Metabolic, Phenotypic, and Neuropathological Characterization of the Tg4-42 Mouse Model for Alzheimer's Disease.
Alzheimer’s disease
behavior
biomarkers
neuroinflammation
neuronal degeneration
nuclear magnetic resonance
Journal
Journal of Alzheimer's disease : JAD
ISSN: 1875-8908
Titre abrégé: J Alzheimers Dis
Pays: Netherlands
ID NLM: 9814863
Informations de publication
Date de publication:
2021
2021
Historique:
pubmed:
2
3
2021
medline:
15
9
2021
entrez:
1
3
2021
Statut:
ppublish
Résumé
Preclinical Alzheimer's disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression. We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model. Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses. Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice. Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.
Sections du résumé
BACKGROUND
Preclinical Alzheimer's disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression.
OBJECTIVE
We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model.
METHODS
Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses.
RESULTS
Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice.
CONCLUSION
Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.
Identifiants
pubmed: 33646155
pii: JAD201204
doi: 10.3233/JAD-201204
pmc: PMC8150512
doi:
Substances chimiques
Amyloid beta-Peptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1151-1168Références
Cell Metab. 2018 Nov 6;28(5):706-720.e6
pubmed: 30122555
Neurol Sci. 2013 Sep;34(9):1575-9
pubmed: 23354600
Alzheimers Dement. 2011 May;7(3):309-17
pubmed: 21075060
Neurology. 2006 Jan 24;66(2 Suppl 1):S74-8
pubmed: 16432151
Alzheimers Dement. 2016 Jul;12(7):815-22
pubmed: 26806385
Molecules. 2018 Mar 21;23(4):
pubmed: 29561816
Acta Neuropathol Commun. 2013 Jun 27;1:28
pubmed: 24252434
J Neural Transm (Vienna). 2015 Apr;122(4):541-50
pubmed: 25742870
Curr Alzheimer Res. 2018;15(2):164-181
pubmed: 28933272
Sci Rep. 2020 Apr 14;10(1):6377
pubmed: 32286473
Clin Exp Neuroimmunol. 2018 Nov;9(4):211-218
pubmed: 30546389
Transl Psychiatry. 2016 May 03;6:e800
pubmed: 27138799
Anal Chem. 2015 Jan 6;87(1):133-46
pubmed: 25375201
Prog Brain Res. 2009;175:83-93
pubmed: 19660650
Naunyn Schmiedebergs Arch Pharmacol. 2001 Feb;363(2):139-45
pubmed: 11218066
Diabetologia. 2016 Aug;59(8):1743-52
pubmed: 27153842
Behav Neurosci. 1992 Jun;106(3):457-64
pubmed: 1616612
J Alzheimers Dis. 2015;46(4):1049-70
pubmed: 26402632
Front Aging Neurosci. 2019 Jan 08;10:425
pubmed: 30670962
Cell Mol Life Sci. 2019 May;76(10):1833-1863
pubmed: 30770953
J Alzheimers Dis. 2013;35(4):643-68
pubmed: 23481689
Methods Mol Biol. 2015;1277:161-93
pubmed: 25677154
J Neurosci Res. 2007 Nov 15;85(15):3347-58
pubmed: 17847118
Behav Neurosci. 1994 Aug;108(4):681-90
pubmed: 7986362
Front Aging Neurosci. 2014 Apr 16;6:75
pubmed: 24795628
Methods Mol Biol. 2017;1641:229-258
pubmed: 28748468
Acta Neuropathol. 2013 Aug;126(2):189-205
pubmed: 23685882
Front Behav Neurosci. 2019 May 17;13:107
pubmed: 31156407
Acta Neuropathol. 2014;127(6):787-801
pubmed: 24803226
J Am Geriatr Soc. 2001 Dec;49(12):1700-7
pubmed: 11844006
Alzheimers Dement (Amst). 2019 Sep 27;11:679-689
pubmed: 31673598
FASEB J. 2017 Feb;31(2):732-742
pubmed: 27811061
Int J Neurosci. 2014 May;124(5):307-21
pubmed: 23930978
Sci Rep. 2015 Dec 02;5:17338
pubmed: 26626428
Eur Radiol. 2017 Jul;27(7):2698-2705
pubmed: 27966041
Mol Neurodegener. 2017 Oct 10;12(1):73
pubmed: 29017573
Sci Rep. 2018 Nov 26;8(1):17368
pubmed: 30478269
Neurochem Res. 2005 Nov;30(11):1443-51
pubmed: 16341942
Neurochem Int. 2007 Jun;50(7-8):1052-66
pubmed: 17141374
Neuroreport. 2002 Jan 21;13(1):183-6
pubmed: 11924885
Metabolites. 2019 Jun 27;9(7):
pubmed: 31252628
J Neuropathol Exp Neurol. 2004 May;63(5):418-28
pubmed: 15198121
Brain Res. 2005 May 10;1043(1-2):48-56
pubmed: 15862517
Clinics (Sao Paulo). 2011;66 Suppl 1:45-54
pubmed: 21779722
Mol Neurobiol. 2020 Mar;57(3):1374-1388
pubmed: 31734880
J Biol Chem. 2018 Oct 5;293(40):15419-15428
pubmed: 30143530
Acta Neurol Belg. 2016 Dec;116(4):445-450
pubmed: 27118573
J Alzheimers Dis. 2014;39(2):441-55
pubmed: 24240639
Alzheimers Dement. 2016 Jun;12(6):719-32
pubmed: 27179961
Neurobiol Aging. 2014 Sep;35(9):1992-2003
pubmed: 24746363
Acta Neuropathol Commun. 2018 Jun 29;6(1):52
pubmed: 29958544
Cell. 2008 Sep 5;134(5):714-7
pubmed: 18775301
JAMA Neurol. 2017 May 1;74(5):557-566
pubmed: 28346578
Alzheimers Res Ther. 2017 Oct 4;9(1):80
pubmed: 28978359
J Neurochem. 1998 Aug;71(2):767-74
pubmed: 9681468
Front Aging Neurosci. 2018 Mar 08;10:64
pubmed: 29568268
Neurology. 2001 Mar 27;56(6):737-42
pubmed: 11274307
Int J Geriatr Psychiatry. 2001 Feb;16(2):192-202
pubmed: 11241725
Mol Neurodegener. 2013 Jan 14;8:2
pubmed: 23316765
Neuroscience. 2008 Oct 28;156(4):898-910
pubmed: 18790019