Early Impairments of Hippocampal Neurogenesis in 5xFAD Mouse Model of Alzheimer’s Disease Are Associated with Altered Expression of SOXB Transcription Factors
Restricted accessResearch articleFirst published online September 11, 2018
Early Impairments of Hippocampal Neurogenesis in 5xFAD Mouse Model of Alzheimer’s Disease Are Associated with Altered Expression of SOXB Transcription Factors
Dysregulation of neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus has been related to cognitive deficits and memory loss in neurodegenerative diseases, such as Alzheimer’s disease (AD). Members of the B group of SOX transcription factors play critical roles in regulating neurogenesis in the embryonic and adult nervous system, including maintaining the multipotency, renewal, and cell fate decision of neural stem/progenitor cells. The aim of the present study was to evaluate the expression patterns of selected SOXB proteins in the SGZ, of 8-week-old male and female 5xFAD mice, which represent a transgenic model of AD with a severe and very early development of amyloid pathology. Immunohistochemical analysis showed a significant decrease in the number of cells expressing SOX1, SOX2, and SOX21 transcription factors within the SGZ of 5xFAD mice in comparison to their non-transgenic counterparts which coincidences with reduced number of doublecortin immunoreactive immature neurons found in Tg males. Despite observed changes in expressional pattern of examined SOXB proteins, the proliferative capacity evaluated by the number of Ki-67 immunoreactive cells remained unaffected in transgenic mice of both genders. Based on our results, we suggest that SOXB proteins might be considered as new biomarkers for the detection of early impairments in adult neurogenesis in different animal models or/and new targets in human regenerative medicine.
HymanBT, PhelpsCH, BeachTG, BigioEH, CairnsNJ, CarrilloMC, DicksonDW, DuyckaertsC, FroschMP, MasliahE, MirraSS, NelsonPT, SchneiderJA, ThalDR, ThiesB, TrojanowskiJQ, VintersHV, MontineTJ (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement8, 1–13.
2.
MuY, GageFH (2011) Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener6, 85.
3.
RodríguezJJ, VerkhratskyA (2011) Neurogenesis in Alzheimer’s disease. J Anat219, 78–89.
4.
DemarsM, HuY-S, GadadharA, LazarovO (2010) Impaired neurogenesis is an early event in the etiology of familial Alzheimer’s disease in transgenic mice. J Neurosci Res88, 2103–2117.
5.
UngerMS, MarschallingerJ, KaindlJ, HöflingC, RossnerS, HenekaMT, Van der LindenA, AignerL (2016) Early changes in hippocampal neurogenesis in transgenic mouse models for Alzheimer’s disease. Mol Neurobiol53, 5796–5806.
HollandsC, BartolottiN, LazarovO (2016) Alzheimer’s disease and hippocampal adult neurogenesis; exploring shared mechanisms. Front Neurosci10, 178.
8.
Varela-NallarL, AranguizFC, AbbottAC, SlaterPG, InestrosaNC (2010) Adult hippocampal neurogenesis in aging and Alzheimer’s disease. Birth Defects Res C Embryo Today90, 284–296.
9.
WinnerB, WinklerJ (2015) Adult neurogenesis in neurodegenerative diseases.a. Cold Spring Harb Perspect Biol7, 021287.
10.
JinK, PeelAL, MaoXO, XieL, CottrellBA, HenshallDC, GreenbergDA (2004) Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A101, 343–347.
11.
ChenQ, NakajimaA, ChoiSH, XiongX, SisodiaSS, TangY-P (2008) Adult neurogenesis is functionally associated with AD-like neurodegeneration. Neurobiol Dis29, 316–326.
12.
ChevallierNL, SorianoS, KangDE, MasliahE, HuG, KooEH (2005) Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation. Am J Pathol167, 151–159.
13.
Ziegler-WaldkirchS, d’ErricoP, SauerJ-F, ErnyD, SavanthrapadianS, LorethD, KatzmarskiN, BlankT, BartosM, PrinzM, Meyer-LuehmannM (2018) Seed-induced Aβ deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer’s disease. EMBO J37, 167–182.
14.
WenPH, HofPR, ChenX, GluckK, AustinG, YounkinSG, DeGasperiR, Gama SosaMA, RobakisNK, HaroutunianV, ElderGA (2004) The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp Neurol188, 224–237.
15.
DonovanMH, YazdaniU, NorrisRD, GamesD, GermanDC, EischAJ (2006) Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer’s disease. J Comp Neurol495, 70–83.
SteinerB, KlempinF, WangL, KottM, KettenmannH, KempermannG (2006) Type-2 cells as link between glial and neuronal lineage in adult hippocampal neurogenesis. Glia54, 805–814.
18.
KempermannG (2015) Adult neurogenesis: An evolutionary perspective.a. Cold Spring Harb Perspect Biol8, 018986.
19.
LefebvreV, DumitriuB, Penzo-MéndezA, HanY, PallaviB (2007) Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int J Biochem Cell Biol39, 2195–2214.
20.
KamachiY, KondohH (2013) Sox proteins: Regulators of cell fate specification and differentiation. Development140, 4129–4144.
21.
ReiprichS, WegnerM (2015) From CNS stem cells to neurons and glia: Sox for everyone. Cell Tissue Res359, 111–124.
22.
BowlesJ, SchepersG, KoopmanP (2000) Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol227, 239–255.
23.
UchikawaM, KamachiY, KondohH (1999) Two distinct subgroups of Group B Sox genes for transcriptional activators and repressors: Their expression during embryonic organogenesis of the chicken. Mech Dev84, 103–120.
24.
PopovicJ, StanisavljevicD, SchwirtlichM, KlajnA, MarjanovicJ, StevanovicM (2014) Expression analysis of SOX14 during retinoic acid induced neural differentiation of embryonal carcinoma cells and assessment of the effect of its ectopic expression on SOXB members in HeLa cells. PLoS One9, e91852.
25.
PevnyLH, SockanathanS, PlaczekM, Lovell-BadgeR (1998) A role for SOX1 in neural determination. Development125, 1967–1978.
26.
DeloguA, SellersK, ZagoraiouL, Bocianowska-ZbrogA, MandalS, GuimeraJ, RubensteinJL, SugdenD, JessellT, LumsdenA (2012) Subcortical visual shell nuclei targeted by ipRGCs develop from a Sox14+-GABAergic progenitor and require Sox14 to regulate daily activity rhythms. Neuron75, 648–662.
27.
SandbergM, KällströmM, MuhrJ (2005) Sox21 promotes the progression of vertebrate neurogenesis. Nat Neurosci8, 995–1001.
28.
MatsudaS, KuwakoK, OkanoHJ, TsutsumiS, AburataniH, SagaY, MatsuzakiY, AkaikeA, SugimotoH, OkanoH (2012) Sox21 promotes hippocampal adult neurogenesis via the transcriptional repression of the Hes5 gene. J Neurosci32, 12543–12557.
29.
WhittingtonN, CunninghamD, LeT-K, De MariaD, SilvaEM (2015) Sox21 regulates the progression of neuronal differentiation in a dose-dependent manner. Dev Biol397, 237–247.
30.
OakleyH, ColeSL, LoganS, MausE, ShaoP, CraftJ, Guillozet-BongaartsA, OhnoM, DisterhoftJ, Van EldikL, BerryR, VassarR (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation. J Neurosci26, 10129–10140.
31.
MoonM, ChaM-Y, Mook-JungI (2014) Impaired hippocampal neurogenesis and its enhancement with ghrelin in 5XFAD mice. J Alzheimers Dis41, 233–241.
KeeN, SivalingamS, BoonstraR, WojtowiczJM (2002) The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis. J Neurosci Methods115, 97–105.
LandelV, BarangerK, VirardI, LoriodB, KhrestchatiskyM, RiveraS, BenechP, FéronF (2014) Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer’s disease. Mol Neurodegener9, 33.
36.
DeviL, AlldredMJ, GinsbergSD, OhnoM (2010) Sex- and brain region-specific acceleration of β-amyloidogenesis following behavioral stress in a mouse model of Alzheimer’s disease. Mol Brain3, 34.
37.
PlümpeT, EhningerD, SteinerB, KlempinF, JessbergerS, BrandtM, RömerB, RodriguezGR, KronenbergG, KempermannG (2006) Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation. BMC Neurosci7, 77.
38.
Van BokhovenP, OomenCA, HoogendijkWJG, SmitAB, LucassenPJ, SpijkerS. (2011) Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment. Eur J Neurosci33, 1833–1840.
39.
López-ToledanoMA, ShelanskiML (2004) Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci24, 5439–5444.
40.
WangL, ChangX, SheL, XuD, HuangW, PooM (2015) Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons. J Neurosci35, 8384–8393.
FerriALM, CavallaroM, BraidaD, Di CristofanoA, CantaA, VezzaniA, OttolenghiS, PandolfiPP, SalaM, DeBiasiS, NicolisSK (2004) Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development131, 3805–3819.
43.
Amador-ArjonaA, CimadamoreF, HuangC-T, WrightR, LewisS, GageFH, TerskikhAV (2015) SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. Proc Natl Acad Sci U S A112, E1936–1945.
44.
CrewsL, AdameA, PatrickC, DelaneyA, PhamE, RockensteinE, HansenL, MasliahE (2010) Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. J Neurosci30, 12252–12262.
45.
BrileyD, GhirardiV, WoltjerR, RenckA, ZolochevskaO, TaglialatelaG, MicciMA (2016) Preserved neurogenesis in non-demented individuals with AD neuropathology. Sci Rep6, 27812.
46.
FreudeKK, PenjwiniM, DavisJL, LaFerlaFM, Blurton-JonesM (2011) Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells. J Biol Chem286, 24264–24274.
47.
SarlakG, VincentB (2016) The roles of the stem cell-controlling Sox2 transcription factor: From neuroectoderm development to Alzheimer’s disease?Mol Neurobiol53, 1679–1698.
48.
VenereM, HanY-G, BellR, SongJS, Alvarez-BuyllaA, BlellochR (2012) Sox1 marks an activated neural stem/progenitor cell in the hippocampus. Development139, 3938–3949.
49.
KuipersSD, SchroederJE, TrentaniA (2015) Changes in hippocampal neurogenesis throughout early development. Neurobiol Aging36, 365–379.
50.
KarnavasT, MandalosN, MalasS, RemboutsikaE (2013) SoxB, cell cycle and neurogenesis. Front Physiol4, 298.
51.
NittaKR, TakahashiS, HaramotoY, FukudaM, OnumaY, AsashimaM (2006) Expression of Sox1 during Xenopus early embryogenesis. Biochem Biophys Res Commun351, 287–293.
52.
ElkourisM, BalaskasN, PoulouM, PolitisPK, PanayiotouE, MalasS, ThomaidouD, RemboutsikaE (2011) Sox1 maintains the undifferentiated state of cortical neural progenitor cells via the suppression of Prox1-mediated cell cycle exit and neurogenesis. Stem Cells29, 89–98.
53.
BylundM, AnderssonE, NovitchBG, MuhrJ (2003) Vertebrate neurogenesis is counteracted by Sox1-3 activity. Nat Neurosci6, 1162–1168.
54.
HolmbergJ, HanssonE, MalewiczM, SandbergM, PerlmannT, LendahlU, MuhrJ (2008) SoxB1 transcription factors and Notch signaling use distinct mechanisms to regulate proneural gene function and neural progenitor differentiation. Development135, 1843–1851.
55.
McCarthyMM, NugentBM (2015) At the frontier of epigenetics of brain sex differences. Front Behav Neurosci9, 221.
56.
ChakravarthyH, OrmsbeeBD, MallannaSK, RizzinoA (2011) Rapid activation of the bivalent gene Sox21 requires displacement of multiple layers of gene-silencing machinery. FASEB J25, 206–218.
57.
MallannaSK, OrmsbeeBD, IacovinoM, GilmoreJM, CoxJL, KybaM, WashburnMP, RizzinoA (2010) Proteomic analysis of Sox2-associated proteins during early stages of mouse embryonic stem cell differentiation identifies Sox21 as a novel regulator of stem cell fate. Stem Cells28, 1715–1727.
58.
KuzmichevAN, KimS-K, D’AlessioAC, ChenowethJG, WittkoIM, CampanatiL, McKayRD (2012) Sox2 acts through Sox21 to regulate transcription in pluripotent and differentiated cells. Curr Biol22, 1705–1710.
59.
ZhaoB, ZhongM, JinK (2008) Neurogenesis and neurodegenerative diseases in human. Panminerva Med50, 55–64.
60.
WinnerB, WinklerJ (2015) Adult neurogenesis in neurodegenerative diseases.a. Cold Spring Harb Perspect Biol7, 021287.
61.
FantesJ, RaggeNK, LynchS-A, McGillNI, CollinJRO, Howard-PeeblesPN, HaywardC, VivianAJ, WilliamsonK, van HeyningenV, FitzPatrickDR (2003) Mutations in SOX2 cause anophthalmia. Nat Genet33, 461–463.
62.
WilliamsonKA, HeverAM, RaingerJ, RogersRC, MageeA, FiedlerZ, KengWT, SharkeyFH, McGillN, HillCJ, SchneiderA, MessinaM, TurnpennyPD, FantesJA, van HeyningenV, FitzPatrickDR (2006) Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet15, 1413–1422.
