Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer’s disease

Abstract

Lipid metabolism is abnormal in Alzheimer’s disease (AD) brain leading to ceramide and sphingosine accumulation and reduced levels of brain sphingosine-1-phosphate (S1P). We hypothesize that changes in S1P signaling are central to the inflammatory and immune-pathogenesis of AD and the therapeutic benefits of fingolimod, a structural analog of sphingosine that is FDA approved for the treatment of multiple sclerosis. We recently reported that the neuroprotective effects of fingolimod in 5xFAD transgenic AD mice treated from 1–3 months of age were greater at 1 mg/kg/day than at 5 mg/kg/day. Here we performed a dose-response study using fingolimod from 0.03 to 1 mg/kg/day in 5xFAD mice treated from 1–8 months of age. At 1 mg/kg/day, fingolimod decreased both peripheral blood lymphocyte counts and brain Aβ levels, but at the lowest dose tested (0.03 mg/kg/day), we detected improved memory, decreased activation of brain microglia and astrocytes, and restored hippocampal levels of GABA and glycerophosphocholine with no effect on circulating lymphocyte counts. These findings suggests that, unlike the case in multiple sclerosis, fingolimod may potentially have therapeutic benefits in AD at low doses that do not affect peripheral lymphocyte function.

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…FTY720 treatment also increased the cell survival of neurons in co-culture with microglia on microfluidic chips and exposed to neurotoxic oligomers of amyloid-beta (Aβ) [81]. In support of a less inflammatory CNS environment, FTY720 also reduced the total brain Aβ-levels in a mouse model of AD [45], possibly via microglia cells which play a major role in the internalization and degradation of Aβ [82].…”

“…Both in vitro and in vivo studies have shown that FTY720 has inhibitory effects on the pro-inflammatory (M1) microglia phenotype and stimulates the anti-inflammatory (M2) microglia phenotype . In rodent models for several diseases, such as stroke, cuprizone-induced demyelination, MS (experimental autoimmune encephalitis, EAE), familial Alzheimer's disease (AD) and in irradiation-induced injury, FTY720 decreased microglia activation by polarization towards an anti-inflammatory M2 phenotype characterized by the increased expression of markers such as arginase 1 (ARG1) and mannose receptor C-type 1 (MRC1/CD206) [42][43][44] and a decreased microglia M1 state, defined by the expression of allograft inflammatory factor 1 (IBA1), cluster of differentiation 68 (CD68) and lysosome-associated membrane protein 2 (LAMP-2; CD107b/MAC-3) [42,43,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64]71] Consistent with these findings, in vitro FTY720 inhibited the expression of M1 microglia markers and promoted the M2 polarization of oxygen-glucose deprivation (OGD)-insulted microglia [55], photothrombotic stroke-derived primary microglia cultures [42] and white matter-derived microglia from an ischemia rat model [43] as well as in the microglia cell line N9 [63], and human and murine primary microglia cultures [65]. Moreover, FTY720 downregulated the mRNA expression of the pro-inflammatory cluster (e.g., C-C motif chemokine ligand (CCL)7, chemokine (C-X-C motif) ligand (CXCL)13 and CCL5) and upregulated genes in the anti-inflammatory cluster (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), chitinase 3-like 3 (CHI3L3) and interleukin (IL)-10) in microglia cells from non-obese EAE mice [65].…”

“…FTY720 reduced the number of cells positive for reactive A1 astrocytic markers glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein B (S100β) in multiple rodent models, including in a model of familial AD [45,51], cuprizone-induced demyelination [48], MS [50,61,82], Huntington's disease (HD) [84], Status epilepticus (SE) [54], and models of infection [85], stroke [86], ICH [47], Pentylenetetrazol (PTZ)-induced kindling [56], and maternal inflammation [87] as well as wild-type rodents [88]. In contrast, FTY720-treated immortalized astrocytes displayed increased release of the astrocyte-secreted protein GM-CSF [89], whereas LPS-stimulated primary astrocytes decreased GM-CSF release following treatment with FTY720 [65].…”

Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner

“…Interestingly, the increase in BDNF protein was shown to be inversely correlated with the drug concentration [11]. A low dosage of FTY720 was also reported to influence in vitro viability of neural stem cells [27] and recently, also to rescue memory impairment in a mouse model of Alzheimer's disease [28]. Thus, we next tested the activity of a 5-fold lower concentration of FTY720-P in modulating the dendritic architecture of hippocampal neurons in primary hippocampal cultures.…”

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

“…Later studies indicated that the numbers of GABA inhibitory interneurons in the hippocampus were significantly decreased in transgenic mice such as TgCRND8, Tg2576, 5xFAD, and TauPS2APP (Krantic et al, 2012;Loreth et al, 2012;Verret et al, 2012;Flanigan et al, 2014;Huh et al, 2016;Palop and Mucke, 2016;Shu et al, 2016;Cattaud et al, 2018;Lerdkrai et al, 2018;Carreras et al, 2019; Table 2). Loss of PV and CR interneurons in the hippocampal CA1 of aged 3xTg-AD mice might be in part due to the global network excitability defects associated with AD (Zallo et al, 2018).…”