestingly, treatment of cultured primary neurons with amyloid-␤ (A␤) peptides caused an increase in the level of ␤-site APP-cleaving enzyme 1 (BACE1), the key enzyme responsible for APP processing and A␤ production. This effect was inhibited by CAST overexpression. Consistently, overexpression of calpain in heterologous APP expressing cells up-regulated the level of BACE1 and increased A␤ production. Finally, CAST transgene prevented the increase of BACE1 in APP/PS1 mice. Thus, calpain activation plays an important role in APP processing and plaque formation, probably by regulating the expression of BACE1. Aggregation of amyloid-␤ (A␤)3 peptides into compact plaques is a characteristic feature in the pathogenesis of Alzheimer disease (AD) (1, 2). Recently, it is suggested that soluble A␤ oligomers, in the process of aggregation, adversely affect synaptic structure and plasticity (2-9). A␤ peptides are generated in neurons by the sequential proteolytic cleavage of the transmembrane glycoprotein amyloid precursor protein (APP) that is cleaved initially by ␤-site APP-cleaving enzyme 1 (BACE1, also known as ␤-secretase) and subsequently by ␥-secretase, whose activity is associated with a presenilin (PS)-containing macromolecular complex (10 -12), in the transmembrane region of APP (13,14). Thus, BACE1 has been proposed to be a therapeutic target for AD (15).Calpains are a family of calcium-activated intracellular cysteine proteases that are involved in many physiological events including long term potentiation (16 -18) or neurotoxic insults ranging from ischemia to Alzheimer disease (19 -21). Inhibition of calpain by synthetic inhibitors exerts neuroprotection in various models of brain injuries, such as ischemia or excitotoxicity-induced neuronal death (22-24). Interestingly, A␤ aggregation is associated with neuronal and astrocytic calcium dysregulation (25-27). Treatment of cultured cortical neurons with A␤ oligomers caused calcium influx and subsequently calpain activation (21).A number of proteins hav...

“…13-15; for review, see Ref. 16). GSK3 generates diseaseassociated phospho-epitopes on tau (17) and co-localizes with aggregates of hyperphosphorylated tau (18).…”

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confidence: 99%

The Roles of Cyclin-dependent Kinase 5 and Glycogen Synthase Kinase 3 in Tau Hyperphosphorylation

Plattner

Angelo

Giese

2006

320

270

Hyperphosphorylation of the microtubule-associated protein tau is a characteristic feature of neurodegenerative tauopathies including Alzheimer disease. Over-activation of proline-directed kinases, such as cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3 (GSK3), has been implicated in the aberrant phosphorylation of tau at prolinedirected sites. In this study we tested the roles of Cdk5 and GSK3 in tau hyperphosphorylation in vivo using transgenic mice with p25-induced Cdk5 over-activation. We found that over-activation of Cdk5 in young transgenic animals does not induce tau hyperphosphorylation at sites recognized by the antibodies AT8, AT100, PHF-1, and TG3. In fact, we observed that Cdk5 over-activation leads to inhibition of GSK3. However, in old transgenic animals the inhibition of GSK3 is lost and results in increased GSK3 activity, which coincides with tau hyperphosphorylation at the AT8 and PHF-1 sites. Pharmacological inhibition of GSK3 in old transgenic mice by chronic treatment with lithium leads to a reduction of the age-dependent increase in tau hyperphosphorylation. Furthermore, we found that Cdk5, GSK3, and PP2A co-immunoprecipitate, suggesting a functional association of these molecules. Together, these results reveal the role of GSK3 as a key mediator of tau hyperphosphorylation, whereas Cdk5 acts as a modulator of tau hyperphosphorylation via the inhibitory regulation of GSK3. Furthermore, these findings suggest that disruption of regulation of GSK3 activity underlies tau hyperphosphorylation in neurodegenerative tauopathies. Hence, GSK3 may be a prime target for therapeutic intervention in tauopathies including Alzheimer disease.