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

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http://hdl.handle.net/10138/309832

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Sarajärvi , T , Jäntti , M , Paldanius , K M A , Natunen , T , Wu , J C , Mäkinen , P , Tarvainen , I , Tuominen , R K , Talman , V & Hiltunen , M 2018 , ' Protein kinase C-activating isophthalate derivatives mitigate Alzheimer's disease-related cellular alterations ' , Neuropharmacology , vol. 141 , pp. 76-88 . https://doi.org/10.1016/j.neuropharm.2018.08.020

Title: Protein kinase C-activating isophthalate derivatives mitigate Alzheimer's disease-related cellular alterations
Author: Sarajärvi, T.; Jäntti, M.; Paldanius, K. M. A.; Natunen, T.; Wu, J. C.; Mäkinen, P.; Tarvainen, I.; Tuominen, R. K.; Talman, V.; Hiltunen, M.
Contributor: University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
Date: 2018-10
Language: eng
Number of pages: 13
Belongs to series: Neuropharmacology
ISSN: 0028-3908
URI: http://hdl.handle.net/10138/309832
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 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.
Subject: Protein kinase C
Alzheimer's disease
APP-Processing
Neuroinflammation
Neuroprotection
Isophthalate derivates
AMYLOID PRECURSOR PROTEIN
NEURITE OUTGROWTH
ALPHA-SECRETASE
TRANSGENIC MICE
PHORBOL ESTER
BETA-PROTEIN
MOUSE-BRAIN
PHOSPHORYLATION
EPSILON
PEPTIDE
317 Pharmacy
3112 Neurosciences
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