Whether hippocampal neurogenesis persists throughout life in the human brain is not fully resolved. Here, we demonstrate that hippocampal neurogenesis is persistent through the tenth decade of life and is detectable in patients with mild cognitive impairments and Alzheimer's disease. In a cohort of 18 participants with a mean age of 90.6 years, Nestin + Sox2 + neural progenitor cells (NPCs) and DCX + neuroblasts and immature neurons were detected, but their numbers greatly varied between participants. Nestin + cells localize in the anterior hippocampus, and NPCs, neuroblasts, and immature neurons are evenly distributed along the anterior to posterior axis. The number of DCX + PCNA + cells is reduced in mild cognitive impairments, and higher numbers of neuroblasts are associated with better cognitive status. The number of DCX + PCNA + cells correlates with functional interactions between presynaptic SNARE proteins. Our results suggest that hippocampal neurogenesis persists in the aged and diseased human brain and that it is possibly associated with cognition.
This review covers the pathogenesis of ischemic stroke and future directions regarding therapeutic options after injury. Ischemic stroke is a devastating disease process affecting millions of people worldwide every year. The mechanisms underlying the pathophysiology of stroke are not fully understood but there is increasing evidence demonstrating the contribution of inflammation to the drastic changes after cerebral ischemia. This inflammation not only immediately affects the infarcted tissue but also causes long-term damage in the ischemic penumbra. Furthermore, the interaction between inflammation and subsequent neurogenesis is not well understood but the close relationship between these two processes has garnered significant interest in the last decade or so. Current approved therapy for stroke involving pharmacological thrombolysis is limited in its efficacy and new treatment strategies need to be investigated. Research aimed at new therapies is largely about transplantation of neural stem cells and using endogenous progenitor cells to promote brain repair. By understanding the interaction between inflammation and neurogenesis, new potential therapies could be developed to further establish brain repair mechanisms.
BackgroundThe molecular mechanism underlying progressive memory loss in Alzheimer’s disease is poorly understood. Neurogenesis in the adult hippocampus is a dynamic process that continuously changes the dentate gyrus and is important for hippocampal plasticity, learning and memory. However, whether impairments in neurogenesis affect the hippocampal circuitry in a way that leads to memory deficits characteristic of Alzheimer’s disease is unknown. Controversial results in that regard were reported in transgenic mouse models of amyloidosis.MethodsHere, we conditionally ablated adult neurogenesis in APPswe/PS1ΔE9 mice by crossing these with mice expressing nestin-driven thymidine kinase (δ-HSV-TK).ResultsThese animals show impairment in performance in contextual conditioning and pattern separation tasks following depletion of neurogenesis. Importantly, these deficits were not observed in age-matched APPswe/PS1ΔE9 or δ-HSV-TK mice alone. Furthermore, we show that cognitive deficits were accompanied by the upregulation of hyperphosphorylated tau in the hippocampus and in immature neurons specifically. Interestingly, we observed upregulation of the immediate early gene Zif268 (Egr-1) in the dentate gyrus, CA1 and CA3 regions of the hippocampus following learning in the neurogenesis-depleted δ-HSV-TK mice. This may suggest overactivation of hippocampal neurons in these areas following depletion of neurogenesis.ConclusionsThese results imply that neurogenesis plays an important role in the regulation of inhibitory circuitry of the hippocampus. This study suggests that deficits in adult neurogenesis may contribute to cognitive impairments, tau hyperphosphorylation in new neurons and compromised hippocampal circuitry in Alzheimer’s disease.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0207-7) contains supplementary material, which is available to authorized users.
Background Brain repair mechanisms fail to promote recovery after stroke, and approaches to induce brain regeneration are scarce. Mesenchymal stem cells ( MSC ) are thought to be a promising therapeutic option. However, their efficacy is not fully elucidated, and the mechanism underlying their effect is not known. Methods and Results The middle cerebral artery occlusion model was utilized to determine the efficacy of interferon‐γ–activated mesenchymal stem cells ( aMSC γ) as an acute therapy for stroke. Here we show that treatment with aMSC γ is a more potent therapy for stroke than naive MSC . aMSC γ treatment results in significant functional recovery assessed by the modified neurological severity score and open‐field analysis compared with vehicle‐treated animals. aMSC γ‐treated animals showed significant reductions in infarct size and inhibition of microglial activation. The aMSC γ treatment suppressed the hypoxia‐induced microglial proinflammatory phenotype more effectively than treatment with naive MSC . Importantly, treatment with aMSC γ induced recruitment and differentiation of oligodendrocyte progenitor cells to myelin‐producing oligodendrocytes in vivo. To elucidate the mechanism underlying high efficacy of aMSC γ therapy, we examined the secretome of aMSC γ and compared it to that of naive MSC . Intriguingly, we found that aMSC γ but not nMSC upregulated neuron‐glia antigen 2, an important extracellular signal and a hallmark protein of oligodendrocyte progenitor cells. Conclusions These results suggest that activation of MSC with interferon‐γ induces a potent proregenerative, promyelinating, and anti‐inflammatory phenotype of these cells, which increases the potency of aMSC γ as an effective therapy for ischemic stroke.
Presenilin-1 (PS1), the catalytic core of the aspartyl protease γ-secretase, regulates adult neurogenesis. However, it is not clear whether the role of neurogenesis in hippocampal learning and memory is PS1-dependent, or whether PS1 loss of function in adult hippocampal neurogenesis can cause learning and memory deficits. Here we show that downregulation of PS1 in hippocampal neural progenitor cells causes progressive deficits in pattern separation and novelty exploration. New granule neurons expressing reduced PS1 levels exhibit decreased dendritic branching and dendritic spines. Further, they exhibit reduced survival. Lastly, we show that PS1 effect on neurogenesis is mediated via β-catenin phosphorylation and notch signaling. Together, these observations suggest that impairments in adult neurogenesis induce learning and memory deficits and may play a role in the cognitive deficits observed in Alzheimer’s disease.
According to the Global Healthcare Security (GHS) Index, the United States was the most prepared nation in the world to deal with pandemics (October, 2019). 1 Now in the midst of the COVID-19 crisis, it is ironic that the United States has had more cases and deaths than any other nation. 2 The same report found that other countries were even less prepared and there were major gaps in global healthcare security. 1,2 Governments have had to make difficult decisions during this pandemic, balancing health against economic collapse. The decision to proceed with social distancing, banning nonessential travel, and closing large portions of the economy has been widely adopted around the world recognizing this will likely have longstanding economic consequences. 3-5 The aim of our study was to explore the impact of this pandemic on neurosurgeons with the hope of improving preparedness for future crisis. We created a 20-question survey designed to explore demographics (nation, duration and scope of practice, and caseburden), knowledge (source of information), clinical impact (elective clinic/surgery cancellations), hospital preparedness (availability of personal protective equipment [PPE] and cost of the supplies), and personal factors (financial burden, workload, scientific and research activities). The survey was first piloted with 10 neurosurgeons and then revised. Surveys were distributed electronically in 7 languages (Chinese, English, French, German, Italian, Portuguese, and Spanish) between March 20 and April 3, 2020 using Google Forms, WeChat used to obtain responses, and Excel (Microsoft) and SPSS (IBM) used to analyze results. All responses were crossverified by 2 members of our team. After obtaining results, we analyzed our data with histograms and standard statistical methods (Chi-square and Fisher's exact tests and logistic regression). Participants were first informed about the objectives of our survey and assured confidentiality after they agreed to participate (Helsinki declaration). 6 We received 187 responses from 308 invitations (60.7%), and 474 additional responses were obtained from social mediabased neurosurgery groups (total responses = 661). The respondents were from 96 countries representing 6 continents (Figure 1A-1C). Ethical Committee Ethics board approval was waived by the ethical committee of the neurosurgery department at Cairo University. CORRESPONDENCE We encourage increased resource allocation for better pandemic preparedness. Neurosurgeons must develop disaster strategies to curtail future crises through collaboration and communication, which has never been seen before.
Study DesignNarrative review.ObjectiveDespite the numerous treatment options for vertebral compression fractures, a consensus opinion for the management of patients with these factures has not been established. This review is meant to provide an up-to-date overview of the most common treatment strategies for compression fractures and to suggest possible routes for the development of clearer treatment guidelines.MethodsA comprehensive database search of PubMed was performed. All results from the past 30 years were obtained and evaluated based on title and abstract. The full length of relevant studies was analyzed for level of evidence, and the strongest studies were used in this review.ResultsThe major treatment strategies for patients with compression fractures are conservative pain management and vertebral augmentation. Despite potential adverse effects, medical management, including nonsteroidal anti-inflammatory drugs, calcitonin, teriparatide, and bisphosphonates, remains the first-line therapy for patients. Evidence suggests that vertebral augmentation, especially some of the newer procedures, have the potential to dramatically reduce pain and improve quality of life. At this time, balloon-assisted kyphoplasty is the procedure with the most evidence of support.ConclusionsBased on current literature, it is evident that there is a lack of standard of care for patients with vertebral compression fractures, which is either due to lack of evidence that a procedure is successful or due to serious adverse effects encountered with prolonged treatment. For a consensus to be reached, prospective clinical trials need to be formulated with potential new biomarkers to assess efficacy of treatment strategies.
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