A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice.
Humanin (HN), a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD)-related cytotoxicities, including exposure to amyloid beta (Abeta), in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APP(swe), tau(P310L), and PS-1(M146V) that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G-HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD.
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada. tniikura@sfu.ca
Takako
T
Niikura
Elkhansa
E
Sidahmed
Chiho
C
Hirata-Fukae
Paul S
PS
Aisen
Yasuji
Y
Matsuoka
D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D006624:Hippocampus; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D015260:Neprilysin / Q000096:biosynthesis
D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; C427211:humanin; D015260:Neprilysin
Neurosci Lett. 2002 May 24;324(3):227-31
12009529
Methods Mol Biol. 2005;299:267-78
15980611
Biochem Biophys Res Commun. 2004 Jul 2;319(3):733-7
15184044
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13042-7
14561895
J Neurochem. 2003 Jan;84(2):266-72
12558989
Metabolism. 2010 Mar;59(3):343-9
19800083
J Neurosci. 1997 Sep 15;17(18):7053-9
9278541
Neurobiol Dis. 2007 Apr;26(1):212-20
17306982
Neurobiol Aging. 2001 Nov-Dec;22(6):993-1005
11755008
Biochem Biophys Res Commun. 2001 May 4;283(2):460-8
11327724
Brain Res. 2008 Aug 28;1227:12-8
18590709
J Neurosci Res. 2005 Mar 1;79(5):714-23
15678515
Nat Rev Drug Discov. 2010 May;9(5):387-98
20431570
Neuroreport. 2002 May 7;13(6):903-7
11997711
Alzheimer Dis Assoc Disord. 2006 Oct-Dec;20(4):298-301
17132977
Nat Med. 2005 Apr;11(4):434-9
15778722
Neuron. 2005 Mar 3;45(5):675-88
15748844
Brain Res. 2008 Jun 24;1216:92-103
18486110
Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5161-6
16549764
J Neurosci. 2010 Apr 7;30(14):4845-56
20371804
Mol Cell Biochem. 2003 Dec;254(1-2):83-9
14674685
J Neurosci Res. 2002 Nov 1;70(3):493-500
12391610
PLoS One. 2009 Jul 22;4(7):e6334
19623253
J Biol Chem. 2005 Apr 22;280(16):15815-24
15661737
Behav Brain Res. 2008 Sep 1;192(1):106-13
18359102
Brain Res. 2002 Aug 2;945(2):259-65
12126888
Biochem Biophys Res Commun. 2004 Nov 5;324(1):255-61
15465011
Stroke. 2006 Oct;37(10):2613-9
16960089
Nature. 2002 Apr 4;416(6880):535-9
11932745
Mol Psychiatry. 2009 Feb;14(2):206-22
18813209
Neuroscience. 2004;127(2):481-96
15262337
Neuropeptides. 2005 Apr;39(2):97-101
15752543
FASEB J. 2003 Jan;17(1):50-2
12475907
Brain Pathol. 2008 Apr;18(2):240-52
18363935
Neuroscience. 2008 Jul 17;154(4):1155-72
18554812
J Biol Chem. 1998 Dec 4;273(49):32730-8
9830016
Mol Cell Neurosci. 2004 Jan;25(1):95-102
14962743
FEBS Lett. 1994 May 23;345(1):33-7
8194595
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6336-41
11371646
Neurosci Lett. 2001 Jan 12;297(2):97-100
11121879
Trends Mol Med. 2004 Mar;10(3):102-5
15106598
J Neurosci. 2007 Mar 21;27(12):3090-7
17376970
Neurosci Lett. 1994 Mar 28;170(1):63-6
8086012
PLoS Med. 2007 Aug;4(8):e262
17760499
Neuron. 2005 May 19;46(4):541-54
15944124
J Immunol. 2004 Jun 1;172(11):7078-85
15153530
J Biol Chem. 2005 Apr 22;280(16):15825-35
15661735
J Neurosci. 2004 Jun 30;24(26):5901-8
15229237
J Biol Chem. 2006 Dec 22;281(51):39413-23
17056594
Acta Neuropathol. 2005 Apr;109(4):367-72
15759134
Apoptosis. 2005 Oct;10(5):963-71
16151632
Mol Neurobiol. 2004 Dec;30(3):327-40
15655255
Br J Pharmacol. 2001 Dec;134(8):1597-9
11739234
Life Sci. 2005 Oct 28;77(24):3092-104
16005025
Behav Brain Res. 1999 Mar;99(2):191-200
10512585
J Neurosci. 2008 Oct 29;28(44):11409-20
18971483
J Pept Sci. 2004 Oct;10(10):636-9
15526713
J Neurosci. 2004 Mar 31;24(13):3370-8
15056716
Curr Alzheimer Res. 2009 Oct;6(5):455-60
19874271
Nature. 2003 May 22;423(6938):456-61
12732850
Behav Genet. 2006 Sep;36(5):763-74
16402282
Jpn J Pharmacol. 1997 Jan;73(1):51-7
9032134
J Mol Neurosci. 2005;25(2):165-9
15784964
Neuropeptides. 2008 Oct-Dec;42(5-6):557-67
18929410
J Pharmacol Exp Ther. 2008 Apr;325(1):146-53
18199809
Neuropsychopharmacology. 2008 Jul;33(8):2020-32
17928813
Neuron. 2007 Feb 1;53(3):337-51
17270732
Mol Biol Cell. 2009 Jun;20(12):2864-73
19386761
Neuron. 2003 Jul 31;39(3):409-21
12895417
Oncogene. 2008 Oct 27;27(50):6473-88
18955974
J Neurosci. 2001 Dec 1;21(23):9235-45
11717357
Br J Pharmacol. 1999 Jan;126(1):235-44
10051141