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Neural Stem Cells Secretome Increased Neurogenesis and Behavioral Performance and the Activation of Wnt/β-Catenin Signaling Pathway in Mouse Model of Alzheimer’s Disease

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Abstract

Alzheimer’s disease is a progressive and age-related neurodegenerative disorder that is manifested by neuropathological changes and clinical symptoms. Recently, cell-based therapeutic interventions have been considered as the promising and effective strategies in this field. Herein, we investigated therapeutic effects of neural stem cell secretome on Alzheimer’s disease-like model by triggering of Wnt/β-catenin signaling pathway. In this study, mice were randomly allocated into three different groups as follows: Control, AD + Vehicle, and AD + NSCs-CM groups. To induce mouse model of AD, Aβ1-42 was injected into intracerebroventricular region. Following AD-like confirmation through thioflavin S staining and Passive avoidance test, about 5 µl mouse NSCs-CM was injected into the target areas 21 days after AD induction. For evaluation of endogenous proliferation rate (BrdU/Nestin+ cells), 50 µg/kbW BrdU was intraperitoneally injected for 5 consecutive days. To track NSC differentiation, percent of BrdU/NeuN+ cells were monitored via immunofluorescence staining. Histological Nissl staining was done to neurotoxicity and cell death in AD mice after NSCs-CM injection. Morris Water maze test was performed to assess learning and memory performance. Data showed that NSCs-CM could reverse the learning and memory deficits associated with Aβ pathology. The reduced expression of Wnt/β-catenin-related genes such as PI3K, Akt, MAPK, and ERK in AD mice was increased. Along with these changes, NSCs-CM suppressed overactivity of GSK3β activity induced by Aβ deposition. Besides, NSCs increased BrdU/Nestin+ and BrdU/NeuN+ cells in a paracrine manner, indicating proliferation and neural differentiation of NSCs. Moreover, neurotoxicity rate and cell loss were deceased after NSCs-CM injection. In summary, NSCs can regulate adult neurogenesis through modulating of Wnt/β-catenin signaling pathway and enhance the behavioral performance in the AD mice. These data present the alternative and effective approach in the management of AD and other cognitive impairments.

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Data Availability

The datasets presented/analyzed during the current study are available.

Abbreviations

DAPI:

4,6-diamidino-2-phenylindole

BrdU:

5-Bromo-20-deoxyuridine

AD:

Alzheimer’s disease

Aβ:

Amyloid β

FGF-2:

Basic fibroblast growth factor-2

BDNF:

Brain-derived neurotrophic factor

ICV:

Cerebroventricular

DMEM/F-12:

Dulbecco’s modified eagle medium/nutrient mixture

ELISA:

Enzyme-linked immunosorbent assay

EGF:

Epidermal growth factor

GSK-3β:

Glycogen synthase kinase-3β

IF:

Immunofluorescence

MWM:

Morris water maze

NGF:

Nerve growth factor

NSCs-CM:

Neural stem cell condition medium

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Acknowledgements

Authors wish to thank the personnel of Neuroscience Research Center for help and guidance.

Funding

This study was supported by a Grant from Tabriz University of Medical Sciences (63595).

Author information

Authors and Affiliations

  1. Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran

    Farzaneh Hijroudi & Saeed Sadigh-Eteghad

  2. Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Farzaneh Hijroudi, Gozal Bahlakeh & Mohammad Karimipour

  3. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Rahbarghazi & Mehdi Hassanpour

  4. Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Reza Rahbarghazi & Mohammad Karimipour

  5. Department of Neurosurgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohammad Shimia

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  6. Mohammad Shimia
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  7. Mohammad Karimipour
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Contributions

FH, RR, SSE, GB, MH, and MS performed different analyses. MK supervised the study.

Corresponding author

Correspondence to Mohammad Karimipour.

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The authors declare that they have no competing interest.

Ethical Approval

All phases of this study were approved by Local Ethics Committee of Tabriz University of Medical Sciences (IR.TBZMED.VCR.REC.1397.239).

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Hijroudi, F., Rahbarghazi, R., Sadigh-Eteghad, S. et al. Neural Stem Cells Secretome Increased Neurogenesis and Behavioral Performance and the Activation of Wnt/β-Catenin Signaling Pathway in Mouse Model of Alzheimer’s Disease. Neuromol Med 24, 424–436 (2022). https://doi.org/10.1007/s12017-022-08708-z

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  • DOI: https://doi.org/10.1007/s12017-022-08708-z

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