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Co-Administration of TiO2 Nanowired Mesenchymal Stem Cells with Cerebrolysin Potentiates Neprilysin Level and Reduces Brain Pathology in Alzheimer’s Disease

Abstract

Neprilysin (NPL), the rate-limiting enzyme for amyloid beta peptide (AβP), appears to play a crucial role in the pathogenesis of Alzheimer’s disease (AD). Since mesenchymal stem cells (MSCs) and/or cerebrolysin (CBL, a combination of neurotrophic factors and active peptide fragments) have neuroprotective effects in various CNS disorders, we examined nanowired delivery of MSCs and CBL on NPL content and brain pathology in AD using a rat model. AD-like symptoms were produced by intraventricular (i.c.v.) administration of AβP (1-40) in the left lateral ventricle (250 ng/10 μl, once daily) for 4 weeks. After 30 days, the rats were examined for NPL and AβP concentrations in the brain and related pathology. Co-administration of TiO2-nanowired MSCs (106 cells) with 2.5 ml/kg CBL (i.v.) once daily for 1 week after 2 weeks of AβP infusion significantly increased the NPL in the hippocampus (400 pg/g) from the untreated control group (120 pg/g; control 420 ± 8 pg/g brain) along with a significant decrease in the AβP deposition (45 pg/g from untreated control 75 pg/g; saline control 40 ± 4 pg/g). Interestingly, these changes were much less evident when the MSCs or CBL treatment was given alone. Neuronal damages, gliosis, and myelin vesiculation were also markedly reduced by the combined treatment of TiO2, MSCs, and CBL in AD. These observations are the first to show that co-administration of TiO2-nanowired CBL and MSCs has superior neuroprotective effects in AD probably due to increasing the brain NPL level effectively, not reported earlier.

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Acknowledgements

The study was supported by grants from the Air Force Office of Scientific Research (EOARD, London, UK), and Air Force Material Command, USAF, under grant number FA8655-05-1-3065; the Alzheimer’s Association (IIRG-09-132087), the National Institutes of Health (R01 AG028679) and the Dr. Robert M. Kohrman Memorial Fund (MAS, RJC); Swedish Medical Research Council (Nr 2710-HSS), Göran Gustafsson Foundation, Stockholm, Sweden (HSS); Astra Zeneca, Mölndal, Sweden (HSS/AS); The University Grants Commission, New Delhi, India (HSS/AS), Ministry of Science & Technology, Govt. of India (HSS/AS), Indian Medical Research Council, New Delhi, India (HSS/AS), and India-EU Co-operation Program (RP/AS/HSS) and IT 794/13 (JVL); Government of Basque Country and UFI 11/32 (JVL) University of Basque Country, Spain; and Society for Neuroprotection and Neuroplasticity (SSNN), Romania. Technical and human support provided by Dr. Ricardo Andrade from SGIker (UPV/EHU) is gratefully acknowledged. We thank Suraj Sharma, Uppsala, Sweden, for computer and graphic support. The US Government is authorized to reproduce and distribute reprints for government purpose notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the Air Force Office of Scientific Research or the US Government.

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Correspondence to Hari Shanker Sharma.

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All experiments were carried out according to the National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals and approved by the Local Institutional Ethics Committee.

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Sharma, H.S., Muresanu, D.F., Lafuente, J.V. et al. Co-Administration of TiO2 Nanowired Mesenchymal Stem Cells with Cerebrolysin Potentiates Neprilysin Level and Reduces Brain Pathology in Alzheimer’s Disease. Mol Neurobiol 55, 300–311 (2018). https://doi.org/10.1007/s12035-017-0742-9

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Keywords

  • Alzheimer’s disease (AD)
  • Neprilysin (NPL)
  • Amyloid-beta peptide (aβP)
  • Mesenchymal stem cells (MSCs)
  • Cerebrolysin (CBL)
  • TiO2 nanowires
  • Nanodelivery