Time- and Sex-Dependent Effects of Fingolimod Treatment in a Mouse Model of Alzheimer’s Disease

Abstract

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.

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice

“…A recent study showed that the beneficial effect of FTY720 on AD pathology was limited to male mice, a limitation we did not observe with Ponesimod. 53 The authors suggested that FTY720 mainly affects the neuroinflammatory reaction to ongoing Aβ deposition. Therefore, we conclude that the activity of FTY720 is distinct from that of Ponesimod, which stimulates phagocytosis and therefore, preserves the neuroprotective function of activated microglia in AD, even after deposition of amyloid plaques.…”

Apolar Extracts of St. John’s Wort Alleviate the Effects of β-Amyloid Toxicity in Early Alzheimer’s Disease

“…For this purpose, H. perforatum extracts with different polarities were used as an oral treatment in APPtg mice. Appropriate treatment regimens and concentrations were pre-tested and, finally, an early treatment paradigm [39] was employed with a duration of 40 days from 40 days of age. After treatment, protein brain extracts were fractionated to evaluate the treatment's effects on the content of soluble and insoluble Aβ.…”

“…Animal model maintenance and husbandry were performed as previously described [39,59,60]. The individuals used in this study were housed at the Department of Comparative Medicine (section of the Radium Hospital) at the Oslo University Hospital (Oslo, Norway).…”

Repurposing drugs against Alzheimer’s disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?

“…Fingolimod has emerged recently as a promising neuroprotective agent in a wide range of CNS diseases, including Alzheimer's disease (AD; reviewed, e.g., in Angelopoulou and Piperi 2019;Bascunana et al 2020;Pournajaf et al 2022). Importantly, fingolimod tackles those immunological and neuro-inflammatory processes that are triggered by amyloid-β and tau fibrillary tangle pathology (Aytan et al 2016;Baloni et al 2022;Bascunana et al 2023;Fagan et al 2022;Kartalou et al 2020).…”