Tau Deletion Prevents Stress-Induced Dendritic Atrophy in Prefrontal Cortex: Role of Synaptic Mitochondria
TL;DR: Findings provide evidence for a causal role of Tau in mediating stress‐elicited neuronal atrophy and cognitive impairment and indicate that Tau may exert its effects through synaptic mitochondria.
Abstract: Tau protein in dendrites and synapses has been recently implicated in synaptic degeneration and neuronal malfunction. Chronic stress, a well-known inducer of neuronal/synaptic atrophy, triggers hyperphosphorylation of Tau protein and cognitive deficits. However, the cause-effect relationship between these events remains to be established. To test the involvement of Tau in stress-induced impairments of cognition, we investigated the impact of stress on cognitive behavior, neuronal structure, and the synaptic proteome in the prefrontal cortex (PFC) of Tau knock-out (Tau-KO) and wild-type (WT) mice. Whereas exposure to chronic stress resulted in atrophy of apical dendrites and spine loss in PFC neurons as well as significant impairments in working memory in WT mice, such changes were absent in Tau-KO animals. Quantitative proteomic analysis of PFC synaptosomal fractions, combined with transmission electron microscopy analysis, suggested a prominent role for mitochondria in the regulation of the effects of stress. Specifically, chronically stressed animals exhibit Tau-dependent alterations in the levels of proteins involved in mitochondrial transport and oxidative phosphorylation as well as in the synaptic localization of mitochondria in PFC. These findings provide evidence for a causal role of Tau in mediating stress-elicited neuronal atrophy and cognitive impairment and indicate that Tau may exert its effects through synaptic mitochondria.
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TL;DR: Glucose is the long-established, obligatory fuel for brain that fulfills many critical functions, including ATP production, oxidative stress management, and synthesis of neurotransmitters, neuromodulators, and structural components.
Abstract: Glucose is the long-established, obligatory fuel for brain that fulfills many critical functions, including ATP production, oxidative stress management, and synthesis of neurotransmitters, neuromod...
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Abstract: The eigenchannel method, generalizing the familiar phaseshift method, is formulated for scattering from a Hermitian short range potential. Scattering eigenchannels are defined as eigenstates of some generalized (weighted) operator spectral problem. Eigenvalues of that problem define eigenphaseshifts, the former being the negative of cotangents of the latter. Eigenchannel representations of generalized scattering states, transition operators, and Green operators are constructed. A variational approach to the method is also presented. The general theory is illustrated by applications to scattering of Schr€ odinger and Dirac particles. 2003 Elsevier Inc. All rights reserved.
177 citations
TL;DR: Atypical, non-standard roles of Tau on neuronal function and dysfunction in AD and other neurological pathologies providing novel insights about neuroplastic and neuropathological implications of Tau in both the central and the peripheral nervous system are focused on.
Abstract: Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau’s role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer’s disease (AD) brains. In recent years, however, research efforts identified new interaction partners and different sub-cellular localizations for Tau suggesting additional roles beyond its standard function as microtubule regulating protein. Moreover, despite the increasing research focus on AD over the last decades, Tau was only recently considered as a promising therapeutic target for the treatment and prevention of AD as well as for neurological pathologies beyond AD e.g. epilepsy, excitotoxicity, and environmental stress. This review will focus on atypical, non-standard roles of Tau on neuronal function and dysfunction in AD and other neurological pathologies providing novel insights about neuroplastic and neuropathological implications of Tau in both the central and the peripheral nervous system.
157 citations
TL;DR: It is likely that structural changes in dendritic spines are both instigators and results of behavioral changes, and improved research tools and methods are needed to experimentally and directly manipulate spine dynamics in order to more empirically delineate the relationship between spine structure and behavior.
Abstract: Dendritic spines are multifunctional integrative units of the nervous system and are highly diverse and dynamic in nature. Both internal and external stimuli influence dendritic spine density and morphology on the order of minutes. It is clear that the structural plasticity of dendritic spines is related to changes in synaptic efficacy, learning and memory, and other cognitive processes. However, it is currently unclear whether structural changes in dendritic spines are primary instigators of changes in specific behaviors, a consequence of behavioral changes, or both. In this review, we first review the basic structure and function of dendritic spines in the brain, as well as laboratory methods to characterize and quantify morphological changes in dendritic spines. We then discuss the existing literature on the temporal and functional relationship between changes in dendritic spines in specific brain regions and changes in specific behaviors mediated by those regions. Although technological advancements have allowed us to better understand the functional relevance of structural changes in dendritic spines that are influenced by environmental stimuli, the role of spine dynamics as an underlying driver or consequence of behavior still remains elusive. We conclude that while it is likely that structural changes in dendritic spines are both instigators and results of behavioral changes, improved research tools and methods are needed to experimentally and directly manipulate spine dynamics in order to more empirically delineate the relationship between spine structure and behavior.
123 citations
Cites background or methods from "Tau Deletion Prevents Stress-Induce..."
...Spine loss is also associated with brain aging, and there is some evidence of overlap between the mechanisms of spine loss in neurodegenerative diseases such as AD and those induced by chronic stress, namely a critical role for tau proteins (Lopes et al. 2016; Sotiropoulos and Sousa 2016)....
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...2005) among others such as chronic variable or unpredictable stress (Lopes et al. 2016)....
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...Commonly used models include restraint (Esparza et al. 2012; Platt and Stone 1982), footshock (Long and Fanselow 2012), or social defeat stress (Covington et al. 2005) among others such as chronic variable or unpredictable stress (Lopes et al. 2016)....
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TL;DR: Findings indicate the cooperative functions of tau and MAP1B in vivo in axonal elongation and neuronal migration as regulators of microtu-
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References
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TL;DR: Reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Aβ levels, and protected both transgenic and nontransgenic mice against excitotoxicity.
Abstract: Many potential treatments for Alzheimer9s disease target amyloid-β peptides (Aβ), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Aβ-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Aβ levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Aβ- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer9s disease and related conditions.
1,790 citations
"Tau Deletion Prevents Stress-Induce..." refers background or result in this paper
...Previous evidence suggests that Tau ablation has a neuroprotective role against neurotoxic insults such as amyloid beta (Aβ) (Rapoport et al. 2002; Roberson et al. 2007)....
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...The present findings add support to previous indications that Tau reduction or prevention of Tau malfunction could be neuroprotective (Roberson et al. 2007; Vossel et al. 2010) and they suggest a close link between Tau and synaptic mitochondria in themechanisms underlying stress-induced synaptic damage and neuronal malfunction....
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TL;DR: It is shown that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR), which uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity.
1,611 citations
"Tau Deletion Prevents Stress-Induce..." refers background in this paper
...Hyperphosphorylated Tau is strongly associated with synaptic malfunction and loss as well as neuronal degeneration in Alzheimer’s disease (AD) (Kimura et al. 2007; Ittner et al. 2010)....
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...Recently, localization of the Tau protein at the synapses has been reported where Tau is suggested to be involved in the N-methyl-D-aspartate (NMDA) signaling (Ittner et al. 2010; Gotz et al. 2013)....
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...Tau protein, which plays a key role in microtubule stabilization and intracellular cargo trafficking, has recently been shown to be important for the regulation of synaptic plasticity (Ittner et al. 2010; Frandemiche et al. 2014), albeit throughmechanisms that are still poorly understood....
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TL;DR: The mitochondrial metabolism of cancer cells is deregulated owing to the use of glycolytic intermediates, which are normally destined for oxidative phosphorylation, in anabolic reactions and activation of the cell death machinery by stimulating mitochondrial membrane permeabilization could therefore be promising therapeutic approaches.
Abstract: Mitochondria are the cells' powerhouse, but also their suicidal weapon store. Dozens of lethal signal transduction pathways converge on mitochondria to cause the permeabilization of the mitochondrial outer membrane, leading to the cytosolic release of pro-apoptotic proteins and to the impairment of the bioenergetic functions of mitochondria. The mitochondrial metabolism of cancer cells is deregulated owing to the use of glycolytic intermediates, which are normally destined for oxidative phosphorylation, in anabolic reactions. Activation of the cell death machinery in cancer cells by inhibiting tumour-specific alterations of the mitochondrial metabolism or by stimulating mitochondrial membrane permeabilization could therefore be promising therapeutic approaches.
1,458 citations
"Tau Deletion Prevents Stress-Induce..." refers background in this paper
...The implication of mitochondria in the mediation of stress effects via Tau protein encourages exploration of the potential importance of mitochondrial pathways in the search for means to prevent, delay or treat neurodegenerative conditions; it is worth noting that mitochondrial pathways have already been shown to be amenable to pharmacological manipulation in various disease settings (Fulda et al. 2010; Edeas and Weissig 2013), including stress-related pathologies (Nussbaumer et al....
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TL;DR: It is found that nitric oxide produced in response to β-amyloid protein, thought to be a key mediator of Alzheimer's disease, triggered mitochondrial fission, synaptic loss, and neuronal damage, in part via S-nitrosylation of dynamin-related protein 1 (forming SNO-Drp1).
Abstract: Mitochondria continuously undergo two opposing processes, fission and fusion. The disruption of this dynamic equilibrium may herald cell injury or death and may contribute to developmental and neurodegenerative disorders. Nitric oxide functions as a signaling molecule, but in excess it mediates neuronal injury, in part via mitochondrial fission or fragmentation. However, the underlying mechanism for nitric oxide-induced pathological fission remains unclear. We found that nitric oxide produced in response to beta-amyloid protein, thought to be a key mediator of Alzheimer's disease, triggered mitochondrial fission, synaptic loss, and neuronal damage, in part via S-nitrosylation of dynamin-related protein 1 (forming SNO-Drp1). Preventing nitrosylation of Drp1 by cysteine mutation abrogated these neurotoxic events. SNO-Drp1 is increased in brains of human Alzheimer's disease patients and may thus contribute to the pathogenesis of neurodegeneration.
993 citations
"Tau Deletion Prevents Stress-Induce..." refers background in this paper
...Indeed, it is proposed that mitochondria play a key role in conserving synapses (Cho et al. 2009)....
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TL;DR: The results indicate that the reversible atrophy induced by 21 days of daily restraint stress requires corticosterone secretion and that excitatory mechanisms involving N-methyl-D-aspartate receptors play a major role in driving the atrophy.
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