Fingolimod Rescues Memory and Improves Pathological Hallmarks in the 3xTg-AD Model of Alzheimer’s Disease

Abstract

Therapeutic strategies for Alzheimer’s disease (AD) have largely focused on the regulation of amyloid pathology while those targeting tau pathology, and inflammatory mechanisms are less explored. In this regard, drugs with multimodal and concurrent targeting of Aβ, tau, and inflammatory processes may offer advantages. Here, we investigate one such candidate drug in the triple transgenic 3xTg-AD mouse model of AD, namely the disease-modifying oral neuroimmunomodulatory therapeutic used in patients with multiple sclerosis, called fingolimod. In this study, administration of fingolimod was initiated after behavioral symptoms are known to emerge, at 6 months of age. Treatment continued to 12 months when behavioral tests were performed and thereafter histological and biochemical analysis was conducted on postmortem tissue. The results demonstrate that fingolimod reverses deficits in spatial working memory at 8 and 12 months of age as measured by novel object location and Morris water maze tests. Inflammation in the brain is alleviated as demonstrated by reduced Iba1-positive and CD3-positive cell number, less ramified microglial morphology, and improved cytokine profile. Finally, treatment with fingolimod was shown to reduce phosphorylated tau and APP levels in the hippocampus and cortex. These results highlight the potential of fingolimod as a multimodal therapeutic for the treatment of AD.

Dysregulation of sphingosine-1-phosphate (S1P) and S1P receptor 1 signaling in the 5xFAD mouse model of Alzheimer’s disease

“…We have recently reported that 5xFAD mice orally treated with fingolimod have decreased activation of microglia and reactive astrocytes, decreased Aβ levels, and increased hippocampal neurogenesis 28,29 . Recently another group showed reduced phosphorylated Tau and APP levels in the brain of fingolimod treated 3xTg-AD mice 30 .…”

“…food and drug administration. Extensive number of studies have shown its beneficial effects in murine models of neurological disorders such as MS 27 , epilepsy 53 , spinal cord injury 54 , and cerebral ischemia and Rett syndrome 21 besides those in AD [27][28][29][30] . Fingolimod actions involve the systemic immune system, which is particularly relevant in MS and the CNS where it has been shown to affect both glial 22,23 and neuronal cells 24 , and use diverse mechanisms involving cytokine production 22 , synaptic activity 55 , and anti-apoptotic functions 24 .…”

Blocking microglial proliferation by CSF-1R inhibitor does not alter the neuroprotective effects of adoptive regulatory T cells in 3xTg Alzheimer's disease mice

“…As demonstrated in human AD patients, microglial proliferation increases in 3xTg-AD mice [28][29][30]. Therefore, CSF-1R inhibitors that suppress microglial proliferation, such as GW2580 and PLX3397, have been explored as therapeutic agents for the treatment of AD.…”

Neurocognitive impairment in multiple sclerosis and its association with thiol‐disulfide homeostasis and ischemia‐modified albumin

“…Moreover, there was a trend toward improved results in total recall test in patients who received fingolimod therapy (El Ayoubi et al, 2021). Interestingly, in a recent study, in a mouse model of Alzheimer's disease, fingolimod treatment for 12 months improved spatial working memory deficiencies; moreover, inflammation was reduced in the brain (Fagan et al, 2022).…”