Atypical Protein Kinase C in Neurodegenerative Disease I

Crary, John F.; Shao, Charles; Mirra, Suzanne S.; Hernández, A. Iván; Sacktor, Todd Charlton

doi:10.1097/01.jnen.0000218442.07664.04

Cited by 50 publications

(27 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous results have shown that PKMζ is present in neocortex, including motor cortex [16]–[18]. We found that bilateral injections of the PKMζ inhibitor ZIP into the sensorimotor cortex of rats erased the sensorimotor memories learned in a skilled reach-to-grasp task [19].…”

Section: Discussionmentioning

confidence: 55%

Erasing Sensorimotor Memories via PKMζ Inhibition

2010

View full text Add to dashboard Cite

Sensorimotor cortex has a role in procedural learning. Previous studies suggested that this learning is subserved by long-term potentiation (LTP), which is in turn maintained by the persistently active kinase, protein kinase Mzeta (PKMζ). Whereas the role of PKMζ in animal models of declarative knowledge is established, its effect on procedural knowledge is not well understood. Here we show that PKMζ inhibition, via injection of zeta inhibitory peptide (ZIP) into the rat sensorimotor cortex, disrupts sensorimotor memories for a skilled reaching task even after several weeks of training. The rate of relearning the task after the memory disruption by ZIP was indistinguishable from the rate of initial learning, suggesting no significant savings after the memory loss. These results indicate a shared molecular mechanism of storage for declarative and procedural forms of memory.

show abstract

Section: Discussionmentioning

confidence: 55%

Erasing Sensorimotor Memories via PKMζ Inhibition

2010

View full text Add to dashboard Cite

show abstract

“…KIBRA also interacts with the protein kinase Mζ (PKMζ) (Buther et al, 2004), an active atypical PKC isoform that plays a role in LTP maintenance (Serrano et al, 2005) and memory (Drier et al, 2002). PKMζ accumulates in NFTs in human AD brain (Crary et al, 2006), raising the possibility of a mechanistic link between tau, KIBRA and PKMζ. Taken together, our results demonstrate that acetylated tau in AD disrupts one or more KIBRA-mediated signaling pathways that are crucial for the expression of synaptic plasticity.…”

Section: Discussionmentioning

confidence: 99%

Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss

Tracy

Sohn

Minami

et al. 2016

Neuron

210

246

View full text Add to dashboard Cite

Summary Tau toxicity has been implicated in the emergence of synaptic dysfunction in Alzheimer’s disease (AD), but the mechanism by which tau alters synapse physiology and leads to cognitive decline is unclear. Here, we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIBRA (KIdney/BRAin protein), a memory-associated protein. Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA. These findings suggest a novel mechanism by which pathogenic tau causes synaptic dysfunction and cognitive decline in AD pathogenesis.

show abstract

“…The assay’s procedures were based on those used in our previous studies (Lu et al, 2003, 2005; Li et al, 2008) and previous studies of Sacktor and colleagues (Sacktor et al, 1993; Hrabetova and Sacktor, 1996; Naik et al, 2000; Crary et al, 2006; Kelly et al, 2007; Yao et al, 2008). Loading buffer (4×; 16% glycerol, 20% mercaptoethanol, 2% SDS, 0.05% bromophenol blue) was added to each sample (3:1, sample:loading buffer) before boiling for 3 min.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of PKMζ in Nucleus Accumbens Core Abolishes Long-Term Drug Reward Memory

Li¹,

Xue²,

He³

et al. 2011

J. Neurosci.

102

View full text Add to dashboard Cite

During abstinence, memories of drug-associated cues persist for many months, and exposure to these cues often provokes relapse to drug use. The mechanisms underlying the maintenance of these memories are unknown. A constitutively active atypical protein kinase C (PKC) isozyme, protein kinase M ζ (PKMζ), is required for maintenance of spatial memory, conditioned taste aversion, and other memory forms. We used conditioned place preference (CPP) and conditioned place aversion (CPA) procedures to study the role of nucleus accumbens PKMζ in the maintenance of drug reward and aversion memories in rats. Morphine CPP training (10 mg/kg, 4 pairings) increased PKMζ levels in accumbens core but not shell. Injections of the PKMζ inhibitor ζ inhibitory peptide (ZIP) into accumbens core but not shell after CPP training blocked morphine CPP expression for up to 14 d after injections. This effect was mimicked by the PKC inhibitor chelerythrine, which inhibits PKMζ, but not by the conventional and novel PKC inhibitor staurosporine, which does not effectively inhibit PKMζ. ZIP injections into accumbens core after training also blocked the expression of cocaine (10 mg/kg) and high-fat food CPP but had no effect on CPA induced by naloxone-precipitated morphine withdrawal. Accumbens core injections of Tat-GluR23Y, which inhibits GluR2-dependent AMPA receptor endocytosis, prevented the impairment in morphine CPP induced by local ZIP injections, indicating that the persistent effect of PKMζ is on GluR2-containing AMPA receptors. Results indicate that PKMζ activity in accumbens core is a critical cellular substrate for the maintenance of memories of relapse-provoking reward cues during prolonged abstinence periods.

show abstract

Atypical Protein Kinase C in Neurodegenerative Disease I

Cited by 50 publications

References 21 publications

Erasing Sensorimotor Memories via PKMζ Inhibition

Erasing Sensorimotor Memories via PKMζ Inhibition

Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss

Inhibition of PKMζ in Nucleus Accumbens Core Abolishes Long-Term Drug Reward Memory

Contact Info

Product

Resources

About