title: The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease.
abstract: The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide (GIP) have been developed to treat type 2 diabetes and also act as growth factors. We have tested several long-acting incretin mimetics in the amyloid precursor protein (APP)(Swe)/presenilin 1 (PS1)(ΔE9) model of Alzheimer's disease (AD). We found that liraglutide, lixisenatide, and D-Ala2-GIP cross the blood-brain barrier and prevent the impairment in memory formation and synaptic plasticity, increase synapse numbers, reduce amyloid plaque load and soluble amyloid-β levels, reduce oxidative stress and the chronic inflammation response in the brain, enhance the proliferation of neuronal progenitor cells, and increase neurogenesis in the dentate gyrus. In an (18)fluorodeoxyglucoe positron emission tomographic/computed tomographic imaging study in PLB1-triple mice, a mouse model that expresses human mutated APP, PS1, and tau proteins, glucose metabolism was found to be normalized in forebrain areas after liraglutide treatment, demonstrating that neuronal metabolic activity was normalized. A clinical trial testing liraglutide in patients with AD is currently ongoing.
authors: Biomedical and Life Sciences, Lancaster University, Lancaster, UK. Electronic address: c.holscher@lancaster.ac.uk.
authors: Christian
authors: C
authors: Hölscher
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005749:Gastric Inhibitory Polypeptide / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1
keywords: Alzheimer's disease; GLP-1; Growth factors; Liraglutide; Lixisenatide; Parkinson's disease