Activation of Protein Kinase C Isozymes for the Treatment of Dementias

https://doi.org/10.1016/B978-0-12-394816-8.00008-8Get rights and content

Abstract

Memories are much more easily impaired than improved. Dementias, a lasting impairment of memory function, occur in a variety of cognitive disorders and become more clinically dominant as the population ages. Protein kinase C is one of the “cognitive kinases,” and plays an essential role in both memory acquisition and maintenance. Deficits in protein kinase C (PKC) signal cascades in neurons represent one of the earliest changes in the brains of patients with Alzheimer’s disease (AD) and other types of memory impairment, including those related to cerebral ischemia and ischemic stroke. Inhibition or impairment of PKC activity results in compromised learning and memory, whereas an appropriate activation of certain PKC isozymes leads to an enhancement of learning and memory and/or antidementic effects. In preclinical studies, PKC activators have been shown to increase the expression and activity of PKC isozymes, thereby restoring PKC signaling and downstream activity, including stimulation of neurotrophic activity, synaptic/structural remodeling, and synaptogenesis in the hippocampus and related cortical areas. PKC activators also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation and support anti-apoptotic processes in the brain. These observations strongly suggest that PKC pharmacology may represent an attractive area for the development of effective cognition-enhancing therapeutics for the treatment of dementias.

Introduction

Dementia, a lasting impairment of memory function, represents a major challenge to modern medicine. According to Alzheimer’s Disease International, the total worldwide cost of care for patients with dementias in 2010 is $604 billion (Alzheimer’s Disease International, 2010), which is also set to soar as the population ages in the near future. Dementias—including Alzheimer’s disease (AD), vascular dementia, dementia with Lewy bodies, and frontotemporal dementia—are memory disorders that are caused by a variety of neural impairments or injuries that lead to compromised cognitive function. There are currently no curative therapeutics for any type of dementia, highlighting an unmet and urgent need for the development of new, cost-effective agents that can target the processes of neural injury that lead to cognitive dysfunction and memory impairment characteristic of dementia.

Cognition, including the formation and retention of memories, results from activity-generated (i.e., acquiring experience and maintaining knowledge of that experience) neuronal Ca2+ and other signals that promote gene transcription and protein synthesis in the brain. Protein kinase C (PKC) belongs to a multigene family of phospholipid-dependent serine–threonine kinases, and is part of an essential signaling network in the brain. PKC isoforms are critically involved in modulating synaptic function/transmission; neurite outgrowth/neuronal plasticity; functions of membrane proteins, including enzymes and channels; neuronal metabolism, inflammation, carcinogenesis, proliferation, and gene expression; neuroprotection and neurodegeneration; and behavior, learning, and memory (Alkon et al., 1998, Hama et al., 2004). PKC signaling cascades are impaired or become dysfunctional in many disease processes, and loss of normal PKC signaling may underlie the pathogenesis of various brain disorders, including dementias. Thus, the PKC signaling system represents an important target for discovering new therapeutics for dementias.

Section snippets

PKC Isoforms

Twelve PKC isoforms have so far been identified in mammals. Based on their homology and sensitivity to activators, they are commonly divided into three subgroups (Fig. 1): (1) classical PKC (cPKC); (2) novel PKC (nPKC); and (3) atypical PKC (aPKC). The number of isoforms differs from other species. For example, in Aplysia, at least three isoforms, Apls I, II, and III, have been identified so far.

The cPKC subgroup members contain four homologous domains (C1, C2, C3, and C4) separated by

Memory and Alzheimer’s Dementia

PKC isoforms play a critical role in learning and memory. PKCε activation results in an enhanced BDNF activity, which increases hippocampal expression of the Ca2+ release channel isoforms ryanodine receptor RyR2, RyR3 (Fig. 2), and PKMζ in the hippocampus (Adasme et al., 2011). PKMζ is believed to play key roles in hippocampal memory maintenance (Shema et al., 2011), through several mechanisms, including persistent inhibition of GluR2-AMPAR removal from the surface of postsynaptic sites (Migues

Ischemic Dementia

It has been well established that ischemia and hypoxia dramatically impair cognitive function. Not only are synapses and neural structures directly impaired by ischemia, but also the process of acquiring and maintaining knowledge that requires energy. PKC is involved in synaptic dysfunction and memory impairments in patients surviving ischemic events (cerebral ischemia, cardiac arrest, etc.; Perez-Pinzon et al., 2005). Global cerebral ischemia triggers DAG kinase (DGK)ξ translocation from the

Conclusion

PKC isoforms are distributed in neuronal structures and involved in a broad range of vital functions (Brenner et al., 2004, Lee et al., 2006, Pascale et al., 2007). PKC is ubiquitously and densely expressed in the brain (Saito et al., 1988) and activated by Ca2+, phospholipids and DAG, phorbol esters, and other PKC activators.

PKC activators, such as DAG, arachidonic acid, phorbol esters, bryostatins, aplysiatoxins, and teleocidins, bind to a hydrophilic cleft in a largely hydrophobic surface of

References (213)

  • S. Chaki et al.

    Involvement of protein kinase C activation of acetylcholine release from rat hippocampal slices by minaprine

    Neurochemistry International

    (1994)
  • A. Chauhan et al.

    Action of amyloid beta-protein on protein kinase C activity

    Life Sciences

    (1991)
  • Y. Chen et al.

    Specific modulation of Na+ channels in hippocampal neurons by protein kinase C epsilon

    Journal of Neuroscience

    (2005)
  • Y. Chen et al.

    Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C

    Neuron

    (2006)
  • J.H. Cho et al.

    Glycogen synthase kinase 3 beta induces caspase-cleaved tau aggregation in situ

    The Journal of Biological Chemistry

    (2004)
  • G. Cole et al.

    Decreased levels of protein kinase C in Alzheimer brain

    Brain Research

    (1988)
  • L. Conboy et al.

    Curcumin-induced degradation of PKC delta is associated with enhanced dentate NCAM PSA expression and spatial learning in adult and aged Wistar rats

    Biochemical Pharmacology

    (2009)
  • D. Della-Morte et al.

    Post-ischemic activation of protein kinase C epsilon protects the hippocampus from cerebral ischemic injury via alterations in cerebral blood flow

    Neuroscience Letters

    (2011)
  • F. Desdouits et al.

    Amyloid alpha peptide formation in cell-free preparations. Regulation by protein kinase C, calmodulin, and calcineurin

    The Journal of Biological Chemistry

    (1996)
  • K. Dev et al.

    The PDZ domain of PICK1 differentially accepts protein kinase C-α and GluR2 as interacting ligands

    The Journal of Biological Chemistry

    (2004)
  • T. Dobransky et al.

    Protein kinase C isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity

    Journal of Neurochemistry

    (2004)
  • E.A. Eckman et al.

    Degradation of the Alzheimer’s amyloid β peptide by endothelin-converting enzymes

    The Journal of Biological Chemistry

    (2001)
  • L. Gao et al.

    Activation of protein kinase C reduces benzodiazepine potency at GABAA receptors in NT2-N neurons

    Neuropharmacology

    (2005)
  • R.W. Gereau et al.

    Role of protein kinase C phosphorylation in rapid desensitization of metabolic glutamate receptor 5

    Neuron

    (1998)
  • H. Hama et al.

    PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes

    Neuron

    (2004)
  • C. Hoareau et al.

    Amyloid precursor protein cytoplasmic domain antagonizes reelin neurite outgrowth inhibition of hippocampal neurons

    Neurobiology of Aging

    (2008)
  • C. Holmes et al.

    Long-term effects of Abeta42 immunisation in Alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase I trial

    Lancet

    (2008)
  • D. Jerusalinsky et al.

    Post-training intrahippocampal infusion of protein kinase C inhibitors causes amnesia in rats

    Behavioral and Neural Biology

    (1994)
  • J. Jo et al.

    Metabotropic glutamate receptor-mediated LTD involves two interacting Ca2+ sensors, NCS-1 and PICK1

    Neuron

    (2008)
  • J.A. Johnson et al.

    A protein kinase C translocation inhibitor as an isozyme-selective antagonist of cardiac function

    The Journal of Biological Chemistry

    (1996)
  • L.K. Kaczmarek

    The role of protein kinase C in the regulation of ion channels and neurotransmitter release

    Trends in Neurosciences

    (1987)
  • T. Kanno et al.

    The linoleic acid derivative DCP-LA selectively activates PKC-epsilon, possibly binding to the phosphatidylserine binding site

    Journal of Lipid Research

    (2006)
  • T. Kinouchi et al.

    Conventional protein kinase C (PKC)-alpha and novel PKC epsilon, but not–delta, increase the secretion of an N-terminal fragment of Alzheimer’s disease amyloid precursor protein from PKC cDNA transfected 3Y1 fibroblasts

    FEBS Letters

    (1995)
  • M. Kitazawa et al.

    Dieldrin induces apoptosis by promoting caspase-3-dependent proteolytic cleavage of protein kinase Cδ in dopaminergic cells: Relevance to oxidative stress and dopaminergic degeneration

    Neuroscience

    (2003)
  • B.J. Krishek et al.

    Regulation of GABAA receptor function by protein kinase C phosphorylation

    Neuron

    (1994)
  • T. Kubo et al.

    Protein kinase C activation-induced increases of neural activity are enhanced in the hypothalamus of spontaneously hypertensive rats

    Brain Research

    (2005)
  • Y.-T. Lai et al.

    Activation of amygdaloid PKC pathway is necessary for conditioned cues-provoked cocaine memory performance

    Neurobiology of Learning and Memory

    (2008)
  • L. Lavoie et al.

    Regulation of glycogen synthase in rat hepatocytes. Evidence for multiple signaling pathway

    The Journal of Biological Chemistry

    (1999)
  • W. Lee et al.

    Amyloid beta peptide directly inhibits PKC activation

    Molecular and Cellular Neurosciences

    (2004)
  • T. Adasme et al.

    Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation

    Proceedings of the National Academy of Sciences of the United States of America

    (2011)
  • N.J. Alkayed et al.

    Gender-linked brain injury in experimental stroke

    Stroke

    (1998)
  • D.L. Alkon et al.

    A spatial-temporal model of cell activation

    Science

    (1988)
  • D.L. Alkon et al.

    Protein synthesis required for long-term memory is induced by PKC activation on days before associative learning

    Proceedings of the National Academy of Sciences of the United States of America

    (2005)
  • Alzheimer’s Disease International

    World Alzheimer Report 2010. The global economic impact of dementia

    (2010)
  • B. Bank et al.

    Classical conditioning induces long-term translocation of protein kinase C in rabbit hippocampal CA1 cells

    Proceedings of the National Academy of Sciences of the United States of America

    (1988)
  • A. Basu et al.

    Two faces of protein kinase Cδ: The contrasting roles of PKCδ in cell survival and cell death

    The Science World Journal

    (2010)
  • P.E. Bickler et al.

    Hypoxia increases calcium flux through cortical neuron glutamate receptor via protein kinase C

    Journal of Neurochemistry

    (2004)
  • A.R. Brennan et al.

    Protein kinase C activity is associated with prefrontal cortical decline in aging

    Neurobiology of Aging

    (2007)
  • G. Brenner et al.

    Peripheral noxious stimulation induces phosphorylation of the NMDA receptor NR1 subunit at the PKC-dependent site, serine-896, in spinal cord dorsal horn neurons

    The European Journal of Neuroscience

    (2004)
  • R. Bright et al.

    Protein kinase C delta mediates cerebral reperfusion injury in vivo

    Journal of Neuroscience

    (2004)

    • Cited by (0)

    View full text
    Copyright © 2012 Elsevier Inc. All rights reserved.