Age-dependent effects of dimethyl fumarate on cognitive and neuropathological features in the streptozotocin-induced rat model of Alzheimer’s disease

Irena Majkutewicz , Ewelina Kurowska , Magdalena Podlacha , Dorota Myślińska , Beata Grembecka , Jan Ruciński , Karolina Pierzynowska , Danuta Wrona

Abstract

We previously demonstrated that dimethyl fumarate (DMF), an anti-oxidative and immunosuppresive compound, prevents intracerebroventricular (ICV) streptozotocin-induced disruption of spatial memory and neurodegeneration in 4-month-old rats. The present study evaluated the influence of age on DMF’s therapeutic effect. Aged rats (22-months-old, n = 40) were provided rodent chow containing DMF (0.4%) and given ICV injections of streptozotocin (STZ) or vehicle (Sham) on days 2 and 4. Spatial memory was evaluated using the Morris water maze (MWM) on days 14–21. Hippocampal samples from young (4- month-old, n = 36, collected previously) and aged rats were assessed for presence of activated (CD68- positive) microglia, IL-10 and oxidative/nitrative stress marker nitrotyrosine. Aged rat samples were also stained with Fluoro-Jade B marker for neurodegeneration. Previously obtained MWM and Fluoro-Jade B data from young rats served as a reference for assessing impact of age. Aged Sham DMF-fed rats exhibited better spatial memory and less neurodegeneration in the CA3 region of the hippocampus compared to corresponding young rats. Aged STZ rats displayed greater memory impairment and increased CA2 neurodegeneration, CA1 nitrotyrosine immunoreactivity, and microglial activation in the dentate gyrus (DG), compared to young STZ rats. Notably, within aged STZ-injected rats, DMF treatment was associated with improved performance in MWM, reduced neurodegeneration in all hippocampal areas, reduced DG microglia activation, and reduced CA1 nitrotyrosine labeling compared to age-matched rats without DMF treatment. This beneficial age-related effect of DMF treatment after STZ ICV injections may result from reduced microglial activation in the hippocampus that leads to an alleviation of oxidative stress, neurodegeneration, and memory impairments.
Author Irena Majkutewicz KFZiC
Irena Majkutewicz,,
- Department of Animal and Human Physiology
, Ewelina Kurowska KFZiC
Ewelina Kurowska,,
- Department of Animal and Human Physiology
, Magdalena Podlacha KFZiC
Magdalena Podlacha,,
- Department of Animal and Human Physiology
, Dorota Myślińska KFZiC
Dorota Myślińska,,
- Department of Animal and Human Physiology
, Beata Grembecka KFZiC
Beata Grembecka,,
- Department of Animal and Human Physiology
, Jan Ruciński KFZiC
Jan Ruciński,,
- Department of Animal and Human Physiology
, Karolina Pierzynowska KBM
Karolina Pierzynowska,,
- Department of Molecular Biology
, Danuta Wrona KFZiC
Danuta Wrona,,
- Department of Animal and Human Physiology
Journal seriesBrain Research, ISSN 0006-8993
Issue year2018
Vol1686
Pages19-33
Publication size in sheets0.7
Keywords in Englishdimethyl fumarate, memory disorder, streptozotocin, neurodegeneration, microglia, Alzheimer’s disease, age
DOIDOI:10.1016/j.brainres.2018.02.016
URL https://doi.org/10.1016/j.brainres.2018.02.016
Languageen angielski
Score (nominal)25
ScoreMinisterial score = 25.0, 30-03-2018, ArticleFromJournal
Ministerial score (2013-2016) = 25.0, 30-03-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 2.746 (2) - 2016=2.75 (5)
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