Protein Kinase C Activators as Synaptogenic and Memory Therapeutics

Sun, Miao‐Kun; Alkon, Daniel L.

doi:10.1002/ardp.200900050

Cited by 27 publications

(19 citation statements)

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“…Overexpression of PSD-95 converts silent synapses to functional synapses (58), whereas synaptophysin may be required for increased presynaptic vesicle density, thereby facilitating neurotransmitter release (59). We found that overexpressing PKC⑀ in primary human neurons induces the mRNA and protein levels of PSD-95 and synaptophysin, whereas knockdown of PKC⑀ reduces PSD-95 and synaptophysin mRNA and protein levels.…”

Section: Discussionmentioning

confidence: 76%

Protein Kinase Cϵ (PKCϵ) Promotes Synaptogenesis through Membrane Accumulation of the Postsynaptic Density Protein PSD-95

Sen

Hongpaisan

Wang

et al. 2016

Journal of Biological Chemistry

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Protein kinase C⑀ (PKC⑀) is one of the novel PKC isotypes and is characterized as a calcium-independent and phorbol ester/diacylglycerol-sensitive serine/threonine kinase. Among the novel PKCs, PKC⑀ is the most abundant species in the central nervous system, mediating various neuronal functions (1, 2). In neuroblastoma cells overexpression of PKC⑀, but not PKC␣, -␤II, or -␦ leads to neurite outgrowth through interaction of actin filaments and the C1 domain of PKC⑀ (3-5). The actin binding site of PKC⑀ is also implicated in exocytosis of neurotransmitters (6). PKC⑀ is essential for many types of learning and memory (7,8) and neuroprotection (9 -13). Neuronal contact with astrocytes also promotes global synaptogenesis through PKC⑀ signaling (14). PKC⑀ activation has been shown to promote the maturation of dendritic synapses during associative learning (9). PKC⑀ activation also protects against neurodegeneration (10, 15). Phosphorylation of long-tailed AMPA receptors GluA4 and GluA1 by PKC promotes their surface expression (16,17). PKC activation induces protein synthesis required for long term memory (12, 18). PKC⑀ activation is also required for HuD-mediated mRNA stabilization of neurotrophic factors (19) and apoE-mediated epigenetic regulation of BDNF (20). PKC activation induces translocation of calcium/ calmodulin-dependent kinase II (CaMKII) 2 to synapses (21) where it participates in PSD-95-induced synaptic strengthening (22). PKC also promotes NMDA receptor trafficking by indirectly triggering CaMKII autophosphorylation and subsequent increased association with NMDA receptors (23).Thus, a number of studies have suggested that PKC activators such as bryostatin and dicyclopropanated linoleic acid methyl ester (DCPLA-ME) may be useful therapeutic candidates for the treatment of Alzheimer disease and other causes of synaptic loss such as ischemia, stroke, and fragile X syndrome (5,6,14,24). Some of these benefits have been attributed to induction of neurotrophic factors such as BDNF or the activation of anti-A␤ repair pathways and anti-apoptotic activity (10,13,20,25). However, the biochemical mechanisms by which PKC⑀ induces synaptogenesis and mediates neuroprotection are still not fully understood.At excitatory synapses, the postsynaptic density is characterized by an electron-dense thick matrix that contains key molecules involved in the regulation of glutamate receptor targeting and trafficking (26). PSD-95 is an abundant scaffold protein in excitatory synapses, where it functions to cluster proteins such as glutamate receptors on the postsynaptic membrane and couples them to downstream signaling molecules, thereby inducing the surface expression and synaptic insertion of glutamate receptors (27)(28)(29). In addition to its role in synaptic function, PSD-95 has also been proposed to affect synapse maturation * The authors declare that they have no conflicts of interest with the contents of this article. □ S This article contains supplemental Fig. 1

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Section: Discussionmentioning

confidence: 76%

Protein Kinase Cϵ (PKCϵ) Promotes Synaptogenesis through Membrane Accumulation of the Postsynaptic Density Protein PSD-95

Sen

Hongpaisan

Wang

et al. 2016

Journal of Biological Chemistry

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“…Pharmacological restoration of the impaired PKC function results in an enhanced memory capacity and synaptic remodeling/repair and synaptogenesis and therefore represents a potentially important strategy for the treatment of memory disorders, such as Alzheimer disease (25,28,52). Here we showed that PKC activators protect against A␤ toxicity.…”

Section: Discussionmentioning

confidence: 79%

Apolipoprotein E3 (ApoE3) but Not ApoE4 Protects against Synaptic Loss through Increased Expression of Protein Kinase Cϵ

Sen

Alkon

Nelson

2012

Journal of Biological Chemistry

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Background: ApoE4 is a genetic risk factor for sporadic AD. PKC is involved in synaptogenesis and shows abnormalities in aging and AD. Results: ApoE3 (not apoE4), acting through LRP1, protects synapses against ASPD by inducing PKC⑀. Conclusion: ApoE3 stimulates synaptogenesis and protection against ASPD by increasing PKC⑀ synthesis. Significance: ApoE3 may reduce the risk for AD by stimulating PKC⑀ synthesis.

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“…Bryostatin 1 passed phase-I and -II, but not phase-III, clinical trials, as a cancer treatment, alone and in combination with other chemotherapy agents (Trindade-Silva et al, 2010). It has been used in applications for the central nervous system (Sun & Alkon, 2009). Bryostatin 1 has initiated phase-II clinical trial for Alzheimer's disease (Etcheberrigaray et al, 2004) and has been proposed as a possible therapy for the human immunodeficiency virus (Mehla et al, 2010).…”

Section: Bryostatinmentioning

confidence: 98%