Time- and Sex-Dependent Effects of Fingolimod Treatment in a Mouse Model of Alzheimer’s Disease
Pablo Bascuñana,
Mirjam Brackhan,
Luisa Möhle,
Jingyun Wu,
Thomas Brüning,
Ivan Eiriz,
Baiba Jansone,
Jens Pahnke
Affiliations
Pablo Bascuñana
Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
Mirjam Brackhan
Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
Luisa Möhle
Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
Jingyun Wu
Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
Thomas Brüning
Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
Ivan Eiriz
Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
Baiba Jansone
Department of Pharmacology, Faculty of Medicine, University of Latvia, Jelgavas iela 3, 1004 Rīga, Latvia
Jens Pahnke
Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod in two different treatment paradigms. To address this aim, we treated male and female APP-transgenic mice for 50 days, starting either before plaque deposition at 50 days of age (early) or at 125 days of age (late). To evaluate the effects, we investigated the neuroinflammatory and glial markers, the Aβ load, and the concentration of the brain-derived neurotrophic factor (BDNF). We found a reduced Aβ load only in male animals in the late treatment paradigm. These animals also showed reduced microglia activation and reduced IL-1β. No other treatment group showed any difference in comparison to the controls. On the other hand, we detected a linear correlation between BDNF and the brain Aβ concentrations. The fingolimod treatment has shown beneficial effects in AD models, but the outcome depends on the neuroinflammatory state at the start of the treatment. Thus, according to our data, a fingolimod treatment would be effective after the onset of the first AD symptoms, mainly affecting the neuroinflammatory reaction to the ongoing Aβ deposition.
