Differential involvement of protein kinase C alpha and epsilon in the regulated secretion of soluble amyloid precursor protein

Lanni, Cristina; Mazzucchelli, Michela; Porrello, Emanuela; Govoni, Stefano; Racchi, Marco

doi:10.1111/j.1432-1033.2004.04240.x

Cited by 47 publications

(37 citation statements)

References 39 publications

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“…Thus, part of the effect could also be mediated by induction of PKC⑀ by PMA. Decreased expression of PKC⑀ also reduces cholinergic regulation of sAPP␣ levels (34), which is consistent with the theory that sAPP␣ and A␤ compete for a limited pool of APP. Thus, in cells in which APP is rate-limiting, direct or indirect activation of ␣-secretase by PKC⑀ could also reduce A␤ levels.…”

Section: Discussionsupporting

confidence: 87%

Reduction of β-Amyloid Levels by Novel Protein Kinase Cϵ Activators

Nelson

Cui

Luo

et al. 2009

Journal of Biological Chemistry

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Isoform-specific protein kinase C (PKC) activators may be useful as therapeutic agents for the treatment of Alzheimer disease. Three new ⑀-specific PKC activators, made by cyclopropanation of polyunsaturated fatty acids, have been developed. These activators, AA-CP4, EPA-CP5, and DHA-CP6, activate PKC⑀ in a dose-dependent manner. Unlike PKC activators that bind to the 1,2-diacylglycerol-binding site, such as bryostatin and phorbol esters, which produce prolonged down-regulation, the new activators produced sustained activation of PKC. When applied to cells expressing human APPSwe/PS1␦, which produce large quantities of ␤-amyloid peptide (A␤), DCP-LA and DHA-CP6 reduced the intracellular and secreted levels of A␤ by 60 -70%. In contrast to the marked activation of ␣-secretase produced by PKC activators in fibroblasts, the PKC activators produced only a moderate and transient activation of ␣-secretase in neuronal cells. However, they activated endothelin-converting enzyme to 180% of control levels, suggesting that the A␤-lowering ability of these PKC⑀ activators is caused by increasing the rate of A␤ degradation by endothelin-converting enzyme and not by activating nonamyloidogenic amyloid precursor protein metabolism.Alzheimer disease is characterized by the accumulation of aggregated ␤-amyloid (A␤), 2 which is a 4-kDa peptide produced by the proteolytic cleavage of amyloid precursor protein (APP) by ␤-and ␥-secretases. Oligomers of A␤ are the most toxic, whereas fibrillar A␤ is largely inert. Monomeric A␤ is found in normal patients and has an as-yet undetermined function. The earliest consistent cytopathological change in Alzheimer disease is loss of synapses (1, 2). Finding a way to protect against the loss of synapses is a major therapeutic goal. Protein kinase C (PKC) activators have demonstrated neuroprotective activity in animal models of Alzheimer disease (3), depression (4), and stroke (5). Bryostatin, a potent PKC activator, also increases the rate of learning in rodents, rabbits, and invertebrates (4, 6, 7). This effect is accompanied by increases in levels of synaptic proteins spinophilin and synaptophysin and structural changes in synaptic morphology (8). PKC activators also can reduce the levels of A␤ and prolong the survival of Alzheimer disease transgenic mice (3). Evidence suggests that PKC␣ and ⑀ are the most important PKC isoforms in eliciting these changes. Antisense inhibition of PKC␣ blocks secretion of sAPP␣, whereas indirect activators of PKC, such as carbachol, increase sAPP␣ secretion (9). Experiments with specific PKC isozyme inhibitors also point to PKC⑀ as the isozyme that most effectively suppresses A␤ production (10). Thus, isoform-specific PKC activators are highly desirable as potential anti-Alzheimer drugs. Specific activators are preferable to compounds such as bryostatin that show less specificity among conventional and novel forms of PKC because nonspecific activation of PKC␦ or ␤ could produce undesirable side effects.One compound known to activate PKC⑀ specifically is DCP-LA...

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Section: Discussionsupporting

confidence: 87%

Reduction of β-Amyloid Levels by Novel Protein Kinase Cϵ Activators

Nelson

Cui

Luo

et al. 2009

Journal of Biological Chemistry

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“…In vitro studies have demonstrated that different PKC isoforms play distinct roles in APP processing. PKCa is specifically involved in phorbol ester-induced sAPPa release, while PKCe is involved in coupling cholinergic receptors with APP metabolism (12). In vivo studies using a guinea-pig model with constitutive overactivation of PKCa and -b isoforms have shown an increase in sAPPa production, indicating that these isoforms are key regulators of a -secretory APP processing (13).…”

Section: Role Of Pkc In Ab Generationmentioning

confidence: 99%

Amyloid Pathology and Protein Kinase C (PKC): Possible Therapeutics Effects of PKC Activators

2005

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Abstract. Amyloid b-protein (Ab) is one of the most studied peptides in human neurodegenerative disorders. Although much has been learned about the biochemistry of this peptide, fundamental questions such as when and how the Ab becomes pathologic remain unanswered. In this article we review the recent findings on the biology and pathology of Ab and the role protein kinase C (PKC) plays in these processes. The potential neuroprotective role of PKC and the possible therapeutic effects of PKC activators in Alzheimer's disease (AD) will be discussed. Briefly, comments will be also addressed on the role of PKC in cell death and neurogenesis in AD.

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“…One of these functions promotes the cleavage and release of soluble signaling proteins that are ini-tially synthesized as membrane-spanning precursors. In addition to NRG1, other proteins released upon PKC activation include epidermal growth factor, transforming growth factor-␣, amyloid precursor protein, L-selectin, and interleukins (1,(37)(38)(39)(40)(41)(42)(43). We hypothesize that neurotrophic factors induce the cleavage and release of NRG1 from pro-NRG1 through PKC activation.…”

mentioning

confidence: 99%

Neurotrophins Induce Neuregulin Release through Protein Kinase Cδ Activation

Esper

Loeb

2009

Journal of Biological Chemistry

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Proper, graded communication between different cell types is essential for normal development and function. In the nervous system, heart, and for some cancer cells, part of this communication requires signaling by soluble and membrane-bound factors produced by the NRG1 gene. We have previously shown that glial-derived neurotrophic factors activate a rapid, localized release of soluble neuregulin from neuronal axons that can, in turn promote proper axoglial development (Esper, R. M., and Loeb, J. A. (2004) J. Neurosci. 24, 6218 -6227). Here we elucidate the mechanism of this localized, regulated release by implicating the delta isoform of protein kinase C (PKC). Blocking the PKC delta isoform with either rottlerin, a selective antagonist, or small interference RNA blocks the regulated release of neuregulin from both transfected cells and primary neuronal cultures. PKC activation also leads to the rapid phosphorylation of the pro-NRG1 cytoplasmic tail on serine residues adjacent to the membrane-spanning segment, that, when mutated markedly reduce the rate of NRG1 activity release. These findings implicate this specific PKC isoform as an important factor for the cleavage and neurotrophin-regulated release of soluble NRG1 forms that have important effects in nervous system development and disease.The neuregulins (NRGs) 2 are a family of growth and differentiation factors with a broad range of functions during development and in the adult. NRGs are necessary for glial and cardiac development and participate in a wide range of biologic processes ranging from proper formation of peripheral nerves and the neuromuscular junction to tumor growth (2-9). The NRGs have also been implicated as both potential mediators and therapeutic targets for a number of human diseases including cancer, schizophrenia, and multiple sclerosis (10 -12). NRGs function as mediators of cell-to-cell communication through a multitude of alternatively spliced isoforms arising from at least four distinct genes that bind to and activate members of the epidermal growth factor receptor family HER-2/3/4 (ErbB-2/3/4) (13)(14)(15)(16)(17)(18)(19).Although all known isoforms of the NRG1 gene have an epidermal growth factor-like domain sufficient to bind to and activate its receptors (20), products of this gene are divided into three classes based on structurally and functionally different N-terminal regions (21) The type I and II forms have a unique N-terminal, heparin-binding Ig-like domain (22)(23)(24)(25)(26). This Iglike domain potentiates the biological activities of soluble NRG1 forms and leads to their highly selective tissue distributions through its affinity for specific cell-surface heparan sulfates (12,20,27,28). These forms are first expressed as transmembrane precursors (pro-NRG1) that undergo proteolytic cleavage to release their soluble ectodomains. The type III NRG1 forms, on the other hand, are not typically released from cells, because their N-terminal domain consists of a cysteinerich domain that can serve as a membrane tether making t...

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Differential involvement of protein kinase C alpha and epsilon in the regulated secretion of soluble amyloid precursor protein

Cited by 47 publications

References 39 publications

Reduction of β-Amyloid Levels by Novel Protein Kinase Cϵ Activators

Reduction of β-Amyloid Levels by Novel Protein Kinase Cϵ Activators

Amyloid Pathology and Protein Kinase C (PKC): Possible Therapeutics Effects of PKC Activators

Neurotrophins Induce Neuregulin Release through Protein Kinase Cδ Activation

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