Anti-Inflammatory Treatment with FTY720 Starting after Onset of Symptoms Reverses Synaptic Deficits in an AD Mouse Model

Abstract

Therapeutic approaches providing effective medication for Alzheimer’s disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of Aβ accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.

Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aβ Plaques

“…Although high frequency stimulation induced conventional LTP at SC-CA1 synapses was reported previously to be impaired in 5–6-month-old animals of the same APP/PS1 mouse strain used in the present study [ 10 , 35 ], our above-described results showed that t-LTP tested was not significantly altered at this age. Since we argued that the proximity of Aβ plaques to the recorded CA1 neuron might be decisive to observe significant t-LTP deficits in APP/PS1 animals, we next focused on t-LTP in CA1 neurons in the vicinity of Aβ plaques that we visualized by staining with the dye methoxy-X04 (for staining procedure, compare Methods).…”

“…Since we argued that the proximity of Aβ plaques to the recorded CA1 neuron might be decisive to observe significant t-LTP deficits in APP/PS1 animals, we next focused on t-LTP in CA1 neurons in the vicinity of Aβ plaques that we visualized by staining with the dye methoxy-X04 (for staining procedure, compare Methods). Stained Aβ plaques in APP/PS1 mice were visible in stratum radiatum, stratum oriens, and in the pyramidal cell layer of the CA1 area, but at this age (6-month), the density of Aβ plaques is relatively sparse (compare [ 10 , 36 ]). Thus, we decided to record t-LTP selectively in CA1 pyramidal neurons in the vicinity of Aβ plaques.…”

“…Importantly, neuroinflammatory signals mediated by microglial cells and concomitant astrogliosis are major hallmarks of AD [ 8 , 9 ]. Consequently, anti-inflammatory treatment of AD mice has been shown to be beneficial to counteract AD related synaptic and memory deficits (see [ 10 ]).…”

“…Although several studies have described that AD pathology in its early stage disrupts high frequency tetanus induced conventional LTP in the hippocampus (reviewed in [ 10 , 27 , 28 , 29 , 30 ]), its impact on STDP in the hippocampus remained elusive. Therefore, we assessed whether t-LTP, evoked by pairing of pre- and postsynaptic APs, at excitatory Schaffer collateral (SC)-CA1 synapses is changed in 6-month-old Alzheimer model mice carrying the KM670/671NL amyloid precursor protein (APP) and the L166P presenilin 1 mutations that are characteristic for familial Alzheimer’s disease (APP⁄PS1 mice; [ 31 ]).…”

“…In fact, we found that the 6× 1:4 t-LTP magnitude was significantly reduced if the recorded CA1 pyramidal neuron was located in the vicinity of Aβ plaques in APP/PS1 mice. Since microglia mediated neuroinflammation is a hallmark in AD mouse models, we tested whether chronic treatment with the anti-inflammatory drug Fingolimod (FTY720) that can alleviate other synaptic deficits in AD mice [ 10 ] could restore impaired t-LTP in these mice—but we did not observe such a rescue of t-LTP. Finally, we observed that the impaired t-LTP in CA1 neurons close to Aβ plaques was not due to changes in neuronal excitability or basal synaptic transmission in the recorded CA1 neurons.…”