The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer's Disease

Abstract

Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APP swe /PS1 ⌬E9 (APP/PS1). Liraglutide was shown to cross the blood-brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall ␤-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40 -50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutidetreated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.

The glucagon-like peptide-1 receptor agonist exenatide restores impaired pro-islet amyloid polypeptide processing in cultured human islets: implications in type 2 diabetes and islet transplantation

“…Similarly, treatment of patients with type 2 diabetes and islet recipients with type 1 diabetes, at early stages of beta cell dysfunction may slow down the process of hIAPP aggregation and thereby amyloid-induced beta cell death. In support, two recent studies have demonstrated that treatment with GLP-1R agonists, such as exenatide and liraglutide, reduces Aβ oligomers, amyloid plaque formation and toxicity in the brains of mice in models of Alzheimer's disease [47,48].…”

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…In contrast, insulin deficiency has been shown to accelerate amyloidogenic pathology in a mouse model of AD [119]. In addition to direct insulin administration, compounds that can promote insulin secretion, such as glucagon-like peptide 1 (GLP-1) analogues, are being actively investigated., Liraglutide and Val(8)GLP-1, GLP-1 analogues, were found to be neuroprotective, rescue long-term potentiation and memory deficits, and reduce plaque loads in an AD mouse model [121][122][123]. Peripherally injected liraglutide and another GLP-1 analogue, lixisenatide, penetrated the BBB and promoted neurogenesis [124].…”

Potentials of incretin‐based therapies in dementia and stroke in type 2 diabetes mellitus

“…Also, sitagliptin, saxagliptin and vildagliptin showed anti‐inflammatory properties77, 78, 79, as well as liraglutide in a late‐stage AD rodent model75. Moreover, peripherally‐administered liraglutide and D‐Ala 2 GIP increased neuronal progenitor cell proliferation and neurogenesis in AD rodent models72, 75, 83.…”

“…However, two other studies reported no reduction of both APP and Aβ levels, despite the fact that treatment did have beneficial effects on memory or LTP82, 86. Peripherally‐administered liraglutide reduced both Aβ and APP levels72, even in a late‐stage AD rodent model75. Furthermore, peripherally‐administered sitagliptin, saxagliptin and vildagliptin lowered the levels of Aβ77, 78, 79.…”