Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: A link between diabetes and Alzheimer's disease

doi:10.1016/j.ejphar.2009.12.023

European Journal of Pharmacology

Volume 630, Issues 1–3, 25 March 2010, Pages 158-162

https://doi.org/10.1016/j.ejphar.2009.12.023 Get rights and content

Abstract

Type 2 diabetes has been identified as a risk factor for patients with Alzheimer's disease. Insulin signalling is often impaired in Alzheimer's disease, contributing to the neurodegenerative process. One potential strategy to help prevent this is the normalisation of insulin signalling in the brain. Therefore, the present study was designed to test the effects of novel enzyme-resistant analogues of the insulin-releasing incretin hormone, glucagon-like peptide 1 (GLP-1). The effects of Liraglutide (Victoza) and other novel GLP-1 analogues were tested on synaptic plasticity (LTP) in area CA1 of the hippocampus. At a dose of 15 nmol in 5 µl i.c.v., Liraglutide (P < 0.005), Asp⁷GLP-1 (P < 0.001), N-glyc-GLP-1 (P < 0.01), and Pro⁹GLP-1 (P < 0.001). In contrast, the GLP-1 receptor antagonist exendin(9-39)amide impaired LTP (P < 0.001). Co-injection of exendin(9-39) and Liraglutide showed no effect on LTP. These results clearly demonstrate that Liraglutide and other GLP-1 analogues elicit effects on neurotransmission in the brain. Furthermore, GLP-1 peptides are not only effective in modulating insulin-release and achieving glycaemic control in type 2 diabetes, but are also effective in modulating synaptic plasticity. These findings are consistent with our previous observations that the novel analogue (Val⁸)GLP-1 enhances LTP and reverses the impairments of LTP induced by beta-amyoid fragments. Therefore, the drug effects seen here could potentially ameliorate the impairments in neuronal communication and cognitive processes observed in Alzheimer's disease.

Introduction

Epidemiological studies have identified type 2 diabetes mellitus as a risk factor for Alzheimer's disease (Li and Hölscher, 2007, Luchsinger et al., 2004, Ristow, 2004). A contributing factor is the desensitisation of insulin receptors in the brains of patients with Alzheimer's disease (Biessels et al., 2006, Carro and Torres-Aleman, 2004a, Carro and Torres-Aleman, 2004b, Hoyer, 2004, Steen et al., 2005). Building on this, new strategies are being developed to normalise insulin signalling in the brain, such as the use of the incretin hormone glucagon-like peptide-1 (GLP-1) as a new treatment for Alzheimer's disease (Hölscher and Li, 2008, Perry and Greig, 2004). GLP-1 is an incretin hormone which regulates postprandial glucose levels through glucose-dependent insulin secretion (Gault et al., 2003). Currently, the GLP-1 receptor agonists exendin-4 (Exenatide, Byetta) and Liraglutide (Victoza) are approved for treatment of Type 2 diabetes, and others are in late stage clinical trials (Lovshin and Drucker, 2009). Interestingly, GLP-1 also plays an important role in the brain, it is expressed in neurons and acts as a neurotransmitter (Sarkar et al., 2003). GLP-1 receptors are also expressed on neurons (Hamilton and Holscher, 2009). GLP-1 has growth factor-like properties and protects neurons from neurotoxic influences (Biswas et al., 2008, During et al., 2003, Perry et al., 2003). GLP-1 also reduces the induction of apoptosis of hippocampal neurons (During et al., 2003, Qin et al., 2008) and improves spatial and associative learning (During et al., 2003).

Several stable GLP-1 analogues have been developed by amino acid substitutions in the native GLP-1 peptide at positions 7-9, where the endogenous protease dipeptidyl-peptidase IV (DPP-IV) degrades native GLP-1, eg. (Pro⁹)GLP-1 or (Asp⁷)GLP-1. Some of these substitutions have been shown to prevent protease degradation whilst retaining long-lasting GLP-1 agonist effects and improve the symptoms of type 2 diabetes (Green and Flatt, 2007, Green et al., 2005). We have previously shown that GLP-1 and the novel agonist analogue (Val⁸)GLP-1 have prominent effects on synaptic plasticity in vivo when injected icv (Gault and Holscher, 2008a). In addition, (Val⁸)GLP-1 crosses the blood brain barrier and chronic administration prevents the impairment of synaptic plasticity that is found in a mouse model of Alzheimer's disease (Gengler et al., 2008, Radde et al., 2006).

Liraglutide (NN2211) is a modified form of human GLP-1 which has been released on the market in Europe as a treatment for type 2 diabetes mellitus (trade name Victoza). The Liraglutide molecule has a fatty acid (C-16 palmitoyl) conjugated to the side-chain of Lys26 and an Arg for Ser amino acid substitution at position 34. Together, these modifications result in a significantly prolonged circulating biological half-life in vivo primarily due to binding to serum albumin and resistance to DPP-IV (Lovshin and Drucker, 2009). Another analogue that we tested is N-glyc-GLP-1 which has two polyethylene glycol attached, and this modification also prolongs the biological half life (Green et al., 2005). In this study, we characterise the role of GLP-1 analogues on long term potentiation of synaptic transmission (LTP) in the hippocampus (Collingridge and Bliss, 1987, Hölscher, 2001) to analyse whether these drugs modulate neuronal transmission and potentially alleviate impairments induced by the accumulation of beta-amyloid in the brain (Gengler et al., 2008). Drugs were injected at a dose that had been previously shown to affect LTP in vivo (Gault and Holscher, 2008a, Gault and Holscher, 2008b).

Section snippets

Surgery and LTP induction protocols

Male Wistar rats (Harlan, UK) weighing 220–280 g were anaesthetised with urethane (ethyl carbamate, 1.8 g/kg, ip) for the duration of all experiments. A cannula (22 gauge, 0.7 mm outer diameter, 11 mm length; Bilaney, Kent, UK) was implanted (1.5 mm anterior to bregma, 0.5 mm lateral to midline and 3.55 mm ventral) into the left hemisphere for icv injections. Electrodes (tungsten with Teflon coating, Bilaney, Kent, UK) were implanted unilaterally 3.4 mm posterior and 2.5 mm lateral to the midline, and

Effects of Liraglutide on LTP

When injecting 15 nmol Liraglutide in 5 µl i.c.v., a significant enhancement of LTP induced by a weak stimulation protocol was found (Fig. 2). A two-way ANOVA showed a difference between the drug group and control (DF_1,10; F = 16.3; P < 0.005) and over time DF_1,119; F = 1.5; P < 0.001). Interaction between factors was not significant (see Fig. 1).

Effects of N-glyc-GLP-1 on LTP

When injecting 15 nmol N-glyc-GLP-1 in 5 µl i.c.v., a significant enhancement of LTP induced by a weak stimulation protocol was found. A two-way ANOVA showed a

Discussion

The results from this study confirm our previous work that GLP-1 and novel protease-resistant analogues facilitate LTP (Gault and Holscher, 2008b). In this study, we show for the first time that the long-acting novel GLP-1 peptide Liraglutide (NN2211, Victoza) has a fast acting facilitatory effect on LTP. The other novel protease resistant GLP-1 agonists N-glyc-GLP-1, (Asp⁷)GLP-1 and (Pro⁹)GLP-1 also facilitate LTP, clearly demonstrating that GLP-1 receptor activation on neurons has modulatory

Acknowledgement

The work was supported by a research grant of the Alzheimer Society UK.

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Endocrine PharmacologyGlucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: A link between diabetes and Alzheimer's disease

Abstract

Introduction

Section snippets

Surgery and LTP induction protocols

Effects of Liraglutide on LTP

Effects of N-glyc-GLP-1 on LTP

Discussion

Acknowledgement

Eur. J. Pharmacol.

Trends Neurosci.

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Best. Pract. Res. Clin. Endocrinol. Metab.

Arch. Biochem. Biophys.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Biochem. Pharmacol.

J. Biol. Chem.

Brain Res. Rev.

Brain Res. Bull.

J. Biol. Chem.

Neurosci. Lett.

Brain Res.

Glucagon-like peptide 1 excites hypocretin/orexin neurons by direct and indirect mechanisms: implications for viscera-mediated arousal

J. Neurosci.

Increased cortical atrophy in patients with Alzheimer's disease and type 2 diabetes mellitus

J. Neurol. Neurosurg. Psychiatry

Glucagon-like peptide-1 (GLP-1) diminishes neuronal degeneration and death caused by NGF deprivation by suppressing Bim induction

Neurochem. Res.

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26 week randomised, parallel-group, multinational, open-label trial (LEAD-6)

The Lancet

Insulin-like growth factor I and Alzheimer's disease: therapeutic prospects?

Expert Rev. Neurother.

Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular risk biomarkers in patients with Type 2 diabetes

Diabet. Med.

Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line

Proc. Natl. Acad. Sci. U.S.A.

Glucagon-like peptide-1 receptor is involved in learning and neuroprotection

Nat. Med.

Recent advances in antidiabetic drug therapies targeting the enteroinsular axis

Curr. Drug Metab.

Protease-resistant glucose-dependent insulinotropic polypeptide agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by Beta-amyloid

J. Neurophysiol.

Val(8)GLP-1, a protease-resistant incretin analogue, prevents the impairment of hippocampal synaptic plasticity in an APP/PS-1 mouse model of Alzheimer's disease

Endocrine Pharmacology
Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: A link between diabetes and Alzheimer's disease