title: A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease.
abstract: Previously, we have developed a retro-inverso peptide inhibitor (RI-OR2, rGffvlkGr) that blocks the in vitro formation and toxicity of the Aβ oligomers which are thought to be a cause of neurodegeneration and memory loss in Alzheimer's disease. We have now attached a retro-inverted version of the HIV protein transduction domain 'TAT' to RI-OR2 to target this new inhibitor (RI-OR2-TAT, Ac-rGffvlkGrrrrqrrkkrGy-NH(2)) into the brain. Following its peripheral injection, a fluorescein-labelled version of RI-OR2-TAT was found to cross the blood brain barrier and bind to the amyloid plaques and activated microglial cells present in the cerebral cortex of 17-months-old APPswe/PS1ΔE9 transgenic mice. Daily intraperitoneal injection of RI-OR2-TAT (at 100 nmol/kg) for 21 days into 10-months-old APPswe/PS1ΔE9 mice resulted in a 25% reduction (p<0.01) in the cerebral cortex of Aβ oligomer levels, a 32% reduction (p<0.0001) of β-amyloid plaque count, a 44% reduction (p<0.0001) in the numbers of activated microglial cells, and a 25% reduction (p<0.0001) in oxidative damage, while the number of young neurons in the dentate gyrus was increased by 210% (p<0.0001), all compared to control APPswe/PS1ΔE9 mice injected with vehicle (saline) alone. Our data suggest that oxidative damage, inflammation, and inhibition of neurogenesis are all a downstream consequence of Aβ aggregation, and identify a novel brain-penetrant retro-inverso peptide inhibitor of Aβ oligomer formation for further testing in humans as a potential disease-modifying treatment for Alzheimer's disease.
authors: School of Biomedical Sciences, University of Ulster, Coleraine, Co. Londonderry, United Kingdom.
authors: Vadivel
authors: V
authors: Parthsarathy
authors: Paula L
authors: PL
authors: McClean
authors: Christian
authors: C
authors: Hölscher
authors: Mark
authors: M
authors: Taylor
authors: Claire
authors: C
authors: Tinker
authors: Glynn
authors: G
authors: Jones
authors: Oleg
authors: O
authors: Kolosov
authors: Elisa
authors: E
authors: Salvati
authors: Maria
authors: M
authors: Gregori
authors: Massimo
authors: M
authors: Masserini
authors: David
authors: D
authors: Allsop
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010539:Permeability; D058225:Plaque, Amyloid; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010455:Peptides
references: J Biol Chem. 1996 Nov 22;271(47):29525-8
references: 8939877
references: Neurotox Res. 2005;7(1-2):17-27
references: 15639795
references: J Biol Chem. 2005 Oct 28;280(43):35789-92
references: 16141213
references: Cell. 1988 Dec 23;55(6):1179-88
references: 2849509
references: Biochemistry. 1999 May 25;38(21):6791-800
references: 10346900
references: Chembiochem. 2007 Oct 15;8(15):1857-64
references: 17763487
references: J Biol Chem. 2005 Feb 18;280(7):5892-901
references: 15590663
references: Mol Cell Neurosci. 2004 Oct;27(2):85-131
references: 15485768
references: Lancet Neurol. 2010 Jul;9(7):702-16
references: 20610346
references: Bioconjug Chem. 2003 Jan-Feb;14(1):86-92
references: 12526697
references: Nat Rev Drug Discov. 2010 May;9(5):387-98
references: 20431570
references: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53
references: 9600986
references: Neurotherapeutics. 2008 Jul;5(3):391-8
references: 18625450
references: PLoS One. 2010 Jun 14;5(6):e11101
references: 20559435
references: Biochemistry. 2010 Apr 20;49(15):3261-72
references: 20230062
references: Mol Pharm. 2009 May-Jun;6(3):836-48
references: 19278221
references: Adv Exp Med Biol. 2010;677:150-67
references: 20687488
references: FASEB J. 2004 Sep;18(12):1366-72
references: 15333579
references: FASEB J. 2003 Jan;17(1):118-20
references: 12424218
references: J Neurobiol. 1999 Jun 5;39(3):371-82
references: 10363910
references: J Alzheimers Dis. 2011;23(3):551-61
references: 21297277
references: Nanomedicine. 2011 Oct;7(5):541-50
references: 21722618
references: J Neurochem. 2007 Jun;101(5):1172-84
references: 17286590
references: Biochemistry. 2001 Jul 27;40(28):8237-45
references: 11444969
references: Nature. 2002 Apr 4;416(6880):535-9
references: 11932745
references: Histol Histopathol. 2011 Dec;26(12):1611-32
references: 21972099
references: Glia. 2002 Nov;40(2):164-74
references: 12379904
references: Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
references: 17245412
references: Biol Chem. 2010 Aug;391(8):849-59
references: 20731541
references: J Biol Chem. 1997 Nov 14;272(46):29390-7
references: 9361021
references: Rev Sci Instrum. 2007 Jan;78(1):013705
references: 17503926
references: Bioorg Med Chem. 2011 Sep 15;19(18):5596-604
references: 21840724
references: Nat Neurosci. 2005 Jan;8(1):79-84
references: 15608634
references: Biochemistry. 2006 Aug 15;45(32):9906-18
references: 16893191
references: Science. 2012 Mar 23;335(6075):1503-6
references: 22323736
references: J Neuropathol Exp Neurol. 2012 Mar;71(3):233-41
references: 22318126
references: Neuroscience. 2007 Nov 30;150(1):40-9
references: 17900813
references: J Neuroimmune Pharmacol. 2012 Mar;7(1):60-73
references: 21932048
references: Pharm Res. 2001 Jul;18(7):950-6
references: 11496954
references: Brain Res. 2002 Jan 11;924(2):133-40
references: 11750898
references: Science. 2003 Dec 5;302(5651):1760-5
references: 14615545
references: J Biol Chem. 1999 Apr 30;274(18):12619-25
references: 10212241
references: Methods Enzymol. 2006;413:273-312
references: 17046402
references: Nat Med. 1998 Jul;4(7):822-6
references: 9662374
references: J Neurosci. 2011 Apr 27;31(17):6587-94
references: 21525299
references: Trends Pharmacol Sci. 1991 Oct;12(10):383-8
references: 1763432
references: Nat Rev Drug Discov. 2011 Aug 19;10(9):698-712
references: 21852788
references: Biochem Biophys Res Commun. 1996 Jul 25;224(3):855-62
references: 8713135
references: J Neurosci. 2009 Jul 15;29(28):9078-89
references: 19605645
references: Biochem Biophys Res Commun. 1996 Sep 24;226(3):672-80
references: 8831674
references: Neurobiol Dis. 1998 Sep;5(3):129-41
references: 9848086
references: J Biol Chem. 1996 Apr 12;271(15):8545-8
references: 8621479
references: Nat Rev Neurosci. 2002 Oct;3(10):824-8
references: 12360327
references: Am J Public Health. 1998 Sep;88(9):1337-42
references: 9736873
references: Neuron. 1999 Jun;23(2):257-71
references: 10399933