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The number of young adult patients with major depression, one of the most common mental disorders, is gradually increasing in modern society. Stressful experiences in early life are considered one of the risk factors for chronic depressive symptoms, along with an abnormal inflammatory response in later life. Although increased inflammatory activity has been identified in patients with depression, the cause of long-lasting depressive states is still unclear. To identify the effects of cumulative mild stress in brain development periods, we generated a young adult depression mouse model exposed to cumulative mild stress (CPMS; cumulative mild prenatal stress, mild maternal separation, and mild social defeat) to mimic early life adversities. CPMS mice exhibited more long-lasting anxiety and depression-like behaviors than groups exposed to single or double combinations of mild stress in young adult age. Using the molecular works, we found that inflammatory cytokines, especially interleukin (IL)-17, upregulated microglial activation in the hippocampus, amygdala, and prefrontal cortex of CPMS mice. In the brains of CPMS mice, we also identified changes in the T helper (Th)-17 cell population as well as differentiation. Finally, anti-IL-17 treatment rescued anxiety and depression-like behavior in CPMS mice. In conclusion, we found that cumulative mild stress promoted long-lasting depressive symptoms in CPMS mice through the upregulation of IL-17. We suggest that the CPMS model may be useful to study young adult depression and expect that IL-17 may be an important therapeutic target for depression in young adults.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder resulting in cognitive decline or dementia, the number of patients with AD is continuously increasing. Although a lot of great progress has been made in research and development of AD therapeutics, there is no fundamental cure for this disease yet. This study demonstrated the memory-improving effects of Cuban policosanol (PCO) in 5xFAD mice, which is an animal model of AD. Following 4-months of treatment with PCO in 5xFAD mice, we found that the number of amyloid plaques decreased in the brain compared to the vehicle-treated 5xFAD mice. Long-term PCO treatment in 5xFAD mice resulted in the reduction of gliosis and abnormal inflammatory cytokines level (interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) in the cortex and hippocampus. Levels of lipid peroxide (4-hydroxynonenal [4-HNE]) and superoxide dismutase (SOD1 and SOD2) levels were also recoverd in the brains of PCO-treated 5xFAD mice. Notably, PCO administration reduced memory deficits in the passive avoidance test, as well as synaptic loss (PSD-95, synaptophysin) in 5xFAD mice. Collectively, we identified the potential effects of PCO as a useful supplement to delay or prevent AD progression by inhibiting the formation of Aβ plaques in the brain.

Background Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood. Methods Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in 3-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane. Results We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs. Conclusions Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with peripheral OSN’s loss could be a leading cause of AD-related hyposmia, a characteristic of early AD.

Additional file 1. Supplementary information.

Additional file 1: Figure S1. Verification of early-stage AD phenotype in 5xFAD transgenic mice. (a) Illustration of the time course for Y-maze and Morris water maze test. (b) Basic mobility tests using Y-maze showed the total number of arm entries (WT, n = 23; 5xFAD, n = 16). (c–d) Spontaneous alternation test using the Y-maze and Morris water maze test was performed to evaluate working memory (two-month: WT, n = 23; 5xFAD, n = 16, four-month: WT, n = 6; 5xFAD, n = 6, six-month: WT, n = 10; 5xFAD, n = 10). (c) A spontaneous alternation test using Y-maze was performed and the number of entries to another arm was measured (top). Scheme illustration (bottom). (d) The Morris water maze task was performed and the ratio of escape latency (WT/5xFAD) was measured (top). Scheme illustration (bottom). (e) Illustration of experimental timepoints identified in this research based on the result interpretation. One-way ANOVA was performed for statistical analysis. All data presented as mean ± SEMs. Statistical significances are noted [ns, non-significant; ***P

Background: Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas. The pathology involving olfactory sensory neurons (OSNs) remains poorly understood. Methods: Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in three-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane. Results: We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs. Conclusions: Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely-associated with peripheral OSN’s loss could be a leading cause of AD-related hyposmia, a characteristic of early AD.

Background: Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although the causes of damage have been proposed in every olfactory system including olfactory epithelium, olfactory bulb and olfactory cortex, the main causes of AD- related hyposmia are largely unknown. Methods: We here focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also histologically confirmed the pathological changes in three-month-old 5xFAD mouse models which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of anatomical plane. Results: We observed the odorant group, which 5xFAD mouse could not detect, also neither did physiologically activate the OSNs that propagate to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the ecto-ventrally located OSNs that showed reduced responses to odorants. We also observed irreversible damage to the ecto-region of the olfactory epithelium by measuring impaired neuronal turnover ratio from the basal cells to the matured OSNs. Conclusions: Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely-associated with peripheral OSN’s loss could be a leading cause of the AD-related hyposmia, a characteristic of early AD.

Despite clinical evidence indicating a close relationship between olfactory dysfunction and Alzheimer’s disease (AD), further investigations are warranted to determine the diagnostic potential of nasal surrogate biomarkers for AD. In this study, we first identified soluble amyloid-β (Aβ), the key biomarker of AD, in patient nasal discharge using proteomic analysis. Then, we profiled the significant differences in Aβ oligomers level between patient groups with mild or moderate cognitive decline (n = 39) and an age-matched normal control group (n = 21) by immunoblot analysis and comparing the levels of Aβ by a self-standard method with interdigitated microelectrode sensor systems. All subjects received the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and the Global Deterioration Scale (GDS) for grouping. We observed higher levels of Aβ oligomers in probable AD subjects with lower MMSE, higher CDR, and higher GDS compared to the normal control group. Moreover, mild and moderate subject groups could be distinguished based on the increased composition of two oligomers, 12-mer Aβ*56 and 15-mer AβO, respectively. The longitudinal cohort study confirmed that the cognitive decline of mild AD patients with high nasal discharge Aβ*56 levels advanced to the moderate stage within three years. Our clinical evidence strongly supports the view that the presence of oligomeric Aβ proteins in nasal discharge is a potential surrogate biomarker of AD and an indicator of cognitive decline progression.

Processing of amyloid precursor protein (APP) occurs through sequential cleavages first by β-secretase and then by the γ-secretase complex. However, abnormal processing of APP leads to excessive production of β-amyloid (Aβ) in the central nervous system (CNS), an event which is regarded as a primary cause of Alzheimer's disease (AD). In particular, gene mutations of the γ-secretase complex-which contains presenilin 1 or 2 as the catalytic core-could trigger marked Aβ accumulation. Olfactory dysfunction usually occurs before the onset of typical AD-related symptoms (eg, memory loss or muscle retardation), suggesting that the olfactory system may be one of the most vulnerable regions to AD. To date however, little is known about why the olfactory system is affected so early by AD prior to other regions. Thus, we examined the distribution of secretases and levels of APP processing in the olfactory system under either healthy or pathological conditions. Here, we show that the olfactory system has distinct APP processing machineries. In particular, we identified higher expressions levels and activity of γ-secretase in the olfactory epithelium (OE) than other regions of the brain. Moreover, APP c-terminal fragments (CTF) are markedly detected. During AD progression, we note increased expression of presenilin2 of γ-secretases in the OE, not in the OB, and show that neurotoxic Aβ*56 accumulates more quickly in the OE. Taken together, these results suggest that the olfactory system has distinct APP processing machineries under healthy and pathological conditions. This finding may provide a crucial understanding of the unique APP-processing mechanisms in the olfactory system, and further highlights the correlation between olfactory deficits and AD symptoms.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication, and patients often display co-occurring repetitive behaviors. Although the global prevalence of ASD has increased over time, the etiology and treatments for ASD are poorly understood. Recently, some researchers have suggested that stem cells have therapeutic potential for ASD. Thus, in the present study, we investigated the therapeutic effects of human adipose-derived stem cells (hASCs), a kind of autologous mesenchymal stem cells (MSCs) isolated from adipose tissue, on valproic acid (VPA)-induced autism model mice. Human ASCs were injected into the neonatal pups (P2 or P3) intraventricularly and then we evaluated major behavior symptoms of ASD. VPA-treated mice showed increased repetitive behaviors, decreased social interactions and increased anxiety but these autistic behaviors were ameliorated through transplantation of hASCs. In addition, hASCs transplantation restored the alteration of phosphatase and tensin homolog (PTEN) expression and p-AKT/AKT ratio in the brains of VPA-induced ASD model mice. The decreased level of vascular endothelial growth factor (VEGF) and interleukin 10 (IL-10) by VPA were rescued in the brains of the hASC-injected VPA mice. With these results, we experimentally found hASCs' therapeutic effects on autistic phenotypes in a ASD model mice for the first time. This animal model system can be used to elucidate further mechanisms of therapeutic effects of hASCs in ASD.

© 2016 - IOS Press and the authors. All rights reserved. Background: Evidence from various consortia on vascular contributions has been inconsistent in determining the etiology of sporadic Alzheimer's disease (AD). Objective: To investigate vascular risk factors and cerebrovascular pathologies associated in manifestation of AD-related neuropathological changes of an elderly population. Methods: Postmortem brain samples from 76 elderly subjects (≥50 years) were used to study genetic polymorphisms, intracranial atherosclerosis of the circle of Willis (IASCW), and microscopic infarcts in deep white matters. From this cohort, 50 brains (≥60 years) were subjected to neuropathological diagnosis using immunohistopathological techniques. Results: Besides the association with age, the apolipoprotein E ϵ4 allele was significantly and strongly associated with Thal amyloid-β phases ≥1 [odds ratio (OR)=6.76, 95 confidence interval (CI) 1.37-33.45] and inversely with Braak neurofibrillary tangle (NFT) stages ≥III (0.02, 0.0-0.47). Illiterates showed a significant positive association for Braak NFT stages ≥IV (14.62, 1.21-176.73) and a significant negative association for microscopic infarcts (0.15, 0.03-0.71) in deep white matters. With respect to cerebrovascular pathologies, cerebral small vessel lesions (white matter hyperintensities and cerebral amyloid angiopathy) showed a higher degree of associations among them and with AD-related neuropathological changes (p

We previously demonstrated that dehydroevodiamine•HCl (DHED), which was purified from Evodia rutaecarpa Bentham (Rutaceae), has beneficial effects on memory impairment and neuronal damage in three disease models. To investigate the preventive action of DHED in Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory decline, amyloid-β (Aβ) protein-containing neuritic plaques and neurofibrillary tangles, in this study, we proposed that DHED may be therapeutically effective against the memory impairment and disease-related neurochemical changes that occur in Tg2576 (Tg) mice. DHED (0.5 mg/kg) was intraperitoneally administered to 7-month-old Tg and wild type mice for 4 months. In passive avoidance and water maze tests, DHED improved memory impairment of Tg mice after 4 months of administration. DHED also reduced cortical levels of soluble Aβ40, soluble Aβ42 and total Aβ peptides in the Tg mice. Additionally, we investigated whether DHED may be a β-secretase inhibitor that affects the production of Aβ related to the formation of neuritic plaques. DHED directly inhibited β-secretase activity in a concentrationdependent manner. The concentration required for 50 % enzyme inhibition (IC50) was 40.96 μM, and DHED may act as a competitive inhibitor of β-secretase. Moreover, DHED interacted strongly with BACE1 (β-secretase 2QP8), as demonstrated in the analysis of the binding mode of DHED in the active site of human BACE1. In conclusion, DHED may exhibit therapeutic effects for AD as a β-secretase inhibitor.

To identify some apparent biomarker candidates for the diagnosis of Alzheimer's disease (AD) pathology, we investigated whether there would be a significant difference between the levels of the plasma proteins of AD patients and healthy people. A total of 115 subjects were enrolled, 60 individuals with AD and 55 healthy controls. There was a statistical difference in the mini-mental status exam (MMSE) scores and the clinical dementia rating (CDR) scores between the two groups. We used the immunoblotting assay to analyze several plasma proteins in the subjects. Amyloid-β (Aβ), S100a9, and soluble neuregulin-1 (sNRG-1), including α-synuclein (α-Syn) as a detection control were detected in the plasma samples. Unlike Aβ, S100a9 and α-Syn, the level of sNRG-1 of the AD patients was significantly higher than that of the healthy control subjects. The AD patients were divided into mild and moderate groups according to their MMSE and CDR scores. We found a significant correlation between the level of sNRG-1 and MMSE scores. The sNRG-1 level was significantly higher in mild AD patients as well as in moderate AD patients compared with that of the control subjects. These new findings indicate that increased plasma sNRG-1 levels might be a novel and reliable biological marker for the early diagnosis of AD.

Alzheimer&rsquo, s disease (AD), a progressive neurodegenerative disorder, is characterized clinically by cognitive decline and pathologically by the development of amyloid plaques. AD is the most common cause of dementia among older people. However, there is currently no cure for AD. In this study, we aimed to elucidate the therapeutic effects of human amniotic epithelial stem cells (hAESCs) in a transgenic mouse model of AD. Tg2576 transgenic (Tg) mice underwent behavioral tests, namely the Morris water maze and Y-maze tests, to assess their cognitive function. In the Morris water maze test, hAESC-treated Tg mice exhibited significantly shorter escape latencies than vehicle-treated Tg mice. In the Y-maze test, hAESC-treated Tg mice exhibited significantly higher rate of spontaneous alteration than vehicle-treated Tg mice, while the total number of arm entries did not differ between the groups. Furthermore, Congo red staining revealed that hAESCs injection reduced the number of amyloid plaques present in the brains of Tg mice. Finally, beta-secretase (BACE) activity was significantly decreased in Tg mice at 60 min after hAESCs injection. In this study, we found that intracerebral injection of hAESCs alleviated cognitive impairment in a Tg2576 mouse model of AD. Our results indicate that hAESCs injection reduced amyloid plaques caused by reduced BACE activity. These results indicate that hAESCs may be a useful therapeutic agent for the treatment of AD-related memory impairment.

Olfactory dysfunction is a common symptom associated with neurodegenerative diseases including Alzheimer’s disease (AD). Although evidence exists to suggest that peripheral olfactory organs are involved in the olfactory dysfunction that accompanies AD pathology, the underlying mechanisms are not fully understood. As confirmed using behavioral tests, transgenic mice overexpressing a Swedish mutant form of human amyloid precursor proteins exhibited olfactory impairments prior to evidence of cognitive impairment. By measuring the expression of tyrosine hydroxylase, we observed that specific regions of the olfactory bulb (OB) in Tg2576 mice, specifically the ventral portion exhibited significant decreases in the number of dopaminergic neurons in the periglomerular regions from the early stage of AD. To confirm the direct linkage between these olfactory impairments and AD-related pathology, β-site amyloid precursor protein cleaving enzyme 1 (BACE1)—the initiating enzyme in Aβ genesis—and β-amyloid peptide (Aβ), hallmarks of AD were analyzed. We found that an increase in BACE1 expression coincided with an elevation of amyloid-β (Aβ) oligomers in the ventral region of OB. Moreover, olfactory epithelium (OE), in particular the ectoturbinate in which axons of olfactory sensory neurons (OSNs) have direct connections with the dendrites of mitral/tufted cells in the ventral part of OB, exhibited significant decreases in both thickness and cell number even at early stages. This result suggests that Aβ oligomer toxicity in the OE may have induced a decline in the number of OSNs and functional impairment of the olfactory system. We first demonstrated that disproportionate levels of regional damage in the peripheral olfactory system may be a specific symptom of AD with Aβ oligomer accumulation occurring prior to damage within the CNS. This regional damage in the olfactory system early in the progression of AD may be closely related to AD-related pathological abnormality and olfactory dysfunction found in AD patients.

Stem cell therapy has been noted as a novel strategy to various diseases including neurological disorders such as Alzheimer’s disease, Parkinson’s disease, stroke, amyotrophic lateral sclerosis, and Huntington’s disease that have no effective treatment available to date. The adipose-derived stem cells (ASCs), mesenchymal stem cells (MSCs) isolated from adipose tissue, are well known for their pluripotency with the ability to differentiate into various types of cells and immuno-modulatory property. These biological features make ASCs a promising source for regenerative cell therapy in neurological disorders. Here we discuss the recent progress of regenerative therapies in various neurological disorders utilizing ASCs. Keywords:: neurological disorder, adipose-derived stem cell (ASC), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD)

Dehydroevodiamine·HCl (DHED) has been reported to prevent memory impairment and neuronal cell loss in a rat model with cognitive disturbance. We investigated the effect of DHED on memory impairment and behavioral abnormality caused by stress. We demonstrated that DHED can improve stress-induced memory impairments and depression-like behaviors by using open-field test, Y-maze test and forced swimming test. DHED treatment significantly recovered the decreases in the levels of neural cell adhesion molecule (NCAM) proteins caused by stress and the decreases in cell viability. Our results suggested that DHED is a potential drug candidate for neuronal death, memory impairment and depression induced by stress.

Circadian rhythm is a biological rhythm governing physiology and behavior with a period of ∼24 h. At the molecular level, circadian output is controlled by a molecular clock composed of positive and negative feedback loops in transcriptional and post-translational processes. CLOCK is a transcription factor known as a central component of the molecular clock feedback loops generating circadian oscillation. Although CLOCK is known to undergo multiple post-translational modifications, the knowledge of their entities remains limited. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine-threonine kinase that is involved in various neuronal processes. Here, we report that Cdk5 is a novel regulator of CLOCK protein. Cdk5 phosphorylates CLOCK at the Thr-451 and Thr-461 residues in association with transcriptional activation of CLOCK. The Cdk5-dependent regulation of CLOCK function is mediated by alterations of its stability and subcellular distribution. These results suggest that Cdk5 is a novel regulatory component of the core molecular clock machinery.

α-Synuclein oligomers can induce neurotoxicity and are implicated in Parkinson's disease etiology and disease progression. Many studies have reported α-synuclein oligomerization by dopamine (DA) and transition metal ions, but few studies provide insight into joint influences of DA and Cu2+ . In this study, DA and Cu2+ were coadministered aerobically to measure α-synuclein oligomerization under these conditions. In the presence of oxygen, DA induced α-synuclein oligomerization in a dose-dependent manner. Cu+/2+ did not effect oligomerization in such a manner in the presence of DA. By electrophoresis, Cu2+ was found easily to induce oligomerization with DA. This implies that oligomerization invoked by DA is reversible in the presence of Cu2+, which appears to be mediated by noncovalent bond interactions. In the absence of oxygen, DA induced less oligomerization of α-synuclein, whereas DA/Cu2+ induced aerobic-level amounts of oligomers, suggesting that DA/Cu2+ induces oligomerization independent of oxygen concentration. Radical species were detected through electron paramagnetic resonance (EPR) spectroscopic analysis arising from coincubation of DA/Cu2+ with α-synuclein. Redox reactions induced by DA/Cu2+ were observed in multimer regions of α-synuclein oligomers through NBT assay. Cellular toxicity results confirm that, for normal and hypoxic conditions, copper or DA/Cu2+ can induce cell death, which may arise from copper redox chemistry. From these results, we propose that DA and DA/Cu2+ induce different mechanisms of α-synuclein oligomerization, cross-linking with noncovalent (or reversible covalent) bonding vs. likely radical-mediated covalent modification.

Three novel molecular probes have been synthesized which can be used as a probe for selective detection of Fe 3+ . Also, H 2 O 2 can be detected in Fenton-like conversions by a Fe 2+ probe ensemble fluorescence “ turn - on ” responses that is operational in neuronal cells with multiple chemical inputs.

Novel, high "turn-on" Hg(2+) and O(2)(-) fluorescence behaviour (∼25-fold) with probes bearing [S(thi)N(py)] and [S(thi)N(py)N(py)] binding receptors, joined by oxidizable sulphides, may involve S-bound transient ROS species; such optical O(2)(-) behaviour operates moderately in neuroblastoma.

Parkinson's disease (PD) is a progressive neurodegenerative disorder of unknown etiology. Considerable evidence suggests that free radical formation and oxidative stress might play an important role in the pathogenesis of PD. In the present investigation we evaluated the therapeutic potential of methylparaben (MP) a well known pharmaceutical preservative against 6-hydroxydopamine (6-OHDA) neurotoxicity in SH-SY5Y cells and in a mouse model of PD. At nanomolar concentrations MP (0.01, 0.1 and 1 nM) significantly attenuated the 6-OHDA- and hydrogen peroxide-induced cytotoxicity in SH-SY5Y cells. The reactive oxygen species generated by 6-OHDA in SH-SY5Y cells was also inhibited by MP in a concentration dependent fashion. Further, intranigral damage induced by stereotaxically injecting 6-OHDA in mouse brain was significantly attenuated by MP treatment. MP (1, 10 or 50 μg/kg, i.p.) prevented apomorphine-induced rotational behavior and significantly improved motor deficits in 6-OHDA-lesioned mice. The cognitive impairments as evaluated by passive avoidance and Y-maze task in mice were also attenuated by MP concentration dependently. Immunohistochemical analysis of substantia nigra in MP treated mice showed significantly higher number of surviving tyrosine hydroxylase positive cells. Furthermore, MP also suppressed the lipid peroxidation products in 6-OHDA-lesioned mouse brain tissues. Considering the results obtained, the marked neuroprotection exhibited by MP might be attributed to its potent antioxidant property. In conclusion, this study reports the neuroprotective properties of MP in experimental models of PD for the first time and can be developed as a potential therapeutic agent.

Stem cell therapy has been noted to be a disease-modifying treatment for Alzheimer's disease (AD). After the failure to develop new drugs for AD, the number of studies on stem cells, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs), has increased from the early 2000 s. Issues pertaining to stem cells have been investigated in many animal studies in terms of stem cell origin, differentiation potency, method of culture, tumor formation, injection route, and mobility. Since 2010, mainly in East Asia, researchers began clinical trials investigating the use of stem cells for AD. Two phase I trials on moderate AD have been completed; though they revealed no severe acute or long-term side effects, no significant clinical efficacy was observed. Several studies, which involve more sophisticated study designs using different injection routes, well-established scales, and biomarkers such as amyloid positron emission tomography, are planned for mild to moderate AD patients. Here, we review the concept of stem cell therapy for AD and the progress of recent clinical trials.

We previously demonstrated that dehydroevodiamine•HCl (DHED), which was purified from Evodia rutaecarpa Bentham (Rutaceae), has beneficial effects on memory impairment and neuronal damage in three disease models. To investigate the preventive action of DHED in Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory decline, amyloid-β (Aβ) protein-containing neuritic plaques and neurofibrillary tangles, in this study, we proposed that DHED may be therapeutically effective against the memory impairment and disease-related neurochemical changes that occur in Tg2576 (Tg) mice. DHED (0.5 mg/kg) was intraperitoneally administered to 7-month-old Tg and wild type mice for 4 months. In passive avoidance and water maze tests, DHED improved memory impairment of Tg mice after 4 months of administration. DHED also reduced cortical levels of soluble Aβ40, soluble Aβ42 and total Aβ peptides in the Tg mice. Additionally, we investigated whether DHED may be a β-secretase inhibitor that affects the production of Aβ related to the formation of neuritic plaques. DHED directly inhibited β-secretase activity in a concentrationdependent manner. The concentration required for 50 % enzyme inhibition (IC50) was 40.96 μM, and DHED may act as a competitive inhibitor of β-secretase. Moreover, DHED interacted strongly with BACE1 (β-secretase 2QP8), as demonstrated in the analysis of the binding mode of DHED in the active site of human BACE1. In conclusion, DHED may exhibit therapeutic effects for AD as a β-secretase inhibitor.

The S100A9 protein is an important proinflammatory factor of innate immunity that has been proposed to participate in inflammation associated with the pathogenesis of Alzheimer’s disease. Here, we provide insights into the potential roles of extracellular S100A9 in the interaction with the immune response in human THP-1 monocytic cells that have been challenged with amyloid β1-42 (Aβ1-42) monomers instead of oligomers. Extracellular S100A9 alone produced a stimulatory effect on tumor necrosis factor-α and interleukin-1β, expression as well as released monocyte chemoattractant protein-1 into culture supernatants, which was accompanied by an increased level of matrix metalloproteinas-9 activity. Importantly, co-stimulation with S100A9 and Aβ1-42 resulted in a marked enhancement of Aβ1-42-mediated release of these proinflammatory mediators under the same experimental conditions, whereas heat inactivated S100A9 had little effect. Our findings clearly suggest that excess S100A9 protein may play an important role in the pathological processes of Alzheimer’s disease by exacerbating the Aβ1-42-induced innate immune response.

Neuregulin-1 (NRG-1) is a ligand of the epidermal growth factor receptor (erbB), and its interaction involves activation of the glutamatergic N-methyl-Daspartate receptor, which increases the expression of the β2 subunit of the γ- aminobutyric acid receptor and subunits of the nicotinic acetylcholine receptor. In the dentate gyrus of 14-month-old Tg2576 mice, NRG-1 was strongly expressed compared with age-matched controls. The supernatant of oligomeric amyloid β peptide (Aβ42)-treated glial cells enhanced the Aβ42;-induced cytotoxic effects, but the expression of Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand in microglial cells was not changed upon cytotoxic treatment. This suggests that the oligomeric form of Aβ42 toxicity is not related to apoptosis, which is mediated by cell-to-cell interaction. During the 24-h incubation, the secretion of the soluble form of NRG-1 was increased, but interleukin 6 secretion was not changed. Further, soluble NRG-1 increased Aβ42-induced toxicity. In conclusion, soluble NRG-1 significantly enhanced oligomeric Aβ42-induced toxicity through the activation of endoplasmic reticulum stress by the increase of a phospho-translation initiation factor 2 alpha (p-eIF2α).

We report a refined and expanded synthetic study of 4,4-difluoro-1,3,5,7-tetramethyl-8-(aryl)-4-bora-3a,4a-diaza-s-indacene under treatment with POCl3/DMSO. The 2-chloro-6-methylsulfide derivative (Kim TI, Park S, Choi Y and Kim Y. Chem. Asian J. 2011; 6: 1358-61.) was one of five co-eluants, including 2,6-disulfido and -dichloro species, and mono-substituted counterparts. The 8-meso tail group modifies product distribution. The different sulfur-containing products undergo different "off-on" responses with NaOCl (10 equiv.). Compounds 4b and 2b exhibit low toxicity and were found to enter juxtanuclear regions in neuroblastoma.

Ethnopharmacological relevance Indigofera tinctoria Linn. ( I. tinctoria , Fabaceae) has been widely used for several years in the traditional Indian and Chinese system of Medicine for the treatment of epilepsy, nervous and brain disorders. Aim of the study The effect of SF-6, a compound isolated from I. tinctoria to exhibit neuroprotection in in vitro and in vivo models of Parkinson's disease (PD), was investigated. Materials and methods Using human neuroblastoma SH-SY5Y cells, the effect of SF-6 on α-synuclein- or 6-hydroxydopamine (6-OHDA)-, hydrogen peroxide (H 2 O 2 )-induced cytotoxicity in vitro was investigated. In in vivo studies SF-6 was challenged against 6-OHDA-induced neuronal damage and behavioral deficits in mice. Results SF-6 (1, 5 and 10 μg/mL) significantly inhibited α-synuclein- or 6-OHDA-, H 2 O 2 -induced cytotoxicity and decreased the reactive oxygen species production in SH-SY5Y cells. SF-6 also scavenged hydroxyl free radicals. In in vivo evaluation, SF-6 attenuated the contralateral rotational asymmetry observed by apomorphine challenge in 6-OHDA-lesioned mice. Further, the behavioral deficits evaluated by rotarod test, Y-maze and passive avoidance tasks were reversed by SF-6 and was found more potent compared with standard compound deprenyl. Conclusion Data suggest that SF-6 showed neuroprotection in experimental models of PD due to its potent antioxidant action supporting the traditional claim for its use in nervous and brain disorders.

Human immunodeficiency virus (HIV)-induced inflammation, and its consequences within the central nervous system (CNS), must be countered by multiple pharmacologic agents, and 15-deoxy-Δ(12,14) -prostaglandin J(2) (15d-PGJ2) may hold promise in the treatment of pathologies associated with this inflammatory response. 15d-PGJ2 can repress the inflammatory response by means of peroxisome proliferator-activated receptor-γ (PPARγ)-dependent and -independent mechanisms. However, its precise role and antiinflammatory mechanism in the hippocampus remain poorly understood. In the present study, rat hippocampal slices were stimulated with full-length HIV-1 Tat protein to investigate the role of 15d-PGJ2 8in the hippocampal inflammatory response. Pretreatment of slices with 15d-PGJ2 markedly reduced Tat-induced monocyte chemoattractant protein-1 (MCP-1/CCL2) production. Interestingly, the PPARγ antagonist GW9662 did not inhibit action of 15d-PGJ2, confirming the latter's PPARγ-independent mechanism of mediating antiinflammatory effects. Despite 15d-PGJ2's increasing the expression of heme oxygenase-1 (HO-1), its action was not abrogated by the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), nor was it recapitulated by HO-1 inducers such as cobalt protoporphyrin (CoPP). Moreover, short interfering RNA (siRNA)-directed knockdown of HO-1 did not abolish the antiinflammatory action of 15d-PGJ2 against Tat-induced MCP-1 production in human microglia-like THP-1 cells. Conversely, 15d-PGJ2 suppressed Tat-induced ERK1/2 activation, decreasing MCP-1 production upon Tat stimulation. The NADPH oxidase inhibitors DPI and apocynin also abrogated Tat-stimulated ERK1/2 activation, reducing MCP-1 production. Collectively, these data demonstrate that the antiinflammatory effects of 15d-PGJ2 on the hippocampus are exerted through inhibition of Tat-mediated ERK1/2 activation, coupled with that of a redox-sensitive pathway, independent of PPARγ and HO-1.