Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of β-amyloid pathology. (January 2019)

• Record Type: Journal Article
• Authors: Holubová, Martina; Hrubá, Lucie; Popelová, Andrea; Bencze, Michal; Pražienková, Veronika; Gengler, Simon; Kratochvílová, Helena; Haluzík, Martin; Železná, Blanka; Kuneš, Jaroslav; Hölscher, Christian; Maletínská, Lenka
• Is Part Of: Neuropharmacology. Volume 144(2019)
• Page Start: 377
• Page End: 387
• Publication Date: 2019-01
• Subjects: Alzheimer's disease -- Palm11-PrRP31 -- APP/PS1 mice -- β-amyloid plaques -- Neuroinflammation -- Tau phosphorylation; Aβ β-amyloid -- AD Alzheimer's disease -- APP amyloid precursor protein -- APP/PS1 APPswe/PSEN1dE9 -- CA1 cornu ammonis 1 -- CNS central nervous system -- DAB 3, 3′-diaminobenzidine -- DCX doublecortin -- DG dentate gyrus -- GFAP glial fibrillary acidic protein -- GLP-1 glucagon-like peptide 1 -- GSK-3β glycogen synthase kinase 3β -- HRP horseradish peroxidase -- Iba1 ionized calcium binding adaptor molecule 1 -- mAb monoclonal antibody -- NFT neurofibrillary tangles -- pAb polyclonal antibody -- PBS phosphate-buffered saline -- PP2A sub. C protein phosphatase 2A subunit C -- PrRP prolactin-releasing peptide -- PS1 presenilin -- s.c. subcutaneous(ly) -- SDS sodium dodecyl sulphate -- SEM standard error of the mean -- SGZ subgranular zone of the dentate gyrus -- T2DM type 2 diabetes mellitus -- TBS Tris-buffered saline -- WT wild-type; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.11.002
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Obesity and type 2 diabetes mellitus (T2DM) are important risk factors for Alzheimer's disease (AD). Drugs originally developed for T2DM treatment, e.g., analog of glucagon-like peptide 1 liraglutide, have shown neuroprotective effects in mouse models of AD. We previously examined the neuroprotective properties of palm 11 -PrRP31, an anorexigenic and glucose-lowering analog of prolactin-releasing peptide, in a mouse model of AD-like Tau pathology, THY-Tau22 mice. Here, we demonstrate the neuroprotective effects of palm 11 -PrRP31 in double transgenic APP/PS1 mice, a model of AD-like β-amyloid (Aβ) pathology. The 7-8-month-old APP/PS1 male mice were subcutaneously injected with liraglutide or palm 11 -PrRP31 for 2 months. Both the liraglutide and palm 11 -PrRP31 treatments reduced the Aβ plaque load in the hippocampus. Palm 11 -PrRP31 also significantly reduced hippocampal microgliosis, consistent with our observations of a reduced Aβ plaque load, and reduced cortical astrocytosis, similar to the treatment with liraglutide. Palm 11 -PrRP31 also tended to increase neurogenesis, as indicated by the number of doublecortin-positive cells in the hippocampus. After the treatment with both anorexigenic compounds, we observed a significant decrease in Tau phosphorylation at Thr231, one of the first epitopes phosphorylated in AD. This effect was probably caused by elevated activity of protein phosphatase 2A subunit C, the main Tau phosphatase. Both liraglutide and palm 11 -PrRP31 reduced the levels of caspase 3, which has multiple roles in the pathogenesis of AD. Palm 11 -PrRP31 increased protein levels of the pre-synaptic marker synaptophysin, suggesting that palm 11 -PrRP31 might help preserve synapses. These results indicate that palm 11 -PrRP31 has promising potential for the treatment of neurodegenerative diseases. Highlights: Palm 11 -PrRP31 is an anorexigenic and glucose-lowering analog of PrRP. Palm 11 -PrRP31 treatment was neuroprotective in APP/PS1 mice, a model of amyloidosis. The treatment reduced β-amyloid plaque load, microgliosis and astrogliosis. The treatment reduced Tau phosphorylation and tended to increase adult neurogenesis.