23 research outputs found

    Dendritic Spine Loss and Synaptic Alterations in Alzheimer's Disease

    Get PDF
    Dendritic spines are tiny protrusions along dendrites, which constitute major postsynaptic sites for excitatory synaptic transmission. These spines are highly motile and can undergo remodeling even in the adult nervous system. Spine remodeling and the formation of new synapses are activity-dependent processes that provide a basis for memory formation. A loss or alteration of these structures has been described in patients with neurodegenerative disorders such as Alzheimer's disease (AD), and in mouse models for these disorders. Such alteration is thought to be responsible for cognitive deficits long before or even in the absence of neuronal loss, but the underlying mechanisms are poorly understood. This review will describe recent findings and discoveries on the loss or alteration of dendritic spines induced by the amyloid β (Aβ) peptide in the context of A

    Predicting stem cell fate changes by differential cell cycle progression patterns

    Get PDF
    Stem cell self-renewal, commitment and reprogramming rely on a poorly understood coordination of cell cycle progression and execution of cell fate choices. Using existing experimental paradigms, it has not been possible to probe this relationship systematically in live stem cells in vitro or in vivo. Alterations in stem cell cycle kinetics probably occur long before changes in phenotypic markers are apparent and could be used as predictive parameters to reveal changes in stem cell fate. To explore this intriguing concept, we developed a single-cell tracking approach that enables automatic detection of cell cycle phases in live (stem) cells expressing fluorescent ubiquitylation-based cell-cycle indicator (FUCCI) probes. Using this tool, we have identified distinctive changes in lengths and fluorescence intensities of G1 (red fluorescence) and S/G2-M (green) that are associated with self-renewal and differentiation of single murine neural stem/progenitor cells (NSCs) and embryonic stem cells (ESCs). We further exploited these distinctive features using fluorescence-activated cell sorting to select for desired stem cell fates in two challenging cell culture settings. First, as G1 length was found to nearly double during NSC differentiation, resulting in progressively increasing red fluorescence intensity, we successfully purified stem cells from heterogeneous cell populations by their lower fluorescence. Second, as ESCs are almost exclusively marked by the green (S/G2-M) FUCCI probe due to their very short G1, we substantially augmented the proportion of reprogramming cells by sorting green cells early on during reprogramming from a NSC to an induced pluripotent stem cell state. Taken together, our studies begin to shed light on the crucial relationship between cell cycle progression and fate choice, and we are convinced that the presented approach can be exploited to predict and manipulate cell fate in a wealth of other mammalian cell systems

    Changes in readthrough acetylcholinesterase expression modulate amyloid-beta pathology

    Get PDF
    Alzheimer's disease has long been known to involve cholinergic deficits, but the linkage between cholinergic gene expression and the Alzheimer's disease amyloid pathology has remained incompletely understood. One known link involves synaptic acetylcholinesterase (AChE-S), shown to accelerate amyloid fibrils formation. Here, we report that the ‘Readthrough' AChE-R splice variant, which differs from AChE-S in its 26 C-terminal residues, inversely exerts neuroprotective effects from amyloid β (Aβ) induced toxicity. In vitro, highly purified AChE-R dose-dependently suppressed the formation of insoluble Aβ oligomers and fibrils and abolished Aβ toxicity to cultured cells, competing with the prevalent AChE-S protein which facilitates these processes. In vivo, double transgenic APPsw/AChE-R mice showed lower plaque burden, fewer reactive astrocytes and less dendritic damage than single APPsw mice, inverse to reported acceleration of these features in double APPsw/AChE-S mice. In hippocampi from Alzheimer's disease patients (n = 10), dentate gyrus neurons showed significantly elevated AChE-R mRNA and reduced AChE-S mRNA. However, immunoblot analyses revealed drastic reductions in the levels of intact AChE-R protein, suggesting that its selective loss in the Alzheimer's disease brain exacerbates the Aβ-induced damages and revealing a previously unforeseen linkage between cholinergic and amyloidogenic event

    Dendritic spine loss and synaptic alterations in Alzheimer's disease

    Full text link
    Dendritic spines are tiny protrusions along dendrites, which constitute major postsynaptic sites for excitatory synaptic transmission. These spines are highly motile and can undergo remodeling even in the adult nervous system. Spine remodeling and the formation of new synapses are activity-dependent processes that provide a basis for memory formation. A loss or alteration of these structures has been described in patients with neurodegenerative disorders such as Alzheimer's disease (AD), and in mouse models for these disorders. Such alteration is thought to be responsible for cognitive deficits long before or even in the absence of neuronal loss, but the underlying mechanisms are poorly understood. This review will describe recent findings and discoveries on the loss or alteration of dendritic spines induced by the amyloid beta (Abeta) peptide in the context of AD

    Metabolic control of adult neural stem cell behavior

    Full text link
    Neural stem cells generate new neurons throughout life in distinct regions of the mammalian brain. This process, called adult neurogenesis, is important for tissue homeostasis and physiological brain function. In addition, failing or altered neurogenesis has been associated with a number of diseases such as major depression and epilepsy. Thus, understanding the molecular mechanisms governing the neurogenic process in the adult brain may enable future therapeutic approaches to target neural stem/progenitor cells (NSPCs) and their progeny to ameliorate disease symptoms and/or disease progression. Recently, the control of cellular metabolism has emerged as a regulator of NSPC activity in the adult brain. Here we review recent findings that attempt to describe stage-specific modulations of metabolism to ensure proper neurogenesis and suggest future avenues of research aiming to understand how metabolism affects NSPC behavior

    Metabolism and neurogenesis

    Full text link
    The generation of neurons in the developing and adult mammalian brain by neural stem/progenitor cells (NSPCs) depends on a tight control of NSPC activity and neuronal differentiation that is regulated by a plethora of intrinsic and extrinsic molecular cues. Besides well-studied morphogenic signaling pathways and transcriptional codes that govern the distinct developmental steps from the dividing NSPC to a functional neuron, a critical role of cellular metabolism to determine the functional properties of NSPCs and newborn neurons has been recently identified. Here, we review advances in our understanding of how metabolism affects NSPC behavior and subsequent neuronal differentiation and suggest how metabolism may serve as a common signal integrator to ensure life-long addition of new neurons in the mammalian brain

    Metabolic control of adult neural stem cell behavior

    No full text
    Neural stem cells generate new neurons throughout life in distinct regions of the mammalian brain. This process, called adult neurogenesis, is important for tissue homeostasis and physiological brain function. In addition, failing or altered neurogenesis has been associated with a number of diseases such as major depression and epilepsy. Thus, understanding the molecular mechanisms governing the neurogenic process in the adult brain may enable future therapeutic approaches to target neural stem/progenitor cells (NSPCs) and their progeny to ameliorate disease symptoms and/or disease progression. Recently, the control of cellular metabolism has emerged as a regulator of NSPC activity in the adult brain. Here we review recent findings that attempt to describe stage-specific modulations of metabolism to ensure proper neurogenesis and suggest future avenues of research aiming to understand how metabolism affects NSPC behavior
    corecore