Protein kinase C -activating isophthalate derivatives mitigate Alzheimer's disease-related cellular alterations

  title={Protein kinase C -activating isophthalate derivatives mitigate Alzheimer's disease-related cellular alterations},
  author={Timo Saraj{\"a}rvi and Maria H J{\"a}ntti and Kaisa M. A. Paldanius and Teemu Natunen and J. C. Wu and Petra M M{\"a}kinen and Ilari Tarvainen and Raimo K. Tuominen and Virpi Talman and Mikko Hiltunen},
ABSTRACT Abnormal protein kinase C (PKC) function contributes to many pathophysiological processes relevant for Alzheimer's disease (AD), such as amyloid precursor protein (APP) processing. Phorbol esters and other PKC activators have been demonstrated to enhance the secretion of soluble APP&agr; (sAPP&agr;), reduce the levels of &bgr;‐amyloid (A&bgr;), induce synaptogenesis, and promote neuroprotection. We have previously described isophthalate derivatives as a structurally simple family of… Expand
8 Citations
Evaluation of Toxic Amyloid β42 Oligomers in Rat Primary Cerebral Cortex Cells and Human iPS-derived Neurons Treated with 10-Me-Aplog-1, a New PKC Activator
A new PKC activator with few side effects is developed, 10-Me-Aplog-1, (1), which decreased Aβ42 in the conditioned medium of rat primary cerebral cortex cells, and suggests that 1 is a potential drug lead for AD therapy. Expand
Protein Kinase C Involvement in Neuroprotective Effects of Thymol and Carvacrol Against Toxicity Induced by Amyloid-Β in Rat Hippocampal Neurons
Introduction: We have reported that thymol and carvacrol can improve cognitive abilities in Alzheimer’s disease (AD) rat model. However, the mechanism of their action is not yet fully understood.Expand
Pharmacological Protein Kinase C Modulators Reveal a Pro-hypertrophic Role for Novel Protein Kinase C Isoforms in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
This work shows similar hypertrophic responses to PKC modulators in NRVMs and hiPSC-CMs, which should be considered when developing PKC-targeted compounds for e.g. cancer or Alzheimer’s disease. Expand
The structure–activity relationship of marine products for neuroinflammatory disorders
This book chapter is based on exploring the structure–activity relationship of marine drugs for neuroinflammatory disorders, which has a promising role in the management of neurovascular disorders via potential antiinflammatory actions. Expand
Highly sensitive and rapid detection of protein kinase C based on liquid crystal biosensor
  • Huan Liu, Xiuxia Su, Jing Zhang, Xu Jia, Dong Yang, Qingcai Chen
  • Chemistry
  • 2021
Abstract Protein kinase C (PKC), a protein which is widely present in organisms, plays a pivotal role in the pathogenesis of many diseases, and has become a target for the diagnosis and treatment ofExpand
Diverse synthesis of the C ring fragment of bryostatins via Zn/Cu-promoted conjugate addition of α-hydroxy iodide with enone
Abstract A convergent approach to 1,5-hydroxy ketones, the general precursors for constructing the C ring of bryostatins, has been developed via a Zn/Cu-promoted conjugate addition of α-hydroxyExpand
Recent Advances in The Rational Drug Design Based on Multi-target Ligands.
In this review, the possible applications of multi-target ligands to guide the repositioning of prospective drugs are discussed. Expand


Enhanced generation of Alzheimer’s amyloid‐β following chronic exposure to phorbol ester correlates with differential effects on alpha and epsilon isozymes of protein kinase C
Evidence is presented that chronic application of phorbol ester treatment causes differential regulation of PKC isozymes and increased Aβ generation, which has implications for the design of amyloid‐lowering strategies based on modulating PKC activity. Expand
Protein kinase C inhibits amyloid β‐peptide neurotoxicity by acting on members of the Wnt pathway
The results suggest that regulation of members of the Wnt signaling pathway by Ca2+‐dependent PKC isoforms may be important in controlling the neurotoxic process induced by Aβ. Expand
Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics.
Observations strongly suggest that PKC isoform pharmacology may represent an attractive area for the development of cognition-enhancing agents and therapeutics against memory loss in the future. Expand
Protein Kinase C ϵ Suppresses Aβ Production and Promotes Activation of α-Secretase
Evidence is provided that PKCϵ decreases Aβ production by promoting α-secretase mediated cleavage of APP, which generally reduces formation of Aβ. Expand
Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice.
Bryostatin 1 at subnanomolar concentrations dramatically enhances the secretion of the alpha-secretase product sAPP alpha in fibroblasts from AD patients, corroborate PKC and its activation as a potentially important means of ameliorating AD pathophysiology and perhaps cognitive impairment. Expand
Activation of protein kinase C isozymes for the treatment of dementias.
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. Expand
Protein Kinase C Activation as a Potential Therapeutic Strategy in Alzheimer's Disease: Is there a Role for Embryonic Lethal Abnormal Vision-like Proteins?
This MiniReview summarizes the current evidence on the role of PKC and ELAV-like proteins in learning and memory, highlighting how their derangement can contribute to AD pathophysiology and emphasizes the potential of pharmacological activation ofPKC as a promising therapeutic strategy for the treatment of AD. Expand
Attenuated protein kinase C activity and translocation in Alzheimer's Disease brain
The results suggest that the reduced PKC activity and the attenuated translocation of the enzyme in AD brain tissue may be attributed to down regulation of PKC or to alteration in PKC protein. Expand
Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models
Results suggest that ubiquilin-1 may mechanistically participate in AD molecular pathogenesis by affecting BACE1 and thereby APP processing and Aβ accumulation. Expand
Signaling pathway cross talk in Alzheimer’s disease
A new set of signaling pathways, collectively termed “anti-ageing pathways”, are highlighted for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired. Expand