Protein kinase C -activating isophthalate derivatives mitigate Alzheimer's disease-related cellular alterations
| Autor: | Maria Jäntti, Virpi Talman, Raimo K. Tuominen, Kaisa M. A. Paldanius, Teemu Natunen, Mikko Hiltunen, Petra Mäkinen, J.C. Wu, Timo Sarajärvi, Ilari Tarvainen |
|---|---|
| Přispěvatelé: | Faculty of Pharmacy, Division of Pharmacology and Pharmacotherapy, Drug Research Program, Regenerative pharmacology group, PREP in neurodegenerative disorders |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Dendritic spine Isophthalate derivates Hippocampus ALPHA-SECRETASE Amyloid beta-Protein Precursor Mice Neuroinflammation Amyloid precursor protein PEPTIDE PHOSPHORYLATION TRANSGENIC MICE Neurons MOUSE-BRAIN biology Microglia Chemistry Alzheimer's disease Bryostatins Neuroprotection Cell biology AMYLOID PRECURSOR PROTEIN medicine.anatomical_structure Alpha secretase 317 Pharmacy BETA-PROTEIN Cell Survival Dendritic Spines Primary Cell Culture Phthalic Acids Enzyme Activators NEURITE OUTGROWTH Nitric Oxide APP-Processing 03 medical and health sciences Cellular and Molecular Neuroscience Protein kinase C Alzheimer Disease Cell Line Tumor medicine Animals Humans Pharmacology Amyloid beta-Peptides Activator (genetics) Tumor Necrosis Factor-alpha PHORBOL ESTER 3112 Neurosciences Coculture Techniques Peptide Fragments 030104 developmental biology EPSILON biology.protein |
| Zdroj: | Neuropharmacology. 141 |
| ISSN: | 1873-7064 |
| Popis: | 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 alpha (sAPP alpha), reduce the levels of beta-amyloid (A beta), induce synaptogenesis, and promote neuroprotection. We have previously described isophthalate derivatives as a structurally simple family of PKC activators. Here, we characterised the effects of isophthalate derivatives HMI-1a3 and HMI-1b11 on neuronal viability, neuroinflammatory response, processing of APP and dendritic spine density and morphology in in vitro. HMI-1a3 increased the viability of embryonic primary cortical neurons and decreased the production of the pro-inflammatory mediator TNF alpha, but not that of nitric oxide, in mouse neuron-BV2 microglia co-cultures upon LPS- and IFN-gamma-induced neuroinflammation. Furthermore, both HMI-1a3 and HMI-1b11 increased the levels of sAPPa relative to total sAPP and the ratio of A beta 42/A beta 40 in human SH-Sv5v neuroblastoma cells. Finally, bryostatin-1, but not HMI-1a3, increased the number of mushroom spines in proportion to total spine density in mature mouse hippocampal neuron cultures. These results suggest that the PKC activator HMI-1a3 exerts neuroprotective functions in the in vitro models relevant for AD by reducing the production of TNF alpha and increasing the secretion of neuroprotective sAPPa. |
| Databáze: | OpenAIRE |
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