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.
Subject(s)
Alzheimer Disease/complications , Brain-Derived Neurotrophic Factor/metabolism , Mesenchymal Stem Cells/physiology , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/pathology , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Animals , Apoptosis/genetics , Brain/cytology , Brain/metabolism , Brain/pathology , Brain-Derived Neurotrophic Factor/genetics , Caspase 3/metabolism , Cells, Cultured , Coculture Techniques , Disease Models, Animal , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Presenilin-1/geneticsABSTRACT
PURPOSE: Stroke is the third leading cause of death and permanent disability in the United States, often producing long-term cognitive impairments, which are not easily recapitulated in animal models. The goals of this study were to assess whether: (1) the endothelin-1 (ET-1) model of chronic stroke produced discernable cognitive deficits; (2) a spatial operant reversal task (SORT) would accurately measure memory deficits in this model; and (3) bone-marrow-derived mesenchymal stem cells (BMMSCs) could reduce any observed deficits. METHODS: Rats were given unilateral intracerebral injections of vehicle or ET-1, a stroke-inducing agent, near the middle cerebral artery. Seven days later, they were given intrastriatal injections of BMMSCs or vehicle, near the ischemic penumbra. The cognitive abilities of the rats were assessed on a novel SORT, which was designed to efficiently distinguish cognitive deficits from potential motoric confounds. RESULTS: Rats given ET-1 had significantly more cognitive errors at six weeks post-stroke on the SORT, and that these deficits were attenuated by BMMSC transplants. CONCLUSIONS: These findings indicate that: (1) the ET-1 model produces chronic cognitive deficits; (2) the SORT efficiently measures cognitive deficits that are not confounded by motoric impairment; and (3) BMMSCs may be a viable treatment for stroke-induced cognitive dysfunction.
