Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease

Highlights

• Liraglutide protected 14-month-old APP/PS1 mice in the key markers for AD.

• The overall plaque load in the brain was reduced by 33%.

• The chronic inflammation response was reduced by 30%.

• Neuronal progenitor cell count in the dentate gyrus was increased by 50%.

• Total brain APP and beta-amyloid oligomer levels were reduced.

Abstract

Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza^®) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall APP and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old APPswe/PS1ΔE9 (APP/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development.

The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-month-old APP/PS1 and littermate control mice were injected with Liraglutide (25 nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in APP/PS1 mice compared with APP/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced in APP/PS1 liraglutide-treated mice compared with APP/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain APP and beta-amyloid oligomer levels were reduced in Liraglutide-treated APP/PS1 mice while IDE levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but also can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients.

This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.

Introduction

Type 2 diabetes (T2DM) has been identified as a risk factor for Alzheimer disease (AD) (Hoyer, 2004, Hölscher, 2005, Craft, 2007, Perry et al., 2007). Impaired insulin signalling has been linked to cerebral degenerative processes in aged T2DM patients (Zhao et al., 2004) and AD patients (Ohara et al., 2011) and insulin receptor desensitisation is observed in the Alzheimer's disease brain (Craft, 2007, Talbot et al., 2012). The desensitisation could play a role in the development of neurodegenerative disorders, as insulin is a growth factor with neuroprotective properties (Gasparini et al., 2002, Hoyer, 2004, Holscher, 2011).

GLP-1 is an incretin hormone (Lovshin and Drucker, 2009). Currently, the GLP-1 receptor agonists exendin-4 (Exenatide, Byetta^®), liraglutide (Victoza^®) and lixisenatide (Lyxumia^®) are approved for treatment of T2DM (Lovshin and Drucker, 2009, Wohlfart et al., 2013). These analogues are injected subcutaneously and are well tolerated.

GLP-1 also acts as a growth factor in the brain, and has been shown to induce neurite outgrowth and to protect against oxidative injury (Perry et al., 2007). Furthermore, mice that overexpress GLP-1 receptors in the hippocampus exhibited increased neurite growth and improved learning (During et al., 2003). The deletion of the GLP-1 receptor impairs learning and of developing long-term potentiation of synaptic transmission (LTP) in the hippocampus (Abbas et al., 2009). Moreover, Liraglutide and exendin-4 have been shown to reduce endogenous levels of beta-amyloid in the brain (Perry et al., 2003, McClean et al., 2011). GLP-1 analogues induce the proliferation of neuronal progenitor cells in the brains of mice (During et al., 2003, Hunter and Holscher, 2012). This induction of cell proliferation has the potential to facilitate the repair of neuronal networks in cortical tissue and could have beneficial effects in patients with AD (Greenberg and Jin, 2006). We have previously shown that injection of Val(8)GLP-1 ip. for 3 weeks rescued LTP in the hippocampus of a APP/PS1 mouse model of AD (Gengler et al., 2012). Importantly, GLP-1 and GLP-1 analogues cross the blood brain barrier (BBB) (Kastin et al., 2002, Perry and Greig, 2002, McClean et al., 2011, Gengler et al., 2012, Hunter and Holscher, 2012). Our recent work testing liraglutide in 7–9 month old APPswe/PS1ΔE9 mice demonstrated that at an intermediate stage of disease progression, when mice are beginning to display behavioural deficits, 8 weeks treatment with liraglutide ip. improved learning and memory, enhanced LTP, reduced beta amyloid plaque load and chronic inflammation, reduced total levels of APP and toxic oligomers (McClean et al., 2011). Building on this encouraging study, the current study aims to address whether liraglutide has restorative effects at a late stage of disease progression with a high amyloid plaque load, memory and synaptic failure and synaptic loss, or only when taken at an early stage to prevent further deterioration. Accordingly, 16 month-old APPswe/PS1ΔE9 and wild-type mice were tested after having been injected ip. with liraglutide for 8 weeks. We analysed the effects on memory, synaptic plasticity of hippocampus, synaptic density, plaque deposition and inflammation, neurogenesis in dentate gyrus, and levels of total APP and soluble aggregated beta amyloid.