Altered Brain Expression of Insulin and Insulin-Like Growth Factors in Frontotemporal Lobar Degeneration: Another Degenerative Disease Linked to Dysregulation of Insulin Metabolic Pathways.
neurodegenerative diseases
neurodevelopmental disorders
neuropathology
Journal
ASN neuro
ISSN: 1759-0914
Titre abrégé: ASN Neuro
Pays: United States
ID NLM: 101507115
Informations de publication
Date de publication:
Historique:
entrez:
14
5
2019
pubmed:
14
5
2019
medline:
14
5
2020
Statut:
ppublish
Résumé
Frontotemporal lobar degeneration (FTLD) is the third most common dementing neurodegenerative disease with nearly 80% having no known etiology. Growing evidence that neurodegeneration can be linked to dysregulated metabolism prompted us to measure a panel of trophic factors, receptors, and molecules that modulate brain metabolic function in FTLD. Postmortem frontal (Brodmann's area [BA]8/9 and BA24) and temporal (BA38) lobe homogenates were used to measure immunoreactivity to Tau, phosphorylated tau (pTau), ubiquitin, 4-hydroxynonenal (HNE), transforming growth factor-beta 1 (TGF-β1) and its receptor (TGF-β1R), brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, neurotrophin-4, tropomyosin receptor kinase, and insulin and insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2) and their receptors by direct-binding enzyme-linked immunosorbent assay. FTLD brains had significantly elevated pTau, ubiquitin, TGF-β1, and HNE immunoreactivity relative to control. In addition, BDNF and neurotrophin-4 were respectively reduced in BA8/9 and BA38, while neurotrophin-3 and nerve growth factor were upregulated in BA38, and tropomyosin receptor kinase was elevated in BA24. Lastly, insulin and insulin receptor expressions were elevated in the frontal lobe, IGF-1 was increased in BA24, IGF-1R was upregulated in all three brain regions, and IGF-2 receptor was reduced in BA24 and BA38. Aberrantly increased levels of pTau, ubiquitin, HNE, and TGF-β1, marking neurodegeneration, oxidative stress, and neuroinflammation, overlap with altered expression of insulin/IGF signaling ligand and receptors in frontal and temporal lobe regions targeted by FTLD. Dysregulation of insulin-IGF signaling networks could account for brain hypometabolism and several characteristic neuropathologic features that characterize FTLD but overlap with Alzheimer's disease, Parkinson's disease, and Dementia with Lewy Body Disease.
Sections du résumé
BACKGROUND
Frontotemporal lobar degeneration (FTLD) is the third most common dementing neurodegenerative disease with nearly 80% having no known etiology.
OBJECTIVE
Growing evidence that neurodegeneration can be linked to dysregulated metabolism prompted us to measure a panel of trophic factors, receptors, and molecules that modulate brain metabolic function in FTLD.
METHODS
Postmortem frontal (Brodmann's area [BA]8/9 and BA24) and temporal (BA38) lobe homogenates were used to measure immunoreactivity to Tau, phosphorylated tau (pTau), ubiquitin, 4-hydroxynonenal (HNE), transforming growth factor-beta 1 (TGF-β1) and its receptor (TGF-β1R), brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, neurotrophin-4, tropomyosin receptor kinase, and insulin and insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2) and their receptors by direct-binding enzyme-linked immunosorbent assay.
RESULTS
FTLD brains had significantly elevated pTau, ubiquitin, TGF-β1, and HNE immunoreactivity relative to control. In addition, BDNF and neurotrophin-4 were respectively reduced in BA8/9 and BA38, while neurotrophin-3 and nerve growth factor were upregulated in BA38, and tropomyosin receptor kinase was elevated in BA24. Lastly, insulin and insulin receptor expressions were elevated in the frontal lobe, IGF-1 was increased in BA24, IGF-1R was upregulated in all three brain regions, and IGF-2 receptor was reduced in BA24 and BA38.
CONCLUSIONS
Aberrantly increased levels of pTau, ubiquitin, HNE, and TGF-β1, marking neurodegeneration, oxidative stress, and neuroinflammation, overlap with altered expression of insulin/IGF signaling ligand and receptors in frontal and temporal lobe regions targeted by FTLD. Dysregulation of insulin-IGF signaling networks could account for brain hypometabolism and several characteristic neuropathologic features that characterize FTLD but overlap with Alzheimer's disease, Parkinson's disease, and Dementia with Lewy Body Disease.
Identifiants
pubmed: 31081340
doi: 10.1177/1759091419839515
pmc: PMC6535914
doi:
Substances chimiques
Insulin
0
Somatomedins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1759091419839515Subventions
Organisme : NIAAA NIH HHS
ID : R01 AA012908
Pays : United States
Organisme : NIAAA NIH HHS
ID : R37 AA011431
Pays : United States
Références
Curr Alzheimer Res. 2013 Jul;10(6):569-77
pubmed: 23627751
J Neurol. 2013 Jul;260(7):1724-30
pubmed: 23400497
Neurochem Int. 2001 Nov-Dec;39(5-6):393-400
pubmed: 11578774
J Pathol. 2013 May;230(1):95-106
pubmed: 23299523
Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5198-203
pubmed: 15758069
J Neurosci. 2016 Feb 17;36(7):2086-100
pubmed: 26888921
Dement Geriatr Cogn Disord. 2006;21(1):9-15
pubmed: 16244482
Ann Neurol. 2008 Jul;64(1):60-70
pubmed: 18546284
N Engl J Med. 2009 Oct 15;361(16):1529-38
pubmed: 19828530
J Endocrinol. 2014 Mar 07;221(1):T31-41
pubmed: 23999914
Neurodegener Dis Manag. 2014;4(1):31-40
pubmed: 24640977
Trends Endocrinol Metab. 2014 Feb;25(2):89-98
pubmed: 24361004
Biomed Res Int. 2017;2017:9248542
pubmed: 29018822
J Cell Sci. 2005 Oct 1;118(Pt 19):4577-86
pubmed: 16179614
Exp Neurol. 2001 Mar;168(1):183-91
pubmed: 11170733
Brain. 2011 Sep;134(Pt 9):2456-77
pubmed: 21810890
Exp Neurol. 2014 Dec;262 Pt B:84-90
pubmed: 24915640
Nature. 1994 Jan 27;367(6461):368-71
pubmed: 8114936
J Neurol Neurosurg Psychiatry. 2010 May;81(5):536-8
pubmed: 20176597
Transl Psychiatry. 2016 Oct 4;6(10):e907
pubmed: 27701410
Hum Mol Genet. 2009 Dec 1;18(23):4629-39
pubmed: 19744960
Cold Spring Harb Perspect Biol. 2018 Apr 2;10(4):
pubmed: 28716886
Curr Med Chem. 2014;21(2):230-7
pubmed: 23848536
Arch Neurol. 2009 Mar;66(3):300-5
pubmed: 19273747
Ann N Y Acad Sci. 1993 Aug 27;692:72-88
pubmed: 8215046
Curr Top Behav Neurosci. 2013;15:117-36
pubmed: 23519767
J Alzheimers Dis. 2005 Feb;7(1):63-80
pubmed: 15750215
J Mol Neurosci. 2011 Nov;45(3):561-73
pubmed: 21863317
Brain. 2005 Sep;128(Pt 9):1996-2005
pubmed: 16033782
Lancet. 2015 Oct 24;386(10004):1672-82
pubmed: 26595641
J Cell Sci. 2013 Dec 1;126(Pt 23):5412-21
pubmed: 24046442
J Alzheimers Dis. 2004 Dec;6(6 Suppl):S7-11
pubmed: 15665417
J Neuropathol Exp Neurol. 2008 Dec;67(12):1122-36
pubmed: 19018247
Mol Neurobiol. 2015 Dec;52(3):1477-1493
pubmed: 25354497
J Clin Invest. 2012 Apr;122(4):1316-38
pubmed: 22476197
J Alzheimers Dis. 2005 Feb;7(1):45-61
pubmed: 15750214
Pharmacol Ther. 2013 May;138(2):155-75
pubmed: 23348013
J Neurochem. 2012 Nov;123(3):406-16
pubmed: 22970712
Psychogeriatrics. 2014 Sep;14(3):196-201
pubmed: 25323961
Neurosci Lett. 2000 Jan 21;279(1):33-6
pubmed: 10670781
Nat Rev Neurosci. 2015 Nov;16(11):660-71
pubmed: 26462756
Mol Psychiatry. 2018 Aug;23(8):1813-1824
pubmed: 29867188
J Neurosci. 2007 Apr 18;27(16):4424-34
pubmed: 17442827
Biochem Pharmacol. 2014 Apr 15;88(4):548-59
pubmed: 24380887
J Alzheimers Dis. 2005 Dec;8(3):247-68
pubmed: 16340083
Front Aging Neurosci. 2016 Feb 01;8:10
pubmed: 26869919
Arch Med Res. 2012 Nov;43(8):671-6
pubmed: 23142262
J Neurosci. 2003 Nov 5;23(31):10137-45
pubmed: 14602830
Alzheimers Dement. 2015 Mar;11(3):310-320
pubmed: 24418058
J Alzheimers Dis. 2008 Sep;15(1):29-44
pubmed: 18780965
Am J Med Genet A. 2017 Oct;173(10):2659-2669
pubmed: 28767196
J Alzheimers Dis. 2002 Jun;4(3):225-32
pubmed: 12226541
Exp Brain Res. 2016 Jul;234(7):1863-1873
pubmed: 26894890
Eur Neuropsychopharmacol. 2014 Dec;24(12):1954-60
pubmed: 25088942
Neurobiol Aging. 2016 Dec;48:135-142
pubmed: 27676333
Curr Opin Investig Drugs. 2009 Oct;10(10):1049-60
pubmed: 19777393
Acta Neurol Belg. 2011 Dec;111(4):306-9
pubmed: 22368970
Transl Neurodegener. 2016 Apr 05;5:7
pubmed: 27054030
Mech Ageing Dev. 2015 Nov;151:60-70
pubmed: 25708826
J Alzheimers Dis. 2013;33 Suppl 1:S263-75
pubmed: 22936011
BMJ. 2013 Aug 06;347:f4827
pubmed: 23920254
Neurology. 2005 Feb 22;64(4):734-6
pubmed: 15728305
Prog Neurobiol. 2016 Oct - Nov;145-146:98-120
pubmed: 27713036
Mol Cell Biochem. 2017 Aug;432(1-2):199-208
pubmed: 28374141
J Aging Res. 2012;2012:384017
pubmed: 22500228
Exp Neurol. 2000 Nov;166(1):99-114
pubmed: 11031087
Development. 1996 Oct;122(10):3255-61
pubmed: 8898237
J Alzheimers Dis. 2018;64(s1):S405-S426
pubmed: 29562518
Curr Opin Genet Dev. 2004 Apr;14(2):188-95
pubmed: 15196466
Cell Tissue Bank. 2008 Sep;9(3):217-27
pubmed: 18612850
J Neurosci. 1995 Sep;15(9):6213-21
pubmed: 7666203
Curr Alzheimer Res. 2012 Sep;9(7):815-21
pubmed: 21605064
J Neurobiol. 1994 Nov;25(11):1418-35
pubmed: 7852995
J Alzheimers Dis. 2009;16(3):585-99
pubmed: 19276553
CNS Neurol Disord Drug Targets. 2008 Dec;7(6):512-23
pubmed: 19128208
Annu Rev Neurosci. 2001;24:677-736
pubmed: 11520916
J Nucl Med. 2005 Feb;46(2):233-9
pubmed: 15695781
Eur Arch Psychiatry Clin Neurosci. 2011 Sep;261(6):433-46
pubmed: 21207049
Radiographics. 2014 May-Jun;34(3):684-701
pubmed: 24819789
Neurodegener Dis. 2017;17(1):44-58
pubmed: 27617773
Neurology. 2016 May 3;86(18):1736-43
pubmed: 27037234
Neurobiol Dis. 1999 Oct;6(5):335-46
pubmed: 10527802
FEBS Lett. 2008 Aug 20;582(19):2899-904
pubmed: 18656473
J Neurol Sci. 2006 Oct 25;248(1-2):3-8
pubmed: 17034818
Ann N Y Acad Sci. 1999;893:154-75
pubmed: 10672236
J Neurochem. 2007 May;101(3):757-70
pubmed: 17448147
Acta Neuropathol. 2008 May;115(5):509-32
pubmed: 17985145
J Alzheimers Dis. 2016 Nov 19;55(2):849-864
pubmed: 27802237
J Alzheimers Dis. 2012;30 Suppl 2:S231-49
pubmed: 22337830
Vitam Horm. 2009;80:699-719
pubmed: 19251056
Pharm Acta Helv. 2000 Mar;74(2-3):273-80
pubmed: 10812969
Microsc Res Tech. 1999 May 15-Jun 1;45(4-5):292-302
pubmed: 10383122
Hosp Pract (1995). 2011 Aug;39(3):149-60
pubmed: 21881402
Drugs. 2017 Jan;77(1):47-65
pubmed: 27988872
Brain Pathol. 1998 Apr;8(2):403-6
pubmed: 9546296