PKCε Activation Restores Loss of PKCε, Manganese Superoxide Dismutase, Vascular Endothelial Growth Factor, and Microvessels in Aged and Alzheimer's Disease Hippocampus.

Guetchyn Millien,Zongxiu Zhang,Dan L Alkon,Huaixing Wang,Jarin Hongpaisan

doi:10.3389/fnagi.2022.836634

Guetchyn Millien, Zongxiu Zhang + Show 3 more

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https://doi.org/10.3389/fnagi.2022.836634

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Journal: Frontiers in aging neuroscience	Publication Date: Mar 1, 2022
Citations: 6	License type: CC BY 4.0

Affiliation: Thomas Jefferson University

Abstract

Vascular endothelial dysfunction and capillary loss are currently considered to be a primary phenotype of normal human aging and Alzheimer’s disease (AD). Activation of protein kinase C (PKCε) improves several molecular, cellular, physiological, and behavioral endpoints, yet it is not known whether a loss of PKCε activity occurs in the microvascular endothelium in aged and AD hippocampi, whether this loss contributes to microvascular change, or whether activation of PKCε protects against microvascular damage, an early change that induces age-associated memory defect and AD. We investigated the effect of the PKCε activation on microvascular loss in the hippocampus, important for memory storage. In cultured human brain microvascular endothelial cells, tert-butyl hydroperoxide induced oxidative stress and a decrease in manganese superoxide dismutase (MnSOD) mRNA and protein expression that were blocked by the antioxidant drugs. The PKCε activators bryostatin and DCPLA methyl ester increased PKCε, associated with an increase in MnSOD mRNA and its protein as well as vascular endothelial growth factor (VEGF), which was inhibited by the mRNA-stabilizing HuR inhibitors. In rats (>24 months old) and AD transgenic mice Tg2576 (5 months old), bryostatin or DCP-LA prevented a decrease in vascular PKCε, MnSOD, and VEGF and prevented microvascular loss and age-related memory impairment. An autopsy-confirmed AD hippocampus showed a decrease in PKCε and MnSOD mRNAs and their proteins and VEGF as well as in microvascular density compared to non-AD controls. In conclusion, the PKCε activation can rescue a decrease in PKCε, MnSOD, and VEGF via posttranscription regulation and alleviate oxidative stress, and in doing so, prevent microvascular loss during aging and AD.

Highlights

Cerebral rarefaction of capillaries and terminal arterioles results in reduced microcirculation and hypoxia, often attributed to neurodegeneration and currently considered to be a primary phenotype of normal human aging and Alzheimer’s disease (AD) (Kemper et al, 1999; Riddle et al, 2003; Desai et al, 2009; Arvanitakis et al, 2011; Brown and Thore, 2011; Toda, 2012; Ungvari et al, 2018)
We studied the effects of the PKCε activator and peroxide tert-butyl hydroperoxide (TBHP)-induced oxidative stress on PKCε, manganese superoxide dismutase (MnSOD), and vascular endothelial growth factor (VEGF) in human brain MV endothelial cells (HBMEC) in cultures
The present study demonstrated that the TBHP-induced shortterm oxidative stress decreased MnSOD—but not PKCε and VEGF—messenger RNA (mRNA) and protein expression in cultured HBMEC cells that were blocked by superoxide degrading drugs, Nac and manganese (III) tetrakis(1methyl-4-pyridyl)porphyrin (MnTMPyP)

Summary

Introduction

Cerebral rarefaction of capillaries and terminal arterioles results in reduced microcirculation and hypoxia, often attributed to neurodegeneration and currently considered to be a primary phenotype of normal human aging and Alzheimer’s disease (AD) (Kemper et al, 1999; Riddle et al, 2003; Desai et al, 2009; Arvanitakis et al, 2011; Brown and Thore, 2011; Toda, 2012; Ungvari et al, 2018). Protein kinase C (PKC) can activate the nuclear export and transport of the mRNA-stabilizing embryonic lethal, abnormal vision (ELAV), Drosophila -like, or human antigen (Hu) family proteins (HuR, HuB, HuC, and HuD) that will bind with AU-rich (ARE) sequence in the 3 -UTR, resulting in the inhibition of mRNA degradation (Chung et al, 1997; Antic and Keene, 1998; Quattrone et al, 2001; Pascale et al, 2004, 2005). The 3 -UTRs of human manganese superoxide dismutase (MnSOD) and vascular endothelial growth factor A (VEGF-A or VEGF) have multiple ARE sequences (King, 2000; Wang et al, 2001; Chaudhuri et al, 2012; Arcondeguy et al, 2013). HuR protein prevents VEGF mRNA degradation that enhances VEGF protein synthesis in vascular endothelial cells (Arcondeguy et al, 2013)

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