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


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 (FB / DAHP)
Irena Majkutewicz,,
- Department of Animal and Human Physiology
, Ewelina Kurowska (FB / DAHP)
Ewelina Kurowska,,
- Department of Animal and Human Physiology
, Magdalena Podlacha (FB / DAHP)
Magdalena Podlacha,,
- Department of Animal and Human Physiology
, Dorota Myślińska (FB / DAHP)
Dorota Myślińska,,
- Department of Animal and Human Physiology
, Beata Grembecka (FB / DAHP)
Beata Grembecka,,
- Department of Animal and Human Physiology
, Jan Ruciński (FB / DAHP)
Jan Ruciński,,
- Department of Animal and Human Physiology
, Karolina Pierzynowska (FB / DMoB)
Karolina Pierzynowska,,
- Department of Molecular Biology
, Danuta Wrona (FB / DAHP)
Danuta Wrona,,
- Department of Animal and Human Physiology
Journal seriesBrain Research, ISSN 0006-8993, (A 25 pkt)
Issue year2018
Publication size in sheets0.7
Keywords in Englishdimethyl fumarate, memory disorder, streptozotocin, neurodegeneration, microglia, Alzheimer’s disease, age
ASJC Classification1309 Developmental Biology; 2728 Clinical Neurology; 1312 Molecular Biology; 2800 General Neuroscience
Languageen angielski
Score (nominal)25
Score sourcejournalList
ScoreMinisterial score = 25.0, 28-01-2020, ArticleFromJournal
Publication indicators WoS Citations = 3; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 0.864; WoS Impact Factor: 2018 = 2.929 (2) - 2018=2.937 (5)
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