Adult hippocampal neurogenesis and its role in Alzheimer's disease

The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD

Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells.

Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients

Dependence of Hippocampal Function on ERRγ-Regulated Mitochondrial Metabolism

SummaryNeurons utilize mitochondrial oxidative phosphorylation (OxPhos) to generate energy essential for survival, function, and behavioral output. Unlike most cells that burn both fat and sugar, neurons only burn sugar. Despite its importance, how neurons meet the increased energy demands of complex behaviors such as learning and memory is poorly understood. Here we show that the estrogen-related receptor gamma (ERRγ) orchestrates the expression of a distinct neural gene network promoting mitochondrial oxidative metabolism that reflects the extraordinary neuronal dependence on glucose. ERRγ−/− neurons exhibit decreased metabolic capacity. Impairment of long-term potentiation (LTP) in ERRγ−/− hippocampal slices can be fully rescued by the mitochondrial OxPhos substrate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ in cerebral cortex and hippocampus exhibit defects in spatial learning and memory. These findings implicate neuronal ERRγ in the metabolic adaptations required for memory formation

Cord blood-derived neuronal cells by ectopic expression of SOX2 and c-MYC

The finding that certain somatic cells can be directly converted into cells of other lineages by the delivery of specific sets of transcrip- tion factors paves the way to novel therapeutic applications. Here we show that human cord blood (CB) CD133+ cells lose their hematopoietic signature and are converted into CB-induced neu- ronal-like cells (CB-iNCs) by the ectopic expression of the transcrip- tion factor Sox2, a process that is further augmented by the combination of Sox2 and c-Myc. Gene-expression analysis, immu- nophenotyping, and electrophysiological analysis show that CB- iNCs acquire a distinct neuronal phenotype characterized by the expression of multiple neuronal markers. CB-iNCs show the ability to fire action potentials after in vitro maturation as well as after in vivo transplantation into the mouse hippocampus. This system highlights the potential of CB cells and offers an alternative means to the study of cellular plasticity, possibly in the context of drug screening research and of future cell-replacement therapies

Comparison of soil erosion models used to study the Chinese Loess Plateau

The Loess Plateau suffers from severe soil erosion that leads to a series of ecological and economic problems such as reduced land productivity, exacerbated rural poverty, decreased biodiversity and sedimentation of the riverbed in the lower reaches of the Yellow River. Soil erosion models are commonly used on the Loess Plateau to help target sustainable land management strategies to control soil erosion. In this study, we compared eleven soil erosion models that were previously used on the Loess Plateau. We studied their prediction accuracy, process representation, data and calibration requirements, and potential application in scenario studies. The selected models consisted of a broad range of model types, structures and scales. The comparison showed that process-based and empirical models did not necessarily yield more accurate results over one another for the Loess Plateau. Among the process-based models, Si’ model, WEPP and MMF had the highest prediction accuracy. However, some of the selected models were tested with total sediment load while others were tested with suspended sediment load (i.e. bedload is not included), which is subject to several drawbacks. Research questions that each of the models can address on the Loess Plateau were suggested. Further improvement of soil erosion models for the Loess Plateau should concentrate on enhancing the quality of data for model implementation and testing, incorporating key processes into process-based models according to their aims and scales, comparing models that address the same research questions, and implementing internal and spatial model testing

Cell-Surface Marker Signatures for the Isolation of Neural Stem Cells, Glia and Neurons Derived from Human Pluripotent Stem Cells

Neural induction of human pluripotent stem cells often yields heterogeneous cell populations that can hamper quantitative and comparative analyses. There is a need for improved differentiation and enrichment procedures that generate highly pure populations of neural stem cells (NSC), glia and neurons. One way to address this problem is to identify cell-surface signatures that enable the isolation of these cell types from heterogeneous cell populations by fluorescence activated cell sorting (FACS).We performed an unbiased FACS- and image-based immunophenotyping analysis using 190 antibodies to cell surface markers on naïve human embryonic stem cells (hESC) and cell derivatives from neural differentiation cultures. From this analysis we identified prospective cell surface signatures for the isolation of NSC, glia and neurons. We isolated a population of NSC that was CD184(+)/CD271(-)/CD44(-)/CD24(+) from neural induction cultures of hESC and human induced pluripotent stem cells (hiPSC). Sorted NSC could be propagated for many passages and could differentiate to mixed cultures of neurons and glia in vitro and in vivo. A population of neurons that was CD184(-)/CD44(-)/CD15(LOW)/CD24(+) and a population of glia that was CD184(+)/CD44(+) were subsequently purified from cultures of differentiating NSC. Purified neurons were viable, expressed mature and subtype-specific neuronal markers, and could fire action potentials. Purified glia were mitotic and could mature to GFAP-expressing astrocytes in vitro and in vivo.These findings illustrate the utility of immunophenotyping screens for the identification of cell surface signatures of neural cells derived from human pluripotent stem cells. These signatures can be used for isolating highly pure populations of viable NSC, glia and neurons by FACS. The methods described here will enable downstream studies that require consistent and defined neural cell populations

Use of double mass curves in hydrologic benefit evaluations

Environmental change resulting from intensified human interventions and climate change has impacted the hydrological function of many large river systems, largely altering the production and transport of run-off and sediment. It is thus vital to quantitatively evaluate the influence of climate change and human activities on streamflow and sediment discharge. Water balance equations, hydrological models, and comparative analyses are commonly used to fulfil this need. Double mass curves (DMCs), being one useful method for comparative analyses, are characterized by low data requirements and high transferability, and thus more practical than water balance equations and hydrological models for hydrologic benefit evaluations. However, the detailed derivation procedure of the DMC has, to date, yet been described in literature. Moreover, in previous studies, changing points of the DMC were determined either rather empirically or as the changing point of streamflow or sediment discharge (i.e., precipitation was not considered). Hence, the changing point detected may be subject to inaccuracies. This paper, for the first time, comprehensively detailed the derivation procedure of the DMC; a new way was proposed to quantitatively examine the changing point of the DMC; an example was also given to demonstrate the use of the DMC in the hydrologic benefit evaluation. It is hopeful that the method given in our paper will be widely adopted by future studies as a standard procedure to derive and use the DMC