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

Volkmar Lessmann,Georgia-Ioanna Kartalou,Plinio Casarotto,Kurt Gottmann,Hélène Marie,Kevin Delanoe,Paula Pousinha,Elke Edelmann,Thomas Endres,Angelina Lesnikova,Ana Rita Salgueiro-Pereira,Eero Castrén

doi:10.3390/ijms21238957

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.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, characterized by a progressive decline of cognitive functions [1]
Using glial fibrillary acidic protein (GFAP) immunohistochemistry (IHC) we found that the percentage of hippocampal cornu ammonis-1 (CA1) area covered by astrocytes in vehicle injected amyloid precursor protein/presenilin-1 (APP/PS1) mice was increased roughly twofold (WT vehicle: 4.63 ± 0.33, AD vehicle: 8.01 ± 1.32) compared to vehicle injected wild type (WT) littermate controls (Figure 5)
Our results show that chronic treatment of APP/PS1 mice with fingolimod (FTY720), starting at five to six months—shortly after onset of synaptic and learning dysfunction in these animals—restores functional and structural plasticity in this mouse model

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, characterized by a progressive decline of cognitive functions [1]. Recent research has seen significant advances in better understanding the cellular and molecular mechanisms of AD. This includes the general consensus that Aβ pathology that starts in the human neocortex 10–15 years before AD becomes symptomatic, and hippocampal tau pathology (which coincides with early stages of symptomatic AD in humans), together, underlie AD onset [2]. While lifestyle factors like physical exercise and a healthy diet might be able to delay the onset of AD, no treatment for AD has far been reported that can effectively counteract dementia symptoms after disease onset. Therapeutic approaches focusing on reduction in neuroinflammatory signaling of microglial cells are among the most promising intervention strategies to ameliorate AD deficits. Repurposing anti-inflammatory drugs for AD therapy that are already approved by the FDA for treatment of human subjects could provide an important benefit to rapidly develop an effective AD medication

Methods

Results

Conclusion