PMID- 29710707
DCOM- 20190610
LR  - 20190613
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Linking)
VI  - 63
IP  - 3
DP  - 2018
TI  - Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons
      of Alzheimer's Disease Hippocampus.
PG  - 1173-1189
LID - 10.3233/JAD-171008 [doi]
AB  - Oxidative stress and amyloid-beta (Abeta) oligomers have been implicated in
      Alzheimer's disease (AD). The growth and maintenance of neuronal networks are
      influenced by brain derived neurotrophic factor (BDNF) expression, which is
      promoted by protein kinase C epsilon (PKCvarepsilon). We investigated the
      reciprocal interaction among oxidative stress, Abeta, and PKCvarepsilon levels
      and subsequent PKCvarepsilon-dependent MnSOD and BDNF expression in hippocampal
      pyramidal neurons. Reduced levels of PKCvarepsilon, MnSOD, and BDNF and an
      increased level of Abeta were also found in hippocampal neurons from
      autopsy-confirmed AD patients. In cultured human primary hippocampal neurons,
      spherical aggregation of Abeta (amylospheroids) decreased PKCvarepsilon and
      MnSOD. Treatment with t-butyl hydroperoxide (TBHP) increased superoxide, the
      oxidative DNA/RNA damage marker, 8-OHG, and Abeta levels, but reduced
      PKCvarepsilon, MnSOD, BDNF, and cultured neuron density. These changes were
      reversed with the PKCvarepsilon activators, bryostatin and DCPLA-ME.
      PKCvarepsilon knockdown suppressed PKCvarepsilon, MnSOD, and BDNF but increased
      Abeta. In cultured neurons, the increase in reactive oxygen species (ROS)
      associated with reduced PKCvarepsilon during neurodegeneration was inhibited by
      the SOD mimetic MnTMPyP and the ROS scavenger NAc, indicating that strong
      oxidative stress suppresses PKCvarepsilon level. Reduction of PKCvarepsilon and
      MnSOD was prevented with the PKCvarepsilon activator bryostatin in 5-6-month-old 
      Tg2576 AD transgenic mice. In conclusion, oxidative stress and Abeta decrease
      PKCvarepsilon expression. Reciprocally, a depression of PKCvarepsilon reduces
      BDNF and MnSOD, resulting in oxidative stress. These changes can be prevented
      with the PKCvarepsilon-specific activators.
FAU - Sen, Abhik
AU  - Sen A
AD  - Center for Neurodegenerative Diseases, Rockefeller Neurosciences Institute, West 
      Virginia University, Morgantown, WV, USA.
FAU - Nelson, Thomas J
AU  - Nelson TJ
AD  - Center for Neurodegenerative Diseases, Rockefeller Neurosciences Institute, West 
      Virginia University, Morgantown, WV, USA.
FAU - Alkon, Daniel L
AU  - Alkon DL
AD  - NeuroDiagnostics LLC, Rockville, MD, USA.
FAU - Hongpaisan, Jarin
AU  - Hongpaisan J
AD  - Center for Neurodegenerative Diseases, Rockefeller Neurosciences Institute, West 
      Virginia University, Morgantown, WV, USA.
LA  - eng
PT  - Journal Article
PL  - Netherlands
TA  - J Alzheimers Dis
JT  - Journal of Alzheimer's disease : JAD
JID - 9814863
RN  - 0 (Adjuvants, Immunologic)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Bryostatins)
RN  - 0 (Metalloporphyrins)
RN  - 0 (Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin)
RN  - 0 (Morpholinos)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - 37O2X55Y9E (bryostatin 1)
RN  - 955VYL842B (tert-Butylhydroperoxide)
RN  - EC (Superoxide Dismutase)
RN  - EC (Protein Kinase C-epsilon)
SB  - IM
MH  - Adjuvants, Immunologic/pharmacology
MH  - Aged
MH  - Aged, 80 and over
MH  - Alzheimer Disease/*pathology
MH  - Amyloid beta-Peptides/metabolism/toxicity
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Bryostatins/metabolism/pharmacology
MH  - Cells, Cultured
MH  - Down-Regulation/*physiology
MH  - Female
MH  - Fetus/anatomy & histology
MH  - Hippocampus/cytology/metabolism/*pathology
MH  - Humans
MH  - Male
MH  - Metalloporphyrins/pharmacology
MH  - Mice
MH  - Middle Aged
MH  - Morpholinos/pharmacology
MH  - Neurons/*metabolism
MH  - Protein Kinase C-epsilon/*deficiency/genetics
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Superoxide Dismutase/metabolism
MH  - Transfection
MH  - tert-Butylhydroperoxide/pharmacology
OT  - *Alzheimer's disease
OT  - *MnSOD
OT  - *PKCvarepsilon
OT  - *hippocampus
OT  - *oxidative stress
EDAT- 2018/05/02 06:00
MHDA- 2019/06/14 06:00
CRDT- 2018/05/02 06:00
PHST- 2018/05/02 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
PHST- 2018/05/02 06:00 [entrez]
AID - JAD171008 [pii]
AID - 10.3233/JAD-171008 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2018;63(3):1173-1189. doi: 10.3233/JAD-171008.