Therapeutic Target For Neurodegenerative Diseases Research Articles

EIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response.

The integrated stress response (ISR) tunes the rate of protein synthesis. Control is exerted by phosphorylation of the general translation initiation factor eIF2. eIF2 is a guanosine triphosphatase that becomes activated by eIF2B, a two-fold symmetric and heterodecameric complex that functions as eIF2's dedicated nucleotide exchange factor. Phosphorylation converts eIF2 from a substrate into an inhibitor of eIF2B. We report cryo-electron microscopy structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures reveal that the eIF2B decamer is a static platform upon which one or two flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange. Phosphorylation refolds eIF2α, allowing it to contact eIF2B at a different interface and, we surmise, thereby sequestering it into a nonproductive complex.

Using proteomics to identify ubiquitin ligase-substrate pairs: how novel methods may unveil therapeutic targets for neurodegenerative diseases.

Ubiquitin ligases play an integral role in fine-tuning signaling cascades necessary for normal cell function. Aberrant regulation of ubiquitin ligases has been implicated in several neurodegenerative diseases, generally, due to mutations within the E3 ligase itself. Several proteomic-based methods have recently emerged to facilitate the rapid identification of ligase-substrate pairs-a previously challenging feat due to the transient nature of ligase-substrate interactions. These novel methods complement standard immunoprecipitations (IPs) and include proximity-dependent biotin identification (BioID), ubiquitin ligase-substrate trapping, tandem ubiquitin-binding entities (TUBEs), and a molecular trapping unit known as the NEDDylator. The implementation of these techniques is expected to facilitate the rapid identification of novel substrates of E3 ubiquitin ligases, a process that is likely to enhance our understanding of neurodegenerative diseases and highlight novel therapeutic targets for the treatment of neurodegenerative diseases.

Plasma membrane redox enzymes: new therapeutic targets for neurodegenerative diseases.

Mitochondrial dysfunction caused by oxidative stress appears at early stages of aging and age-related diseases. Plasma membrane redox enzymes act in a compensatory manner to decrease oxidative stress and supply reductive capacity to ensure cell survival. Plasma membrane redox enzymes transfer electrons from NAD(P)H to oxidized ubiquinone and α-tocopherol, resulting in inhibition of further oxidative damage. Plasma membrane redox enzymes and their partners are affected by aging, leading to progression of neurodegenerative disease pathogenesis. Up-regulating plasma membrane redox enzymes via calorie restriction and phytochemicals make cells more resistant to oxidative damage under stress conditions by maintaining redox homeostasis and improving mitochondrial function. Investigation into plasma membrane redox enzymes can provide mechanistic details underlying the relationships between plasma membrane redox enzymes and mitochondrial complexes and provide a good therapeutic target for prevention and delay of neurodegenerative disorders.

Profiling withanolide A for therapeutic targets in neurodegenerative diseases.

To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR. Neurite outgrowth experiments in human neuroblastoma SH-SY5Y cells further supported a glucocorticoid-dependent mechanism, finding that WitA was able to reverse the outgrowth inhibition mediated by dexamethasone (Dex). However, further GR binding and transactivation assays found no direct interference of WitA. Further molecular modeling analysis suggested that WitA, although forming several contacts with residues in the GR binding pocket, is lacking key stabilizing interactions as observed for Dex. Taken together, the data suggest that WitA-dependent induction of neurite outgrowth is not through a direct effect on GR, but might be mediated through a closely related pathway. Further experiments should evaluate a possible role of GR modulators and/or related signaling pathways such as ERK, Akt, NF-κB, TRα, or Hsp90 as potential targets in the WitA-mediated neuromodulatory effects.

Reactive Astrocytes in Neurodegenerative Diseases.

Astrocytes, the largest and most numerous glial cells in the central nervous system (CNS), play a variety of important roles in regulating homeostasis, increasing synaptic plasticity and providing neuroprotection, thus helping to maintain normal brain function. At the same time, astrocytes can participate in the inflammatory response and play a key role in the progression of neurodegenerative diseases. Reactive astrocytes are strongly induced by numerous pathological conditions in the CNS. Astrocyte reactivity is initially characterized by hypertrophy of soma and processes, triggered by different molecules. Recent studies have demonstrated that neuroinflammation and ischemia can elicit two different types of reactive astrocytes, termed A1s and A2s. However, in the case of astrocyte reactivity in different neurodegenerative diseases, the recently published research issues remain a high level of conflict and controversy. So far, we still know very little about whether and how the function or reactivity of astrocytes changes in the progression of different neurodegenerative diseases. In this review, we aimed to briefly discuss recent studies highlighting the complex contribution of astrocytes in the process of various neurodegenerative diseases, which may provide us with new prospects for the development of an excellent therapeutic target for neurodegenerative diseases.

Analysis of RNA Expression Profiles Identifies Dysregulated Vesicle Trafficking Pathways in Creutzfeldt-Jakob Disease.

Functional genomics applied to the study of RNA expression profiles identified several abnormal molecular processes in experimental prion disease. However, only a few similar studies have been carried out to date in a naturally occurring human prion disease. To better characterize the transcriptional cascades associated with sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, we investigated the global gene expression profile in samples from the frontal cortex of 10 patients with sCJD and 10 non-neurological controls by microarray analysis. The comparison identified 333 highly differentially expressed genes (hDEGs) in sCJD. Functional enrichment Gene Ontology analysis revealed that hDEGs were mainly associated with synaptic transmission, including GABA (q value = 0.049) and glutamate (q value = 0.005) signaling, and the immune/inflammatory response. Furthermore, the analysis of cellular components performed on hDEGs showed a compromised regulation of vesicle-mediated transport with mainly up-regulated genes related to the endosome (q value = 0.01), lysosome (q value = 0.04), and extracellular exosome (q value < 0.01). A targeted analysis of the retromer core component VPS35 (vacuolar protein sorting-associated protein 35) showed a down-regulation of gene expression (p value= 0.006) and reduced brain protein levels (p value= 0.002). Taken together, these results confirm and expand previous microarray expression profile data in sCJD. Most significantly, they also demonstrate the involvement of the endosomal-lysosomal system. Since the latter is a common pathogenic pathway linking together diseases, such as Alzheimer's and Parkinson's, it might be the focus of future studies aimed to identify new therapeutic targets in neurodegenerative diseases.

Modulation of Mitochondrial Dynamics in Neurodegenerative Diseases: An Insight Into Prion Diseases.

Mitochondrial dysfunction is a common and prominent feature of prion diseases and other neurodegenerative disorders. Mitochondria are dynamic organelles that constantly fuse with one another and subsequently break apart. Defective or superfluous mitochondria are usually eliminated by a form of autophagy, referred to as mitophagy, to maintain mitochondrial homeostasis. Mitochondrial dynamics are tightly regulated by processes including fusion and fission. Dysfunction of mitochondrial dynamics can lead to the accumulation of abnormal mitochondria and contribute to cellular damage. Neurons are among the cell types that consume the most energy, have a highly complex morphology, and are particularly dependent on mitochondrial functions and dynamics. In this review article, we summarize the molecular mechanisms underlying the mitochondrial dynamics and the regulation of mitophagy and discuss the dysfunction of these processes in the progression of prion diseases and other neurodegenerative disorders. We have also provided an overview of mitochondrial dynamics as a therapeutic target for neurodegenerative diseases.

Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation.

Neurodegenerative diseases are characterized by a progressive loss of neurons that leads to a broad range of disabilities, including severe cognitive decline and motor impairment, for which there are no effective therapies. Several lines of evidence support a putative therapeutic role of nuclear receptors (NRs) in these types of disorders. NRs are ligand-activated transcription factors that regulate the expression of a wide range of genes linked to metabolism and inflammation. Although the activation of NRs in animal models of neurodegenerative disease exhibits promising results, the translation of this strategy to clinical practice has been unsuccessful. In this review we discuss the role of NRs in neurodegenerative diseases in light of preclinical and clinical studies, as well as new findings derived from the analysis of transcriptomic databases from humans and animal models. We discuss the failure in the translation of NR-based therapeutic approaches and consider alternative and novel research avenues in the development of effective therapies for neurodegenerative diseases.

Physiological and Pathophysiological Roles of Transient Receptor Potential Channels in Microglia-Related CNS Inflammatory Diseases.

Central nervous system (CNS) inflammation is a potential therapeutic target for neurodegenerative diseases. In recent years, a number of studies have focused on the links between neurodegenerative diseases and CNS glial cells, especially microglia. Microglia are the main resident immune cells in the CNS and represent approximately 10-15% of all CNS cells. Microglia play an important role in maintaining brain homeostasis at rest by surveying the environment, and engulfing apoptotic cells and debris in the healthy brain. However, under certain pathological conditions, microglia can generate neurotoxic factors, such as pro-inflammatory cytokines and molecules like nitric oxide (NO), which lead to CNS inflammatory diseases. In this review, we discuss the evidence that regulation of microglial ion channels may modulate CNS inflammation and subsequent tissue damage in neurological disorders. In particular, we discuss the role of transient receptor potential (TRP) channels in microglia in both acute and chronic inflammatory conditions, and describe the physiological and pathophysiological roles of TRP channels in CNS inflammatory pathways. Additionally, we describe the benefits of stimulation/inhibition of TRP channels in animal models of microglia-related CNS inflammatory diseases.

Role of DNA Methylation in Hypobaric Hypoxia-Induced Neurodegeneration and Spatial Memory Impairment

Hypobaric hypoxia (HH) is a major stress factor that is associated with physiological, biochemical, molecular and genomic alterations. Brain is the organ that reacts sensitively to oxygen deprivation, which leads to oxidative stress and cognitive function impairment. Our previous studies have reported that downregulation of brain derived neurotrophic factor (BDNF) leads to neurodegeneration and memory impairment. The aim of the present study was to investigate the effect of HH exposure on DNA methylation and its regulation in BDNF expression, neurodegeneration and spatial memory impairment. For this purpose, Sprague Dawley rats were exposed to HH at a simulated altitude of 25,000 feet for 14 days. Real-time polymerase chain reaction was used for transcriptional expression of DNA Methyltransferases (DNMTs) including DNMT1, DNMT3a and ­DNMT3b, and immunoblotting was used for the translational expression of DNMT1, DNMT3a, DNMT3b, Methyl CpG binding protein 2 (MeCP2), pMeCP2 and BDNF in rat hippocampus. Additionally, neuronal morphology alteration and neurodegeneration in CA1 region of hippocampus were investigated though Cresyl violet (CV) staining and Fluoro-Jade C staining respectively. Results obtained suggested that HH exposure increased the expression of DNMT1 DNMT3b at the mRNA as well as protein level, whereas no significant change was observed in the level of DNMT3a. Furthermore, the level of pMeCP2 and BDNF were significantly decreased; however, the expression level of MeCP2 was significantly increased. The CV and Fluoro-Jade C-positive cells were significantly enhanced in the CA1 region of hippocampus in the HH exposed group as compared to unexposed rats. Thus, the present study concluded that HH decreases neuronal activation by the upregulation of DNA methylation and MeCP2 and decreased the expression of pMeCP2, which result in the downregulation of BDNF. The decreased BDNF expression is associated with neuronal loss and spatial memory impairment. This study highlights that DNMT inhibition could be an important therapeutic target for neurodegenerative diseases.

Neuroprotection against 6-OHDA toxicity in PC12 cells and mice through the Nrf2 pathway by a sesquiterpenoid from Tussilago farfara

Oxidative stress plays a key role in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Therefore, the nuclear factor-E2-related factor 2 (Nrf2), a key regulator of the antioxidative response, is considered to be important as a therapeutic target for neurodegenerative diseases. We investigated the underlying mechanism of Nrf2-mediated neuroprotective effects against oxidative stress in the PC12 cell line by 7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), one of the sesquiterpenoids in Farfarae Flos. Pretreatment of PC12 cells with ECN had a protective effect against hydrogen peroxide (H2O2)- or 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. ECN upregulated the ARE-luciferase activity and induced the mRNA expression of Nrf2 and antioxidant enzyme heme oxygenase-1 (HO-1). Knockdown of Nrf2 by small, interfering RNA (siRNA) abrogated the upregulation of HO-1, indicating that ECN had induced HO-1 via the Nrf2 pathway. Pretreatment with the thiol reducing agents, N-acetylcysteine (NAC) or dithiothreitol (DTT), attenuated Nrf2 activation and HO-1 expression. However, the non-thiol reducing antioxidant, Trolox, failed to inhibit HO-1 induction by ECN. These results suggest that ECN may directly interact with Kelch-like ECH-associated protein 1 (Keap1) and modify critical cysteine thiols present in the proteins responsible for Nrf2-mediated upregulation of HO-1. In a 6-OHDA-induced mouse model of PD, administration of ECN ameliorated motor impairments and dopaminergic neuronal damage. Taken together, ECN exerts neuroprotective effects by activating the Nrf2/HO-1 signaling pathway in both PC12 cells and mice. Thus, ECN, as an Nrf2 activator, could be an attractive therapeutic candidate for the neuroprotection or treatment of neurodegenerative diseases.

Impaired tissue barriers as potential therapeutic targets for Parkinson's disease and amyotrophic lateral sclerosis.

The blood-brain barrier and the intestinal barrier show signs of disruption in patients with idiopathic Parkinson's disease (PD) and animal models of nigrostriatal degeneration, and likewise in amyotrophic lateral sclerosis (ALS) models. A substantial body of evidence shows that defects in epithelial membrane barriers, both in the gut and within the cerebral vasculature, can result in increased vulnerability of tissues to external factors potentially participating in the pathogenesis of PD and ALS. As such, restoration of tissue barriers may prove to be a novel therapeutic target in neurodegenerative disease. In this review, we focus on the potential of new intervention strategies for rescuing and maintaining barrier functions in PD and ALS.

The Aging of Iron Man.

Brain iron is tightly regulated by a multitude of proteins to ensure homeostasis. Iron dyshomeostasis has become a molecular signature associated with aging which is accompanied by progressive decline in cognitive processes. A common theme in neurodegenerative diseases where age is the major risk factor, iron dyshomeostasis coincides with neuroinflammation, abnormal protein aggregation, neurodegeneration, and neurobehavioral deficits. There is a great need to determine the mechanisms governing perturbations in iron metabolism, in particular to distinguish between physiological and pathological aging to generate fruitful therapeutic targets for neurodegenerative diseases. The aim of the present review is to focus on the age-related alterations in brain iron metabolism from a cellular and molecular biology perspective, alongside genetics, and neuroimaging aspects in man and rodent models, with respect to normal aging and neurodegeneration. In particular, the relationship between iron dyshomeostasis and neuroinflammation will be evaluated, as well as the effects of systemic iron overload on the brain. Based on the evidence discussed here, we suggest a synergistic use of iron-chelators and anti-inflammatories as putative anti-brain aging therapies to counteract pathological aging in neurodegenerative diseases.

Regulatory Effects of Neuroinflammatory Responses Through Brain-Derived Neurotrophic Factor Signaling in Microglial Cells.

Inhibition of microglial over-activation is an important strategy to counter balance neurodegenerative progression. We previously demonstrated that the adenosine monophosphate-activated protein kinase (AMPK) may be a therapeutic target in mediating anti-neuroinflammatory responses in microglia. Brain-derived neurotrophic factor (BDNF) is one of the major neurotrophic factors produced by astrocytes to maintain the development and survival of neurons in the brain, and have recently been shown to modulate homeostasis of neuroinflammation. Therefore, the present study focused on BDNF-mediated neuroinflammatory responses and may provide an endogenous regulation of neuroinflammation. Among the tested neuroinflammation, epigallocatechin gallate (EGCG) and minocycline exerted BDNF upregulation to inhibit COX-2 and proinflammatory mediator expressions. Furthermore, both EGCG and minocycline upregulated BDNF expression in microglia through AMPK signaling. In addition, minocycline and EGCG also increased expressions of erythropoietin (EPO) and sonic hedgehog (Shh). In the endogenous modulation of neuroinflammation, astrocyte-conditioned medium (AgCM) also decreased the expression of COX-2 and upregulated BDNF expression in microglia. The anti-inflammatory effects of BDNF were mediated through EPO/Shh in microglia. Our results indicated that the BDNF-EPO-Shh novel-signaling pathway underlies the regulation of inflammatory responses and may be regarded as a potential therapeutic target in neurodegenerative diseases. This study also reveals a better understanding of an endogenous crosstalk between astrocytes and microglia to regulate anti-inflammatory actions, which could provide a novel strategy for the treatment of neuroinflammation and neurodegenerative diseases.

GPR30 activation improves memory and facilitates DHPG-induced LTD in the hippocampal CA3 of middle-aged mice

Reduced estrogen levels and decreased expression of related receptors are typical cerebral features of aging. The G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) is considered a novel therapeutic target for neurodegenerative diseases. In this study, we demonstrated that hippocampal GPR30 expression was reduced in middle-aged mice compared with young adult mice. GPR30 agonist G1 improved both fear and spatial memory in both male and female middle-aged mice, but not in young adult mice, which were blocked by the GPR30 antagonist G15. Interestingly, a group I metabotropic glutamate receptor (mGluR) agonist, 3,5-dihydroxyphenylglycine (DHPG)-induced long-term depression (LTD) in mossy fiber-cornu ammonis 3 (MF-CA3) synapses but not Schaffer collateral-CA1 (SC-CA1) synapses was facilitated in brain slices from G1-treated middle-aged mice. Long-term potentiation (LTP) in SC-CA1 synapses was not affected in slices from G1-treated mice. The effects of GPR30 activation on memory and DHPG-LTD in MF-CA3 synapses were further confirmed by viral expression of GPR30 in the CA3. The regulation of hippocampal synaptic plasticity by G1 treatment might be related to brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling, as G15 also blocked G1-induced activation of the BDNF-TrkB pathway. Moreover, we found that DHPG triggered GluA internalization in slices from G1-treated mice but not control mice. Pharmacological experiments showed that G1-mediated facilitation of DHPG-induced LTD in MF-CA3 synapses was dependent on protein kinase B (Akt), mammalian target of rapamycin (mTor), and TrkB signaling. In conclusion, our results indicate that GPR30 activation improves memory in middle-aged mice, likely through facilitating synaptic plasticity in the CA3. This study provides novel evidence that GPR30 activation can improve memory in middle-aged animals.

Modelling neurodegenerative diseases &lt;em&gt;in vitro&lt;/em&gt;: Recent advances in 3D iPSC technologies

The discovery of induced pluripotent stem cells (iPSC) 12 years ago has fostered the development of innovative patient-derived <em>in vitro</em> models for better understanding of disease mechanisms. This is particularly relevant to neurodegenerative diseases, where availability of live human brain tissue for research is limited and post-mortem interval changes influence readouts from autopsy-derived human tissue. Hundreds of iPSC lines have now been prepared and banked, thanks to several large scale initiatives and cell banks. Patient- or engineered iPSC-derived neural models are now being used to recapitulate cellular and molecular aspects of a variety of neurodegenerative diseases, including early and pre-clinical disease stages. The broad relevance of these models derives from the availability of a variety of differentiation protocols to generate disease-specific cell types and the manipulation to either introduce or correct disease-relevant genetic modifications. Moreover, the use of chemical and physical three-dimensional (3D) matrices improves control over the extracellular environment and cellular organization of the models. These iPSC-derived neural models can be utilised to identify target proteins and, importantly, provide high-throughput screening for drug discovery. Choosing Alzheimer’s disease (AD) as an example, this review describes 3D iPSC-derived neural models and their advantages and limitations. There is now a requirement to fully characterise and validate these 3D iPSC-derived neural models as a viable research tool that is capable of complementing animal models of neurodegeneration and live human brain tissue. With further optimization of differentiation, maturation and aging protocols, as well as the 3D cellular organisation and extracellular matrix to recapitulate more closely, the molecular extracellular-environment of the human brain, 3D iPSC-derived models have the potential to deliver new knowledge, enable discovery of novel disease mechanisms and identify new therapeutic targets for neurodegenerative diseases.

C3 Transferase Gene Therapy for Continuous RhoA Inhibition.

The identification of RhoA inhibition as a therapeutic target in neurodegenerative diseases and traumatic central nervous system (CNS) injuries has introduced a need to develop tools that effectively modulate intracellular RhoA-dependent signaling. In neurons, the bacterial exoenzyme C3 transferase irreversibly inactivates RhoA GTPase signaling to promote neuritogenesis and axon regeneration following an injury. Thus, we have adopted a gene therapy approach for the targeted inhibition of RhoA activity in the CNS by expressing C3 transferase. Herein we describe the construction of adeno-associated viral vectors for the expression of cell-permeable-C3 transferase and their functional characterization in vitro.

Distinct Rab7-related Endosomal–Autophagic–Lysosomal Dysregulation Observed in Cortex and Hippocampus in APPswe/PSEN1dE9 Mouse Model of Alzheimer's Disease

Background:Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer's disease (AD). Dysregulation of the endosomal–autophagic–lysosomal (EAL) pathway, which impairs amyloid precursor protein processing, is one of the earliest changes in AD. However, the precise role of EAL pathway in neurodegeneration remains unclear. This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction.Methods:We used 3-, 7-, and 12-month-old APPswe/PSEN1dE9 (APP/PS1) mice to model different stages of AD with age- and gender-matched wild-type littermates as controls (4–7 mice per group) and detected the changes of EAL markers, endosomal organizers Rab5 and Rab7, autophagosome marker LC3B, and lysosomal proteins Lamp1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis. To further explore the mechanism of EAL dysregulation in AD, components of the class III phosphatidylinositol 3-kinase (PI3KC3) complex, activators of Rab7 (Beclin1 and UVRAG), and the negative regulator of Rab7 (Rubicon) were also measured in this two brain regions.Results:In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly, EAL pathway, and related PI3KC3 members, UVRAG and Beclin1 were upregulated both in cortex and hippocampus (all P < 0.05). By the age of 12 months old, when abundant amyloid plaques formed, EAL markers, UVRAG, and Beclin1 were also upregulated in the cortex (all P < 0.05). However, Rab7 was decreased significantly (P = 0.0447), accompanied by a reduction of its activating PI3KC complex component Beclin1 (P = 0.0215) and enhancement of its inhibiting component Rubicon (P = 0.0055) in the hippocampus.Conclusions:Our study implies that EAL pathway, represented as Rab7 and its PI3KC3 regulators’ expressions, showed temporal and spatial variation in brains at different stages of AD. It provides new insights into the role of EAL pathway in pathogenesis and indicates potential therapeutic targets in neurodegenerative diseases.

PPARα as Potential Therapeutic Target for Neurodegenerative Diseases

PPARα as Potential Therapeutic Target for Neurodegenerative Diseases

Therapeutic effect of autologous compact bone-derived mesenchymal stem cell transplantation on prion disease.

Prion diseases are fatal neurodegenerative disorders of humans and animals and no effective treatments are currently available. Allogenic transplantation of immortalized human mesenchymal stem cells (MSCs) can prolong the survival of mice infected with prions. However, autologous transplantation is an appropriate model for evaluating the effects of MSCs on prion diseases. Therefore, we isolated and purified MSCs from the femur and tibia of mice as compact bone-derived MSCs (CB-MSCs). Flow cytometric analysis showed that CB-MSCs were negative for myeloid stem cell-derived cell markers CD11b and CD45, but positive for molecules such as Sca-1, CD105 and CD90.2, which are reported to be expressed on MSCs. The ability of CB-MSCs to migrate to brain extracts from prion-infected mice was confirmed by an in vitro migration assay. Intra-hippocampus transplantation of CB-MSCs at 120 days post-inoculation marginally but significantly prolonged the survival of mice infected with the Chandler prion strain. The transplantation of CB-MSCs did not influence the accumulation of disease-specific prion protein. However, the CB-MSC transplantation enhanced microglial activation, which appeared to be polarized to the M2-type activation state. These results suggest that autologous MSC transplantation is a possible treatment for prion diseases, while the modification of microglial activation may be a therapeutic target for neurodegenerative diseases.