Amyloid beta peptide directly inhibits PKC activation

Lee, Woojin; Boo, Jung Hyun; Jung, Min Whan; Park, Sang Dai; Kim, Young Ho; Kim, Seung Up; Mook‐Jung, Inhee

doi:10.1016/j.mcn.2003.10.020

Cited by 63 publications

(51 citation statements)

References 44 publications

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“…A␤ has previously been shown to cause in vitro reductions of PKC isozymes and to downregulate PKC by the binding of PKC to a putative PKC substrate domain (A␤28 -30) (Favit et al, 1998;Lee et al, 2004). Furthermore, PKC reduction has been previously observed in the brains and peripheral tissues of AD versus aged-matched, nondemented control patients (Masliah et al, 1990;Matsushima et al, 1996;Favit et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice

Hongpaisan¹,

Sun²,

Alkon³

2011

J. Neurosci.

201

164

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Among the pathologic hallmarks of Alzheimer's disease (AD) neurodegeneration, only synaptic loss in the brains of AD patients closely correlates with the degree of dementia in vivo. Here, we describe a molecular basis for this AD loss of synapses: pathological reduction of synaptogenic PKC isozymes and their downstream synaptogenic substrates, such as brain-derived neurotrophic factor. This reduction, particularly of PKC ␣ and , occurs in association with elevation of soluble ␤ amyloid protein (A␤), but before the appearance of the amyloid plaques or neuronal loss in the Tg2576 AD transgenic mouse strain. Conversely, treatment of the Tg2576 mouse brain with the PKC activator, bryostatin-1, restores normal or supranormal levels of PKC ␣ and , reduces the level of soluble A␤, prevents and/or reverses the loss of hippocampal synapses, and prevents the memory impairment observed at 5 months postpartum. Similarly, the PKC -specific activator, DCP-LA, effectively prevents synaptic loss, amyloid plaques, and cognitive deficits (also prevented by bryostatin-1) in the much more rapidly progressing 5XFAD transgenic strain. These results suggest that synaptic loss and the resulting cognitive deficits depend on the balance between the lowering effects of A␤ on PKC ␣ and versus the lowering effects of PKC on A␤ in AD transgenic mice.

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Section: Discussionmentioning

confidence: 99%

“…Current evidence suggests that soluble ␤ amyloid protein (A␤; more specifically, oligomers) is involved in the synaptic loss. Soluble A␤ has also been shown to reduce PKC isozymes (Favit et al, 1998) and to downregulate PKC by the binding of PKC to a putative PKC substrate domain (A␤28-30) (Lee et al, 2004). …”

Section: Introductionmentioning

confidence: 99%

PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice

Hongpaisan¹,

Sun²,

Alkon³

2011

J. Neurosci.

201

164

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“…Topiramate activity is dependent on the phosphorylation state of the sodium channel, indicating that PKCε phosphorylation of the channel blocks the hyperpolarizing effects of topiramate [88]. Aside from Na + channels, it is also reported that amyloid beta peptide directly inhibits PKCε phosphorylation and translocation to membranes [89].…”

Section: Pkcγ and Pkcε In Neural Tissuesmentioning

confidence: 99%

Protein kinase C as a stress sensor

Barnett

Madgwick

Takemoto

2007

Cellular Signalling

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While there are many reviews which examine the group of proteins known as protein kinase C (PKC), the focus of this article is to examine the cellular roles of two PKCs that are important for stress responses in neurological tissues (PKCγ and ε) and in cardiac tissues (PKCε). These two kinases, in particular, seem to have overlapping functions and interact with an identical target, connexin 43 (Cx43), a gap junction protein which is central to proper control of signals in both tissues. While PKCγ and PKCε both help protect neural tissue from ischemia, PKCε is the primary PKC isoform responsible for responding to decreased oxygen, or ischemia, in the heart. Both do this through Cx43.It is clear that both PKCγ and PKCε are necessary for protection from ischemia. However, the importance of these kinases has been inferred from preconditioning experiments which demonstrate that brief periods of hypoxia protect neurological and cardiac tissues from future insults, and that this depends on the activation, translocation, or ability for PKCγ and/or PKCε to interact with distinct cellular targets, especially Cx43.This review summarizes the recent findings which define the roles of PKCγ and PKCε in cardiac and neurological functions and their relationships to ischemia/reperfusion injury. In addition, a biochemical comparison of PKC γ and PKC ε and a proposed argument for why both forms are present in neurological tissue while only PKC ε is present in heart, are discussed. Finally, the biochemistry of PKCs and future directions for the field are discussed, in light of this new information.

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“…Numerous reports (10,16,24) imply a critical role of deficient functions of PKC isozymes in the pathogenesis of Alzheimer's disease (AD). Intensive efforts have, therefore, been focused on the development of bryostatin-1 and its analogs to treat dementia of the Alzheimer's type.…”

Section: Role In Alzheimer's Diseasementioning

confidence: 99%

“…Reduced PKC activity is associated with AD (10,16), at least partially due to a direct inhibition of PKC activity by neurotoxic Aâ (24). Activation of PKC with bryostatin-1 induces the de novo synthesis of proteins necessary and sufficient for subse- (34).…”

Section: Role In Alzheimer's Diseasementioning

confidence: 99%

Bryostatin-1: Pharmacology and Therapeutic Potential as a CNS Drug

Sun

Alkon

2006

CNS Drug Reviews

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Bryostatin-1 is a powerful protein kinase C (PKC) agonist, activating PKC isozymes at nanomolar concentrations. Pharmacological studies of bryostatin-1 have mainly been focused on its action in preventing tumor growth. Emerging evidence suggests, however, that bryostatin-1 exhibits additional important pharmacological activities. In preclinical studies bryostatin-1 has been shown at appropriate doses to have cognitive restorative and antidepressant effects. The underlying pharmacological mechanisms may involve an activation of PKC isozymes, induction of synthesis of proteins required for long-term memory, restoration of stress-evoked inhibition of PKC activity, and reduction of neurotoxic amyloid accumulation and tau protein hyperphosphorylation. The therapeutic potential of bryostatin-1 as a CNS drug should be further explored.

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Amyloid beta peptide directly inhibits PKC activation

Cited by 63 publications

References 44 publications

PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice

PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice

Protein kinase C as a stress sensor

Bryostatin-1: Pharmacology and Therapeutic Potential as a CNS Drug

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