PMID- 30428311 OWN - NLM STAT- MEDLINE DCOM- 20190304 LR - 20190304 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 144 DP - 2019 Jan TI - Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of beta-amyloid pathology. PG - 377-387 LID - S0028-3908(18)30425-8 [pii] LID - 10.1016/j.neuropharm.2018.11.002 [doi] AB - 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 beta-amyloid (Abeta) 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 Abeta plaque load in the hippocampus. Palm(11)-PrRP31 also significantly reduced hippocampal microgliosis, consistent with our observations of a reduced Abeta 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. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Holubova, Martina AU - Holubova M AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10, Prague 6, Czech Republic. FAU - Hruba, Lucie AU - Hruba L AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10, Prague 6, Czech Republic. FAU - Popelova, Andrea AU - Popelova A AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10, Prague 6, Czech Republic. FAU - Bencze, Michal AU - Bencze M AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10, Prague 6, Czech Republic; Institute of Physiology of the Czech Academy of Sciences, 142 20, Prague 4, Czech Republic. FAU - Prazienkova, Veronika AU - Prazienkova V AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10, Prague 6, Czech Republic. FAU - Gengler, Simon AU - Gengler S AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Bailrigg, Lancaster, LA1 4YW, United Kingdom. FAU - Kratochvilova, Helena AU - Kratochvilova H AD - Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21, Prague 4, Czech Republic; Department of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague and General University Hospital, 128 08, Prague 2, Czech Republic. FAU - Haluzik, Martin AU - Haluzik M AD - Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21, Prague 4, Czech Republic; Department of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague and General University Hospital, 128 08, Prague 2, Czech Republic. FAU - Zelezna, Blanka AU - Zelezna B AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10, Prague 6, Czech Republic. FAU - Kunes, Jaroslav AU - Kunes J AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10, Prague 6, Czech Republic; Institute of Physiology of the Czech Academy of Sciences, 142 20, Prague 4, Czech Republic. FAU - Holscher, Christian AU - Holscher C AD - Biomedical and Life Science, Faculty of Health and Medicine, Lancaster University, Bailrigg, Lancaster, LA1 4YW, United Kingdom. FAU - Maletinska, Lenka AU - Maletinska L AD - Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10, Prague 6, Czech Republic. Electronic address: maletin@uochb.cas.cz. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181111 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Amyloid beta-Peptides) RN - 0 (Mapt protein, mouse) RN - 0 (Neuroprotective Agents) RN - 0 (Prolactin-Releasing Hormone) RN - 0 (tau Proteins) RN - 839I73S42A (Liraglutide) SB - IM MH - Alzheimer Disease/*drug therapy/metabolism/pathology MH - Amyloid beta-Peptides/metabolism MH - Amyloidosis/*drug therapy/metabolism/pathology MH - Animals MH - Disease Models, Animal MH - Gliosis/drug therapy/metabolism/pathology MH - Hippocampus/drug effects/metabolism/pathology MH - Humans MH - Inflammation/drug therapy/metabolism/pathology MH - Liraglutide/*pharmacology MH - Male MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neurogenesis/drug effects MH - Neuroprotective Agents/*pharmacology MH - Plaque, Amyloid/*drug therapy/metabolism/pathology MH - Prolactin-Releasing Hormone/*analogs & derivatives MH - Random Allocation MH - tau Proteins/metabolism OTO - NOTNLM OT - APP/PS1 mice OT - Alzheimer's disease OT - Neuroinflammation OT - Palm(11)-PrRP31 OT - Tau phosphorylation OT - beta-amyloid plaques EDAT- 2018/11/15 06:00 MHDA- 2019/03/05 06:00 CRDT- 2018/11/15 06:00 PHST- 2018/07/25 00:00 [received] PHST- 2018/11/02 00:00 [revised] PHST- 2018/11/03 00:00 [accepted] PHST- 2018/11/15 06:00 [pubmed] PHST- 2019/03/05 06:00 [medline] PHST- 2018/11/15 06:00 [entrez] AID - S0028-3908(18)30425-8 [pii] AID - 10.1016/j.neuropharm.2018.11.002 [doi] PST - ppublish SO - Neuropharmacology. 2019 Jan;144:377-387. doi: 10.1016/j.neuropharm.2018.11.002. Epub 2018 Nov 11.