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Molecular Neurobiology

, Volume 56, Issue 12, pp 8420–8434 | Cite as

Neurotrophic Factors Mediated Activation of Astrocytes Ameliorate Memory Loss by Amyloid Clearance after Transplantation of Lineage Negative Stem Cells

  • P. Bali
  • A. Banik
  • B. Nehru
  • Akshay AnandEmail author
Article

Abstract

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.

Keywords

Alzheimer’s disease Neurotrophic factor BDNF Umbilical cord blood Lineage negative stem cells Amyloid injury Memory loss 

Abbreviations

Lin-ve

Lineage negative

SC

Stem cells

UCB

Umbilical cord blood

BDNF

Brain-derived neurotrophic factor

GDNF

Glial-derived neurotrophic factor

CNTF

Ciliary neurotrophic factor

TrkB

Tyrosine receptor kinase B

Bcl2

B cell lymphoma 2

JAK

Janus kinases (JAKs)

STAT

Signal transducer and activator of transcription proteins

DG

Dentate gyrus

CA

Cornu Ammonis

Amyloid β

Notes

Acknowledgements

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.

Author Contribution

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.

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Authors and Affiliations

  1. 1.Department of BiophysicsPanjab UniversityChandigarhIndia
  2. 2.Neuroscience Research Lab, Department of NeurologyPost Graduated Institute of Medical Education and ResearchChandigarhIndia
  3. 3.Department of Pharmacology and Chemical BiologyEmory University School of MedicineAtlantaUSA

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