Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer's disease.
Animals
Humans
Alzheimer Disease
/ drug therapy
Mice
Neurogenesis
/ drug effects
Receptor, trkB
/ metabolism
Neural Stem Cells
/ drug effects
Neuroprotective Agents
/ pharmacology
Brain-Derived Neurotrophic Factor
/ metabolism
Cell Differentiation
/ drug effects
Cell Proliferation
/ drug effects
Amyloid beta-Peptides
/ metabolism
Hippocampus
/ drug effects
Alzheimer’s disease
BDNF
In-vitro drug testing
Neurogenesis
Stem-cell based screening
TrkB
iPSC
Journal
Stem cell research & therapy
ISSN: 1757-6512
Titre abrégé: Stem Cell Res Ther
Pays: England
ID NLM: 101527581
Informations de publication
Date de publication:
06 Jul 2024
06 Jul 2024
Historique:
received:
01
02
2024
accepted:
26
06
2024
medline:
7
7
2024
pubmed:
7
7
2024
entrez:
6
7
2024
Statut:
epublish
Résumé
Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer's disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations. Here, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-β (Aβ) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs. ENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aβ-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Αβ toxicity and prevent synapse loss after Aβ treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aβ toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq. Our work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimer's disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing.
Sections du résumé
BACKGROUND
BACKGROUND
Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer's disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations.
METHODS
METHODS
Here, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-β (Aβ) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs.
RESULTS
RESULTS
ENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aβ-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Αβ toxicity and prevent synapse loss after Aβ treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aβ toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq.
CONCLUSIONS
CONCLUSIONS
Our work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimer's disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing.
Identifiants
pubmed: 38971770
doi: 10.1186/s13287-024-03818-w
pii: 10.1186/s13287-024-03818-w
doi:
Substances chimiques
Receptor, trkB
EC 2.7.10.1
Neuroprotective Agents
0
Brain-Derived Neurotrophic Factor
0
Amyloid beta-Peptides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
200Subventions
Organisme : Horizon 2020
ID : 765704
Organisme : HORIZON EUROPE European Innovation Council
ID : 101099145
Informations de copyright
© 2024. The Author(s).
Références
Babcock KR, Page JS, Fallon JR, Webb AE. Adult hippocampal neurogenesis in aging and Alzheimer’s disease. Stem Cell Rep. 2021;16:681–93.
doi: 10.1016/j.stemcr.2021.01.019
Winner B, Winkler J. Adult neurogenesis in neurodegenerative diseases. Cold Spring Harb Perspect Biol. 2015;7:a021287.
pubmed: 25833845
pmcid: 4382734
doi: 10.1101/cshperspect.a021287
Crowther AJ, Song J. Activity-dependent signaling mechanisms regulating adult hippocampal neural stem cells and their progeny. Neurosci Bull. 2014;30:542–56.
pubmed: 25082534
pmcid: 4348092
doi: 10.1007/s12264-014-1453-5
Van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature. 2002;415:1030–4.
pubmed: 11875571
pmcid: 9284568
doi: 10.1038/4151030a
Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996;16:2027–33.
pubmed: 8604047
pmcid: 6578509
doi: 10.1523/JNEUROSCI.16-06-02027.1996
Nacher J, Alonso-Llosa G, Rosell DR, McEwen BS. NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging. 2003;24:273–84.
pubmed: 12498961
doi: 10.1016/S0197-4580(02)00096-9
Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313–7.
pubmed: 9809557
doi: 10.1038/3305
Boldrini M, Fulmore CA, Tartt AN, Simeon LR, Pavlova I, Poposka V, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell. 2018;22:589-599.e5.
pubmed: 29625071
pmcid: 5957089
doi: 10.1016/j.stem.2018.03.015
Wang W, Wang M, Yang M, Zeng B, Qiu W, Ma Q, et al. Transcriptome dynamics of hippocampal neurogenesis in macaques across the lifespan and aged humans. Cell Res. 2022;32:729–43.
pubmed: 35750757
pmcid: 9343414
doi: 10.1038/s41422-022-00678-y
Hao ZZ, Wei JR, Xiao D, Liu R, Xu N, Tang L, et al. Single-cell transcriptomics of adult macaque hippocampus reveals neural precursor cell populations. Nat Neurosci. 2022;25:805–17.
pubmed: 35637371
doi: 10.1038/s41593-022-01073-x
De Lucia C, Murphy T, Maruszak A, Wright P, Powell TR, Hartopp N, et al. Serum from older adults increases apoptosis and molecular aging markers in human hippocampal progenitor cells. Aging Dis. 2021;12:2151–72.
pubmed: 34881092
pmcid: 8612606
doi: 10.14336/AD.2021.0409
Altman J, Das GD. Postnatal neurogenesis in the Guinea-pig. Nature. 1967;216:615–6.
Altman J, Das GD. Altman_et_al-1965-The_Journal_of_Comparative_Neurology. J Comp Neurol. 1965;124:319–36.
pubmed: 5861717
doi: 10.1002/cne.901240303
Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med. 2019;25:554–60.
pubmed: 30911133
doi: 10.1038/s41591-019-0375-9
Tobin MK, Musaraca K, Disouky A, Shetti A, Bheri A, Honer WG, et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell. 2019;24:974-982.e3.
pubmed: 31130513
pmcid: 6608595
doi: 10.1016/j.stem.2019.05.003
Crews L, Adame A, Patrick C, DeLaney A, Pham E, Rockenstein E, et al. Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. J Neurosci. 2010;30:12252–62.
pubmed: 20844121
pmcid: 2978735
doi: 10.1523/JNEUROSCI.1305-10.2010
Hanspal MA, Gillotin S. A new age in understanding adult hippocampal neurogenesis in Alzheimer’s disease. Neural Regen Res. 2022;17:2615–8.
pubmed: 35662190
pmcid: 9165372
doi: 10.4103/1673-5374.339472
Lovell MA, Geiger H, Van Zant GE, Lynn BC, Markesbery WR. Isolation of neural precursor cells from Alzheimer’s disease and aged control postmortem brain. Neurobiol Aging. 2006;27:909–17.
pubmed: 15979211
doi: 10.1016/j.neurobiolaging.2005.05.004
Demars M, Hu YS, Gadadhar A, Lazarov O. Impaired neurogenesis is an early event in the etiology of familial Alzheimer’s disease in transgenic mice. J Neurosci Res. 2010;88:2103–17.
pubmed: 20209626
pmcid: 3696038
doi: 10.1002/jnr.22387
Zhou Y, Su Y, Li S, Kennedy BC, Zhang DY, Bond AM, et al. Molecular landscapes of human hippocampal immature neurons across lifespan. Nature. 2022;607:527–33.
pubmed: 35794479
pmcid: 9316413
doi: 10.1038/s41586-022-04912-w
Herdy JR, Traxler L, Agarwal RK, Karbacher L, Schlachetzki JCM, Boehnke L, et al. Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease. Cell Stem Cell. 2022;29:1637-1652.e6.
pubmed: 36459967
pmcid: 10093780
doi: 10.1016/j.stem.2022.11.010
Wu CC, Lien CC, Hou WH, Chiang PM, Tsai KJ. Gain of BDNF function in engrafted neural stem cells promotes the therapeutic potential for Alzheimer’s disease. Sci Rep. 2016;6:1–16.
Salta E, Lazarov O, Fitzsimons CP, Tanzi R, Lucassen PJ, Choi SH. Adult hippocampal neurogenesis in Alzheimer’s disease: a roadmap to clinical relevance. Cell Stem Cell. 2023;30:20–36.
doi: 10.1016/j.stem.2023.01.002
Gillotin S, Sahni V, Lepko T, Hanspal MA, Swartz JE, Alexopoulou Z, et al. Targeting impaired adult hippocampal neurogenesis in ageing by leveraging intrinsic mechanisms regulating neural stem cell activity. Ageing Res Rev. 2021;71:101447.
pubmed: 34403830
doi: 10.1016/j.arr.2021.101447
Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132:645–60.
pubmed: 18295581
doi: 10.1016/j.cell.2008.01.033
Song HJ, Stevens CF, Gage FH. Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nat Neurosci. 2002;5:438–45.
pubmed: 11953752
doi: 10.1038/nn844
Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol. 2005;192:348–56.
pubmed: 15755552
doi: 10.1016/j.expneurol.2004.11.016
Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron. 2008;59:399–412.
pubmed: 18701066
pmcid: 2655199
doi: 10.1016/j.neuron.2008.06.023
Henry RA, Hughes SM, Connor B. AAV-mediated delivery of BDNF augments neurogenesis in the normal and quinolinic acid-lesioned adult rat brain. Eur J Neurosci. 2007;25:3513–25.
pubmed: 17610571
doi: 10.1111/j.1460-9568.2007.05625.x
Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron. 1991;7:695–702.
pubmed: 1742020
doi: 10.1016/0896-6273(91)90273-3
Hock C, Heese K, Hulette C, Rosenberg C, Otten U. Region-specific neurotrophin imbalances in Alzheimer disease. Arch Neurol. 2000;57:846.
pubmed: 10867782
doi: 10.1001/archneur.57.6.846
Peng S, Wuu J, Mufson EJ, Fahnestock M. Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem. 2005;93:1412–21.
pubmed: 15935057
doi: 10.1111/j.1471-4159.2005.03135.x
Iulita MF, Bistué Millón MB, Pentz R, Aguilar LF, Do Carmo S, Allard S, et al. Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer’s disease. Neurobiol Dis. 2017;108:307–23.
pubmed: 28865749
doi: 10.1016/j.nbd.2017.08.019
Bergami M, Rimondini R, Santi S, Blum R, Götz M, Canossa M. Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proc Natl Acad Sci USA. 2008;105:15570–5.
pubmed: 18832146
pmcid: 2557028
doi: 10.1073/pnas.0803702105
Jiao SS, Shen LL, Zhu C, Bu XL, Liu YH, Liu CH, et al. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease. Transl Psychiatry. 2016;6:e907.
pubmed: 27701410
pmcid: 5315549
doi: 10.1038/tp.2016.186
Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science. 1979;2018:361.
Beeri MS, Sonnen J. Brain BDNF expression as a biomarker for cognitive reserve against Alzheimer disease progression. Neurology. 2016;86:702–3.
pubmed: 26819454
doi: 10.1212/WNL.0000000000002389
De Pins B, Cifuentes-Díaz C, Thamila Farah A, López-Molina L, Montalban E, Sancho-Balsells A, et al. Conditional BDNF delivery from astrocytes rescues memory deficits, spine density, and synaptic properties in the 5xFAD mouse model of Alzheimer disease. J Neurosci. 2019;39:2441–58.
pubmed: 30700530
pmcid: 6435824
Rossi C, Angelucci A, Costantin L, Braschi C, Mazzantini M, Babbini F, et al. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. Eur J Neurosci. 2006;24:1850–6.
pubmed: 17040481
doi: 10.1111/j.1460-9568.2006.05059.x
Casarotto PC, Girych M, Fred SM, Kovaleva V, Moliner R, Enkavi G, et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell. 2021;184:1299-1313.e19.
pubmed: 33606976
pmcid: 7938888
doi: 10.1016/j.cell.2021.01.034
Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci USA. 2010;107:2687–92.
pubmed: 20133810
pmcid: 2823863
doi: 10.1073/pnas.0913572107
Zeng Y, Lv F, Li L, Yu H, Dong M, Fu Q. 7,8-Dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats. J Neurochem. 2012;122:800–11.
pubmed: 22694088
doi: 10.1111/j.1471-4159.2012.07830.x
English AW, Liu K, Nicolini JM, Mulligan AM, Ye K. Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves. Proc Natl Acad Sci USA. 2013;110:16217–22.
pubmed: 24043773
pmcid: 3791704
doi: 10.1073/pnas.1303646110
Andero R, Daviu N, Escorihuela RM, Nadal R, Armario A. 7,8-dihydroxyflavone, a TrkB receptor agonist, blocks long-term spatial memory impairment caused by immobilization stress in rats. Hippocampus. 2012;22:399–408.
pubmed: 21136519
doi: 10.1002/hipo.20906
Andero R, Heldt SA, Ye K, Liu X, Armario A, et al. Effect of 7,8-dihydroxyfl avone, a small-molecule TrkB agonist, on emotional learning. Am J Psychiatry. 2011;2010:1–10.
Chen C, Ahn EH, Liu X, Wang ZH, Luo S, Liao J, et al. Optimized TrkB agonist ameliorates Alzheimer’s disease pathologies and improves cognitive functions via inhibiting delta-secretase. ACS Chem Neurosci. 2021;12:2448–61.
pubmed: 34106682
doi: 10.1021/acschemneuro.1c00181
Vakhitova YV, Kalinina TS, Zainullina LF, Lusta AY, Volkova AV, Kudryashov NV, et al. Analysis of antidepressant-like effects and action mechanisms of GSB-106, a small molecule, affecting the TrkB signaling. Int J Mol Sci. 2021;22:13381.
pubmed: 34948177
pmcid: 8704497
doi: 10.3390/ijms222413381
Massa SM, Yang T, Xie Y, Shi J, Bilgen M, Joyce JN, et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Investig. 2010;120:1774–85.
pubmed: 20407211
pmcid: 2860903
doi: 10.1172/JCI41356
Yang T, Massa SM, Tran KC, Simmons DA, Rajadas J, Zeng AY, et al. A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth. Neuropharmacology. 2016;110:343–61.
pubmed: 27334657
doi: 10.1016/j.neuropharm.2016.06.015
Gonzalez S, McHugh TLM, Yang T, Syriani W, Massa SM, Longo FM, et al. Small molecule modulation of TrkB and TrkC neurotrophin receptors prevents cholinergic neuron atrophy in an Alzheimer’s disease mouse model at an advanced pathological stage. Neurobiol Dis. 2022;162:105563.
pubmed: 34838668
doi: 10.1016/j.nbd.2021.105563
Pediaditakis I, Iliopoulos I, Theologidis I, Delivanoglou N, Margioris AN, Charalampopoulos I, et al. Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors. Endocrinology. 2015;156:16–23.
pubmed: 25330101
doi: 10.1210/en.2014-1596
Pediaditakis I, Kourgiantaki A, Prousis KC, Potamitis C, Xanthopoulos KP, Zervou M, et al. BNN27, a 17-spiroepoxy steroid derivative, interacts with and activates p75 neurotrophin receptor, rescuing cerebellar granule neurons from apoptosis. Front Pharmacol. 2016;7:1–14.
doi: 10.3389/fphar.2016.00512
Rogdakis T, Charou D, Latorrata A, Papadimitriou E, Tsengenes A, Athanasiou C, et al. Development and biological characterization of a novel selective TrkA agonist with neuroprotective properties against amyloid toxicity. Biomedicines. 2022;10:614.
pubmed: 35327415
pmcid: 8945229
doi: 10.3390/biomedicines10030614
Mourtzi T, Dimitrakopoulos D, Kakogiannis D, Salodimitris C, Botsakis K, Meri DK, et al. Characterization of substantia Nigra neurogenesis in homeostasis and dopaminergic degeneration: beneficial effects of the microneurotrophin BNN-20. Stem Cell Res Ther. 2021;12:1–18.
doi: 10.1186/s13287-021-02398-3
Panagiotakopoulou V, Botsakis K, Delis F, Mourtzi T, Tzatzarakis MN, Dimopoulou A, et al. Anti-neuroinflammatory, protective effects of the synthetic microneurotrophin BNN-20 in the advanced dopaminergic neurodegeneration of “weaver” mice. Neuropharmacology. 2020;165:107919.
pubmed: 31877321
doi: 10.1016/j.neuropharm.2019.107919
Botsakis K, Mourtzi T, Panagiotakopoulou V, Vreka M, Stathopoulos GT, Pediaditakis I, et al. BNN-20, a synthetic microneurotrophin, strongly protects dopaminergic neurons in the “weaver” mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor. Neuropharmacology. 2017;121:140–57.
pubmed: 28461162
doi: 10.1016/j.neuropharm.2017.04.043
Shi Y, Kirwan P, Livesey FJ. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc. 2012;7:1836–46.
pubmed: 22976355
doi: 10.1038/nprot.2012.116
Andrews S. FastQC: a quality control tool for high throughput sequence data. 2010. Available online at: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/ .
Kim D, Paggi JM, Park C, Bennett C, Salzberg SL. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol. 2019;37:907–15.
pubmed: 31375807
pmcid: 7605509
doi: 10.1038/s41587-019-0201-4
Anders S, Pyl PT, Huber W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.
pubmed: 25260700
doi: 10.1093/bioinformatics/btu638
McCarthy DJ, Chen Y, Smyth GK. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012;40:4288–97.
pubmed: 22287627
pmcid: 3378882
doi: 10.1093/nar/gks042
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.
pubmed: 19910308
doi: 10.1093/bioinformatics/btp616
Varet H, Brillet-Guéguen L, Coppée J-Y, Dillies M-A. SARTools: a DESeq2- and EdgeR-Based R pipeline for comprehensive differential analysis of RNA-Seq data. PLoS ONE. 2016;11:e0157022.
pubmed: 27280887
pmcid: 4900645
doi: 10.1371/journal.pone.0157022
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.
pubmed: 30944313
pmcid: 6447622
doi: 10.1038/s41467-019-09234-6
Linnarsson S, Willson CA, Ernfors P. Cell death in regenerating populations of neurons in BDNF mutant mice. Mol Brain Res. 2000;75:61–9.
pubmed: 10648888
doi: 10.1016/S0169-328X(99)00295-8
Katoh-Semba R, Asano T, Ueda H, Morishita R, Takeuchi IK, Inaguma Y, et al. Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. FASEB J Off Publ Fed Am Soc Exp Biol. 2002;16:1328–30.
Lie DC, Colamarino SA, Song HJ, Désiré L, Mira H, Consiglio A, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370–5.
pubmed: 16251967
doi: 10.1038/nature04108
Lim DA, Alvarez-Buylla A. Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. Proc Natl Acad Sci USA. 1999;96:7526–31.
pubmed: 10377448
pmcid: 22119
doi: 10.1073/pnas.96.13.7526
Barkho BZ, Song H, Aimone JB, Smrt RD, Kuwabara T, Nakashima K, et al. Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation. Stem Cells Dev. 2006;15:407–21.
pubmed: 16846377
doi: 10.1089/scd.2006.15.407
Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002;417:39–44.
pubmed: 11986659
doi: 10.1038/417039a
Wang FW, Hao HB, Zhao SD, Zhang YM, Liu Q, Liu HJ, et al. Roles of activated astrocyte in neural stem cell proliferation and differentiation. Stem Cell Res. 2011;7:41–53.
pubmed: 21530437
doi: 10.1016/j.scr.2011.03.004
Perez-Dominguez M, Ávila-Muñoz E, Domínguez-Rivas E, Zepeda A. The detrimental effects of lipopolysaccharide-induced neuroinflammation on adult hippocampal neurogenesis depend on the duration of the pro-inflammatory response. Neural Regen Res. 2019;14:817–25.
pubmed: 30688267
pmcid: 6375041
doi: 10.4103/1673-5374.249229
Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA. 2003;100:13632–7.
pubmed: 14581618
pmcid: 263865
doi: 10.1073/pnas.2234031100
Liang M, Zhong H, Rong J, Li Y, Zhu C, Zhou L, et al. Postnatal lipopolysaccharide exposure impairs adult neurogenesis and causes depression-like behaviors through astrocytes activation triggering GABAA receptor downregulation. Neuroscience. 2019;422:21–31.
pubmed: 31682957
doi: 10.1016/j.neuroscience.2019.10.025
Jagasia R, Steib K, Englberger E, Herold S, Faus-Kessler T, Saxe M, et al. GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J Neurosci. 2009;29:7966–77.
pubmed: 19553437
pmcid: 2776747
doi: 10.1523/JNEUROSCI.1054-09.2009
Nakagawa S, Kim JE, Lee R, Chen J, Fujioka T, Malberg J, et al. Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus. J Neurosci. 2002;22:9868–76.
pubmed: 12427843
pmcid: 6757843
doi: 10.1523/JNEUROSCI.22-22-09868.2002
Okamoto M, Inoue K, Iwamura H, Terashima K, Soya H, Asashima M, et al. Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis. FASEB J. 2011;25:3570–82.
pubmed: 21746862
doi: 10.1096/fj.11-184697
Arredondo SB, Valenzuela-Bezanilla D, Mardones MD, Varela-Nallar L. Role of Wnt signaling in adult hippocampal neurogenesis in health and disease. Front Cell Dev Biol. 2020;8:1–15.
doi: 10.3389/fcell.2020.00860
Wei R, Lin CM, Tu YY. Strain-specific BDNF expression of rat primary astrocytes. J Neuroimmunol. 2010;220:90–8.
pubmed: 20176405
doi: 10.1016/j.jneuroim.2010.02.002
Climent E, Sancho-Tello M, Miñana R, Barettino D, Guerri C. Astrocytes in culture express the full-length Trk-B receptor and respond to brain derived neurotrophic factor by changing intracellular calcium levels: effect of ethanol exposure in rats. Neurosci Lett. 2000;288:53–6.
pubmed: 10869814
doi: 10.1016/S0304-3940(00)01207-6
Rose CR, Blum R, Pichler B, Lepier A, Kafitz KW, Konnerth A. Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature. 2003;426:74–8.
pubmed: 14603320
doi: 10.1038/nature01983
He N, Jin WL, Lok KH, Wang Y, Yin M, Wang ZJ. Amyloid-β1-42 oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2. Cell Death Dis. 2013;4:1–10.
doi: 10.1038/cddis.2013.437
Walgrave H, Balusu S, Snoeck S, Vanden Eynden E, Craessaerts K, Thrupp N, et al. Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer’s disease. Cell Stem Cell. 2021;28:1805-1821.e8.
pubmed: 34033742
doi: 10.1016/j.stem.2021.05.001
Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid β-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem. 2002;83:1509–24.
pubmed: 12472904
doi: 10.1046/j.1471-4159.2002.01267.x
Haughey NJ, Liu D, Nath A, Borchard AC, Mattson MP. Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid β-peptide: implications for the pathogenesis of Alzheimer’s disease. Neuromolecular Med. 2002;1:125–35.
pubmed: 12025858
doi: 10.1385/NMM:1:2:125
Scopa C, Marrocco F, Latina V, Ruggeri F, Corvaglia V, La Regina F, et al. Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers. Cell Death Differ. 2020;27:934–48.
pubmed: 31591472
doi: 10.1038/s41418-019-0409-3
Verret L, Jankowsky JL, Xu GM, Borchelt DR, Rampon C. Alzheimer’s-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J Neurosci. 2007;27:6771–80.
pubmed: 17581964
pmcid: 4439193
doi: 10.1523/JNEUROSCI.5564-06.2007
Ribeiro MF, Genebra T, Rego AC, Rodrigues CMP, Solá S. Amyloid β peptide compromises neural stem cell fate by irreversibly disturbing mitochondrial oxidative state and blocking mitochondrial biogenesis and dynamics. Mol Neurobiol. 2019;56:3922–36.
pubmed: 30225776
doi: 10.1007/s12035-018-1342-z
Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Götz M, et al. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell. 2010;6:445–56.
pubmed: 20452319
doi: 10.1016/j.stem.2010.03.017
Pansri P, Phanthong P, Suthprasertporn N, Kitiyanant Y, Tubsuwan A, Dinnyes A, et al. Brain-derived neurotrophic factor increases cell number of neural progenitor cells derived from human induced pluripotent stem cells. PeerJ. 2021;9:1–15.
doi: 10.7717/peerj.11388
Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018;98:1141-1154.e7.
pubmed: 29861287
pmcid: 6023751
doi: 10.1016/j.neuron.2018.05.008
Li G, Bien-Ly N, Andrews-Zwilling Y, Xu Q, Bernardo A, Ring K, et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell. 2009;5:634–45.
pubmed: 19951691
pmcid: 2992822
doi: 10.1016/j.stem.2009.10.015
Koutseff A, Mittelhaeuser C, Essabri K, Auwerx J, Meziane H. Impact of the apolipoprotein e polymorphism, age and sex on neurogenesis in mice: Pathophysiological relevance for Alzheimer’s disease? Brain Res. 2014;1542:32–40.
pubmed: 24140109
doi: 10.1016/j.brainres.2013.10.003
Garcia-Leon JA, Caceres-Palomo L, Sanchez-Mejias E, Mejias-Ortega M, Nuñez-Diaz C, Fernandez-Valenzuela JJ, et al. Human pluripotent stem cell-derived neural cells as a relevant platform for drug screening in Alzheimer’s disease. Int J Mol Sci. 2020;21:1–44.
doi: 10.3390/ijms21186867
Liu Y-H, Jiao S-S, Wang Y-R, Bu X-L, Yao X-Q, Xiang Y, et al. Associations between ApoEε4 carrier status and serum BDNF levels—new insights into the molecular mechanism of ApoEε4 actions in Alzheimer’s disease. Mol Neurobiol. 2015;51:1271–7. https://doi.org/10.1007/s12035-014-8804-8 .
doi: 10.1007/s12035-014-8804-8
pubmed: 24986007
Sen A, Nelson TJ, Alkon DL. ApoE isoforms differentially regulates cleavage and secretion of BDNF. Mol Brain. 2017;10:19. https://doi.org/10.1186/s13041-017-0301-3 .
doi: 10.1186/s13041-017-0301-3
pubmed: 28569173
pmcid: 5452344
Sen A, Nelson TJ, Alkon DL. ApoE4 and Aβ oligomers reduce BDNF expression via HDAC nuclear translocation. J Neurosci. 2015;35:7538–51. https://doi.org/10.1523/JNEUROSCI.0260-15.2015 .
doi: 10.1523/JNEUROSCI.0260-15.2015
pubmed: 25972179
pmcid: 6705431
Liu L, Michowski W, Kolodziejczyk A, Sicinski P. The cell cycle in stem cell proliferation, pluripotency and differentiation. Nat Cell Biol. 2019;21:1060–7.
pubmed: 31481793
pmcid: 7065707
doi: 10.1038/s41556-019-0384-4
Roccio M, Schmitter D, Knobloch M, Okawa Y, Sage D, Lutolf MP. Predicting stem cell fate changes by differential cell cycle progression patterns. Development. 2013;140:459–70.
pubmed: 23193167
doi: 10.1242/dev.086215
Pilaz L-J, Patti D, Marcy G, Ollier E, Pfister S, Douglas RJ, et al. Forced G1-phase reduction alters mode of division, neuron number, and laminar phenotype in the cerebral cortex. Proc Natl Acad Sci. 2009;106:21924–9. https://doi.org/10.1073/pnas.0909894106 .
doi: 10.1073/pnas.0909894106
pubmed: 19959663
pmcid: 2788480
Lange C, Huttner WB, Calegari F. Cdk4/CyclinD1 overexpression in neural stem cells shortens G1, delays neurogenesis, and promotes the generation and expansion of basal progenitors. Cell Stem Cell. 2009;5:320–31.
pubmed: 19733543
doi: 10.1016/j.stem.2009.05.026
Lim S, Kaldis P. Loss of Cdk2 and Cdk4 induces a switch from proliferation to differentiation in neural stem cells. Stem Cells. 2012;30:1509–20.
pubmed: 22532528
doi: 10.1002/stem.1114
Chau KF, Shannon ML, Fame RM, Fonseca E, Mullan H, Johnson MB, et al. Downregulation of ribosome biogenesis during early forebrain development. Elife. 2018. https://doi.org/10.7554/eLife.36998.001 .
doi: 10.7554/eLife.36998.001
pubmed: 29745900
pmcid: 5984036
Harnett D, Ambrozkiewicz MC, Zinnall U, Rusanova A, Borisova E, Drescher AN, et al. A critical period of translational control during brain development at codon resolution. Nat Struct Mol Biol. 2022;29:1277–90.
pubmed: 36482253
pmcid: 9758057
doi: 10.1038/s41594-022-00882-9
Hayashi Y, Kuroda T, Kishimoto H, Wang C, Iwama A, Kimura K. Downregulation of rRNA transcription triggers cell differentiation. PLoS ONE. 2014;9:e98586. https://doi.org/10.1371/journal.pone.0098586 .
doi: 10.1371/journal.pone.0098586
pubmed: 24879416
pmcid: 4039485
Wong Y-H, Lee C-M, Xie W, Cui B, Poo M. Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin. Proc Natl Acad Sci. 2015;112:E4475–84.
pubmed: 26216953
pmcid: 4538679
doi: 10.1073/pnas.1511830112
Cubelos B, Sebastián-Serrano A, Beccari L, Calcagnotto ME, Cisneros E, Kim S, et al. Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex. Neuron. 2010;66:523–35.
pubmed: 20510857
pmcid: 2894581
doi: 10.1016/j.neuron.2010.04.038
Heyden A, Ionescu M-CS, Romorini S, Kracht B, Ghiglieri V, Calabresi P, et al. Hippocampal enlargement in Bassoon-mutant mice is associated with enhanced neurogenesis, reduced apoptosis, and abnormal BDNF levels. Cell Tissue Res. 2011;346:11–26.
pubmed: 21935677
doi: 10.1007/s00441-011-1233-3
Méndez-Gómez HR, Vergaño-Vera E, Abad JL, Bulfone A, Moratalla R, de Pablo F, et al. The T-box brain 1 (Tbr1) transcription factor inhibits astrocyte formation in the olfactory bulb and regulates neural stem cell fate. Mol Cell Neurosci. 2011;46:108–21.
pubmed: 20807572
doi: 10.1016/j.mcn.2010.08.011
Hodge RD, Hevner RF. Expression and actions of transcription factors in adult hippocampal neurogenesis. Dev Neurobiol. 2011;71:680–9.
pubmed: 21412988
pmcid: 3134120
doi: 10.1002/dneu.20882
Young FI, Keruzore M, Nan X, Gennet N, Bellefroid EJ, Li M. The doublesex-related Dmrta2 safeguards neural progenitor maintenance involving transcriptional regulation of Hes1. Proc Natl Acad Sci. 2017;114:E5599–607.
pubmed: 28655839
pmcid: 5514752
doi: 10.1073/pnas.1705186114
Konno D, Iwashita M, Satoh Y, Momiyama A, Abe T, Kiyonari H, et al. The mammalian DM domain transcription factor Dmrta2 Is required for early embryonic development of the cerebral cortex. PLoS ONE. 2012;7:e46577.
pubmed: 23056351
pmcid: 3462758
doi: 10.1371/journal.pone.0046577
Tomita H, Cornejo F, Aranda-Pino B, Woodard CL, Rioseco CC, Neel BG, et al. The protein tyrosine phosphatase receptor delta regulates developmental neurogenesis. Cell Rep. 2020;30:215-228.e5.
pubmed: 31914388
doi: 10.1016/j.celrep.2019.11.033
Schauenburg L, Liebsch F, Eravci M, Mayer MC, Weise C, Multhaup G. APLP1 is endoproteolytically cleaved by γ-secretase without previous ectodomain shedding. Sci Rep. 2018;8:1916.
pubmed: 29382944
pmcid: 5789831
doi: 10.1038/s41598-018-19530-8
Minogue AM, Stubbs AK, Frigerio CS, Boland B, Fadeeva JV, Tang J, et al. γ-secretase processing of APLP1 leads to the production of a p3-like peptide that does not aggregate and is not toxic to neurons. Brain Res. 2009;1262:89–99.
pubmed: 19401174
doi: 10.1016/j.brainres.2009.01.008
Shi L, Yue J, You Y, Yin B, Gong Y, Xu C, et al. Dok5 is substrate of TrkB and TrkC receptors and involved in neurotrophin induced MAPK activation. Cell Signal. 2006;18:1995–2003.
pubmed: 16647839
doi: 10.1016/j.cellsig.2006.03.007
Suzuki S, Mizutani M, Suzuki K, Yamada M, Kojima M, Hatanaka H, et al. Brain-derived neurotrophic factor promotes interaction of the Nck2 adaptor protein with the TrkB tyrosine kinase receptor. Biochem Biophys Res Commun. 2002;294:1087–92.
pubmed: 12074588
doi: 10.1016/S0006-291X(02)00606-X
Tang B, Di Lena P, Schaffer L, Head SR, Baldi P, Thomas EA. Genome-wide identification of Bcl11b gene targets reveals role in brain-derived neurotrophic factor signaling. PLoS ONE. 2011;6:e23691.
pubmed: 21912641
pmcid: 3164671
doi: 10.1371/journal.pone.0023691