title: In vitro validation of effects of BDNF-expressing mesenchymal stem cells on neurodegeneration in primary cultured neurons of APP/PS1 mice.
abstract: Alzheimer's disease (AD), the most common type of dementia, is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal loss in defined regions of the brain including the hippocampus and cortex. Transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) offers a safe and potentially effective tool for treating neurodegenerative disorders. However, the therapeutic effects of BM-MSCs on AD pathology remain unclear and their mechanisms at cellular and molecular levels still need to be addressed. In this study, we developed a unique neuronal culture made from 5xFAD mouse, an APP/PS1 transgenic mouse model (FAD neurons) to investigate progressive neurodegeneration associated with AD pathology and efficacy of brain-derived neurotrophic factor expressing-MSCs (BDNF-MSCs). Analyses of the expression of brain-derived neurotrophic factor (BDNF), synaptic markers and survival/apoptotic signals indicate that pathological features of cultured neurons made from these mice accurately mimic AD pathology, suggesting that our protocol provided a valid in vitro model of AD. We also demonstrated amelioration of AD pathology by MSCs in vitro when these FAD neurons were co-cultured with MSCs, a paradigm that mimics the in vivo environment of post-transplantation of MSCs into damaged regions of brains. To overcome failed delivery of BDNF to the brain and to enhance MSCs releasing BDNF effect, we created BDNF-MSCs and found that MSCs protection was enhanced by BDNF-MSCs. This protection was abolished by BDNF-blocking peptides, suggesting that BDNF supply from BDNF-MSCs was enough to prevent AD pathology.
authors: Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, USA; Program of Neuroscience, Central Michigan University, Mt Pleasant, MI, USA. Electronic address: song5m@cmich.edu.
authors: M-S
authors: MS
authors: Song
authors: Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, USA; Program of Neuroscience, Central Michigan University, Mt Pleasant, MI, USA.
authors: C R
authors: CR
authors: Learman
authors: Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
authors: K-C
authors: KC
authors: Ahn
authors: Neurochemical Research Unit, University of Alberta, AB, Canada.
authors: G B
authors: GB
authors: Baker
authors: Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, USA; Program of Neuroscience, Central Michigan University, Mt Pleasant, MI, USA.
authors: J
authors: J
authors: Kippe
authors: Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, USA.
authors: E M
authors: EM
authors: Field
authors: Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, USA; Program of Neuroscience, Central Michigan University, Mt Pleasant, MI, USA. Electronic address: dunba1g@cmich.edu.
authors: G L
authors: GL
authors: Dunbar
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; C580804:presenilin 1, mouse; D053148:Caspase 3
keywords: Alzheimer’s disease; bone marrow-derived mesenchymal cells (BM-MSCs); brain-derived neurotropic factor (BDNF); neurodegeneration; β-amyloid (Aβ)