Bibliographic
The emerging data suggest that type 2 diabetes mellitus (T2DM) can contribute significantly to the onset or progression of Alzheimer's disease (AD). Various in vitro and in vivo animal and human clinical studies have provided evidence that T2DM is a major risk factor in the pathology of AD and the two diseases share common biological mechanisms at the molecular level. The biological mechanisms that are common in the pathology of both T2DM and AD include insulin resistance, impaired glucose metabolism, β-amyloid formation, oxidative stress, and the presence of advanced glycation end products. Recent clinical and basic studies on patients with diabetes and AD revealed previously unreported disturbances in insulin signaling pathways.
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. In this study the investigators tested the effects of peripherally injected liraglutide in an APP/PS1 mouse model of AD. 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 beta-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40 –50%, while levels of soluble beta amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide treated 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. These results demonstrate 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.