Neurotrophic Factors Mediated Activation of Astrocytes Ameliorate Memory Loss by Amyloid Clearance after Transplantation of Lineage Negative Stem Cells
Alzheimer’s disease (AD) is one of the untreatable neurodegenerative disorders with associated societal burden. Current therapies only provide symptomatic relief without altering the rate of disease progression as reported by Lanctot et al. (Therapeutic Advances in Neurological Disorders 2 (3):163–180, 2009). The increased number of failed clinical trials in last two decades indicates the imperative need to explore alternative therapies for AD as reported by Tuszynski et al. (Nature Medicine 11 (5):551–555, 2005) and Liyanage et al. (Alzheimer’s & Dementia 4:628–635, 2005). In this study, we aimed to decipher the role of neurotrophic factors in the reversal of memory loss by transplantation of lineage negative (Lin-ve) stem cells in a male mouse model of cognitive impairment induced by intrahippocampal injection of amyloid β-42 (Aβ-42). The efficacy of human umbilical cord blood (hUCB) derived Lin-ve stem cells were analyzed by neurobehavioral parameters, i.e., Morris water maze and passive avoidance after bilateral intra-hippocampal transplantation using stereotaxic surgery. Real-time PCR and immunohistochemistry was carried out in brain tissues in order to analyze the expression of neurotrophic factors, apoptotic, astrocytic, and other neuronal cell markers. The transplantation of Lin-ve stem cells led to reversal of memory loss associated with reduction of Aβ-42 deposition from the brains. The molecular analysis revealed increase in neurotrophic factors, i.e., glial derived neurotrophic factor (GDNF), ciliary derived neurotrophic factor (CNTF), and Brain-derived neurotrophic factor (BDNF) after transplantation. The administration of ANA-12, a TrkB inhibitor, reversed the behavioral and molecular effects of stem cell transplantation suggesting involvement of BDNF-TrkB pathway in the rescue of memory loss. We believe that the amyloid clearance results from activation of astrocytes and anti-apoptotic pathways added by neurotrophic factors.
KeywordsAlzheimer’s disease Neurotrophic factor BDNF Umbilical cord blood Lineage negative stem cells Amyloid injury Memory loss
Umbilical cord blood
Brain-derived neurotrophic factor
Glial-derived neurotrophic factor
Ciliary neurotrophic factor
Tyrosine receptor kinase B
B cell lymphoma 2
Janus kinases (JAKs)
Signal transducer and activator of transcription proteins
We thank Prof. Jaswinder Kalra for providing samples of umbilical cord blood from CLROT of PGIMER. We also thank Sridhar Bammidi for training the first author in some techniques described in the manuscript and Mr. Gurpreet Singh for imaging.
PB conducted all the experiments, acquisition of the data, and writing of manuscript. AB was involved in manuscript writing/editing and data/statistical analysis. BN was first author’s PhD supervisor and edited the manuscript. AA conceptualized the study, secured research grant, and edited the manuscript.
Source of Funding
Department of Biotechnology, New Delhi, India and Council of Scientific & Industrial Research (CSIR), India.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 4.Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, Carter A, Casey DC, Charlson FJ, Chen AZ, Coggeshall M (2016) Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388(10053):1545–1602. https://doi.org/10.1016/s0140-6736(16)31678-6
- 6.Birks J (2006) Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev (1):Cd005593. https://doi.org/10.1002/14651858.cd005593
- 10.Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, Chen W, Ding Y et al (2015) Translation of pre-clinical studies into successful clinical trials for Alzheimer’s disease: what are the roadblocks and how can they be overcome? J Alzheimers Dis 47(4):815–843. https://doi.org/10.3233/jad-150136 CrossRefPubMedGoogle Scholar
- 11.Chiu GS, Boukelmoune N, Chiang ACA, Peng B, Rao V, Kingsley C, Liu HL, Kavelaars A et al (2018) Nasal administration of mesenchymal stem cells restores cisplatin-induced cognitive impairment and brain damage in mice. Oncotarget 9(85):35581–35597. https://doi.org/10.18632/oncotarget.26272 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, Loring JF, Yamasaki TR, Poon WW et al (2009) Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A 106(32):13594–13599. https://doi.org/10.1073/pnas.0901402106 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Straten G, Eschweiler GW, Maetzler W, Laske C, Leyhe T (2009) Glial cell-line derived neurotrophic factor (GDNF) concentrations in cerebrospinal fluid and serum of patients with early Alzheimer’s disease and normal controls. J Alzheimers Dis 18(2):331–337. https://doi.org/10.3233/jad-2009-1146 CrossRefPubMedGoogle Scholar
- 23.Airavaara M, Pletnikova O, Doyle ME, Zhang YE, Troncoso JC, Liu QR (2011) Identification of novel GDNF isoforms and cis-antisense GDNFOS gene and their regulation in human middle temporal gyrus of Alzheimer disease. J Biol Chem 286(52):45093–45102. https://doi.org/10.1074/jbc.M111.310250 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Revilla S, Sunol C, Garcia-Mesa Y, Gimenez-Llort L, Sanfeliu C, Cristofol R (2014) Physical exercise improves synaptic dysfunction and recovers the loss of survival factors in 3xTg-AD mouse brain. Neuropharmacology 81:55–63. https://doi.org/10.1016/j.neuropharm.2014.01.037 CrossRefPubMedGoogle Scholar
- 25.Revilla S, Ursulet S, Alvarez-Lopez MJ, Castro-Freire M, Perpina U, Garcia-Mesa Y, Bortolozzi A, Gimenez-Llort L et al (2014) Lenti-GDNF gene therapy protects against Alzheimer’s disease-like neuropathology in 3xTg-AD mice and MC65 cells. CNS Neurosci Ther 20(11):961–972. https://doi.org/10.1111/cns.12312 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Garcia P, Youssef I, Utvik JK, Florent-Bechard S, Barthelemy V, Malaplate-Armand C, Kriem B, Stenger C et al (2010) Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer’s disease. J Neurosci 30(22):7516–7527. https://doi.org/10.1523/jneurosci.4182-09.2010 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Escartin C, Pierre K, Colin A, Brouillet E, Delzescaux T, Guillermier M, Dhenain M, Deglon N et al (2007) Activation of astrocytes by CNTF induces metabolic plasticity and increases resistance to metabolic insults. J Neurosci 27(27):7094–7104. https://doi.org/10.1523/jneurosci.0174-07.2007 CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Seidel JL, Faideau M, Aiba I, Pannasch U, Escartin C, Rouach N, Bonvento G, Shuttleworth CW (2015) Ciliary neurotrophic factor (CNTF) activation of astrocytes decreases spreading depolarization susceptibility and increases potassium clearance. Glia 63(1):91–103. https://doi.org/10.1002/glia.22735 CrossRefPubMedGoogle Scholar
- 39.Saarelainen T, Pussinen R, Koponen E, Alhonen L, Wong G, Sirvio J, Castren E (2000) Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons have impaired long-term spatial memory but normal hippocampal LTP. Synapse (N Y) 38(1):102–104. https://doi.org/10.1002/1098-2396(200010)38:1<102::Aid-syn11>3.0.Co;2-k CrossRefGoogle Scholar
- 41.Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182(3):311–322. https://doi.org/10.1002/(sici)1097-4652(200003)182:3<311::aid-jcp1>3.0.co;2-9
- 43.Segal RA (2003) Selectivity in neurotrophin signaling: theme and variations. Annu Rev Neurosci 26:299–330. https://doi.org/10.1146/annurev.neuro.26.041002.131421 CrossRefPubMedGoogle Scholar
- 45.Oberheim NA, Goldman SA, Nedergaard M (2012) Heterogeneity of astrocytic form and function. Methods in molecular biology (Clifton, NJ) 814:23–45. https://doi.org/10.1007/978-1-61779-452-0_3
- 47.Nishizaki T (2018) Fe(3+) Facilitates Endocytic Internalization of Extracellular Abeta1–42 and Enhances Abeta1–42-Induced Caspase-3/Caspase-4 Activation and Neuronal Cell Death. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1408-y
- 49.Parker Jr WD, Davis RE (1997) Primary mitochondrial DNA defects as a causative event in Alzheimer’s disease. Mitochondria and free radicals in neurodegenerative diseases. Wiley-Liss, New York, pp 319–333Google Scholar
- 52.Leaver SG, Cui Q, Bernard O, Harvey AR (2006) Cooperative effects of bcl-2 and AAV-mediated expression of CNTF on retinal ganglion cell survival and axonal regeneration in adult transgenic mice. Eur J Neurosci 24(12):3323–3332. https://doi.org/10.1111/j.1460-9568.2006.05230.x CrossRefPubMedGoogle Scholar