Expression of Phenotypic Astrocyte Marker Is Increased in a Transgenic Mouse Model of Alzheimer's Disease versus Age-Matched Controls: A Presymptomatic Stage Study.
Recent mouse studies of the presymptomatic stage of Alzheimer's disease (AD) have suggested that proinflammatory changes, such as glial activation and cytokine induction, may occur already at this early stage through unknown mechanisms. Because TNFα contributes to increased Aβ production from the Aβ precursor protein (APP), we assessed a putative correlation between APP/Aβ and TNFα during the presymptomatic stage as well as early astrocyte activation in the hippocampus of 3-month-old APPswe/PS1dE9 mice. While Western blots revealed significant APP expression, Aβ was not detectable by Western blot or ELISA attesting that 3-month-old, APPswe/PS1dE9 mice are at a presymptomatic stage of AD-like pathology. Western blots were also used to show increased GFAP expression in transgenic mice that positively correlated with both TNFα and APP, which were also mutually correlated. Subregional immunohistochemical quantification of phenotypic (GFAP) and functional (TSPO) markers of astrocyte activation indicated a selective and significant increase in GFAP-immunoreactive (IR) cells in the dentate gyrus of APPswe/PS1dE9 mice. Our data suggest that subtle morphological and phenotypic alterations, compatible with the engagement of astrocyte along the activation pathway, occur in the hippocampus already at the presymptomatic stage of AD.
UMR Inserm U930, Université François Rabelais, Tours, France.
Aurélie
A
Doméné
Department of Neuroscience, Douglas Hospital Research Centre, Montreal, QC, Canada H4H 1R3.
Chelsea
C
Cavanagh
EA 3808 CiMoTheMA, Université de Poitiers, Poitiers, France.
Guylène
G
Page
UMR Inserm U930, Université François Rabelais, Tours, France.
Sylvie
S
Bodard
Centre de Recherche des Cordeliers, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Université Pierre et Marie Curie Université Paris 06, Sorbonne Universités, Paris, France.
Christophe
C
Klein
Institut du Cerveau et de la Moelle épinière (ICM), CNRS UMR 7225, INSERM U 1127, UPMC-P6 UMR S 1127, Paris, France.
Cécile
C
Delarasse
UMR Inserm U930, Université François Rabelais, Tours, France.
Sylvie
S
Chalon
Centre de Recherche des Cordeliers, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Université Pierre et Marie Curie Université Paris 06, Sorbonne Universités, Paris, France.
Slavica
0000-0002-0785-4549
S
Krantic
Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20504-9
19918059
Am J Pathol. 2001 Mar;158(3):797-801
11238027
Neurobiol Aging. 2012 Nov;33(11):2661-77
22277264
J Neurosci. 2009 Mar 18;29(11):3453-62
19295151
Neuron. 2007 Sep 6;55(5):697-711
17785178
Pharmacol Rev. 2012 Oct;64(4):1004-26
22966039
Neurobiol Aging. 2015 Apr;36(4):1639-52
25680265
Cell. 2012 Apr 27;149(3):708-21
22541439
Science. 2002 Jul 19;297(5580):353-6
12130773
Brain Res Rev. 2009 Oct;61(2):60-8
19445962
J Alzheimers Dis. 2010;21(1):119-32
20413859
Neurobiol Dis. 2008 Dec;32(3):412-9
18786637
J Alzheimers Dis. 2012;29(2):293-308
22232004
J Neurosci. 2012 Aug 8;32(32):10809-18
22875916
Lancet Neurol. 2014 Jun;13(6):614-29
24849862
Trends Pharmacol Sci. 2006 Aug;27(8):402-9
16822554
Nature. 2006 Apr 20;440(7087):1054-9
16547515
FASEB J. 2012 Jan;26(1):334-45
21982949
J Neurosci. 2011 Nov 30;31(48):17680-8
22131428
Neurobiol Aging. 2010 Nov;31(11):1877-84
19070941
J Clin Immunol. 2014 Jul;34 Suppl 1:S64-9
24711006
Brain Struct Funct. 2010 Mar;214(2-3):145-60
20213270
J Neurosci. 2009 Dec 16;29(50):15660-8
20016080
J Biol Chem. 2001 Jun 15;276(24):21562-70
11279122
Neurobiol Aging. 2004 Aug;25(7):885-92
15212842
Brain Behav Immun. 2008 Aug;22(6):797-803
18495419
Brain Behav Immun. 2011 Feb;25(2):181-213
20970492
Neurosci Lett. 2011 Mar 29;492(1):5-10
21295112
J Neurosci. 2008 Dec 31;28(53):14537-45
19118188
Neuron Glia Biol. 2004 Aug;1(3):263-73
16520832
Neurosci Lett. 2004 Sep 2;367(2):164-7
15331144
Nat Neurosci. 2010 Jul;13(7):812-8
20581818
Arch Neurol. 2009 Apr;66(4):435-40
19204149
J Neuropathol Exp Neurol. 2003 Dec;62(12):1220-7
14692698
Neurobiol Aging. 2006 Nov;27(11):1658-72
16271420
J Neurosci. 2014 Mar 5;34(10):3793-806
24599476
Trends Neurosci. 2012 Oct;35(10):638-47
22749718
J Alzheimers Dis. 2013;36(2):233-8
23579326
Trends Neurosci. 1999 May;22(5):208-15
10322493
J Neurosci. 2013 May 15;33(20):8891-7
23678130
Neurobiol Aging. 2015 Jan;36(1):1-11
25444609
Neuropathol Appl Neurobiol. 2009 Jun;35(3):306-28
19077109
J Neurosci. 2008 Nov 5;28(45):11650-61
18987201
Eur J Neurosci. 2013 Jun;37(12):1896-902
23773058
Pharmacol Ther. 2008 Apr;118(1):1-17
18374421
Am J Pathol. 2008 Dec;173(6):1768-82
18974297