Public space is increasingly recognised to be central to spatial discourse of cities. A city’s urbanism is displayed in public spaces, representing a myriad of complex socio-cultural, economic and ...democratic practices of everyday life. In cities of the Global South, especially those with nascent democracies, different values attached to a space by various actors – both material and symbolic – frame the contestation, making the physical space a normative instrument for contestation. Tundikhel, once believed to be the largest open space in Asia, is an important part of Kathmandu’s urbanism, which has witnessed two civil wars popularly known as Jana Andolans, and the subsequent political upheavals, to emerge as the symbolic meeting point of the city, democracy, and its people. The paper argues that the confluence of the three modalities of power – institutionalisation, militarisation and informalisation – has underpinned its historical transformation, resulting in what I call ‘urban rupturing’: a process of (un)making of public space, through physical and symbolic fragmentation and spatial estrangement. The paper contends that unlike the common notion that public spaces such as Tundikhel are quintessentially public, hypocrisy is inherent to the ‘publicness’ agenda of the state and the institutional machinery in Kathmandu. It is an urban condition that not only maligns the public space agenda but also creeps into other spheres of urban development.
人们日益认识到，公共空间对于城市的空间话语发挥核心作用。一个城市的都市风貌展现 在公共空间中，它们代表了日常生活中纷繁复杂的社会文化、经济和民主实践。在南半球 城市，尤其是那些新建立民主政体的国家，不同的行动者对空间赋予了物质上和象征意义 上的不同价值，这些价值形成了竞争，使得物理空间成为了竞争的一种规范工具。通迪凯 尔广场一度被认为是亚洲最大的公共空间，是加德满都城市风貌的重要组成部分。这一广 场见证了通常称为“人民运动” 的两场内战以及随后的政治动乱，成为了该城市、民主活 动及其人民的象征性集会点。本文认为，体制化、军事化和非正规化这三种权力模式的汇 流，支撑了通迪凯尔广场的历史转型，导致了笔者称为“城市撕裂” 的过程，即通过物理 和象征意义的碎片化和空间的异化塑造（消解）公共空间。一般认为，像通迪凯尔广场这 样的公共空间在本质上是公共的，而本文则指出，伪善内在于加德满都政府的“公共性” 日程和体制机器中。这种都市状况不仅有害公共空间的发展，也潜入了城市发展的其他领 域。
Oligomeric assemblies of tau and the RNA-binding proteins (RBPs) Musashi (MSI) are reported in Alzheimer's disease (AD). However, the role of MSI and tau interaction in their aggregation process and ...its effects are nor clearly known in neurodegenerative diseases. Here, we investigated the expression and cellular localization of MSI1 and MSI2 in the brains tissues of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as in the wild-type mice and tau knock-out and P301L tau mouse models. We observed that formation of pathologically relevant protein inclusions was driven by the aberrant interactions between MSI and tau in the nuclei associated with age-dependent extracellular depositions of tau/MSI complexes. Furthermore, tau and MSI interactions induced impairment of nuclear/cytoplasm transport, chromatin remodeling and nuclear lamina formation. Our findings provide mechanistic insight for pathological accumulation of MSI/tau aggregates providing a potential basis for therapeutic interventions in neurodegenerative proteinopathies.
The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD) patients remains an area of contention. Innovative data are emerging from ...biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate.
Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I), and activated caspase-9, which is related to the apoptotic mitochondrial pathway.
This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.
Neurofibrillary tangles (NFTs) are a pathological hallmark of Alzheimer's disease (AD); however, the relationship between NFTs and disease progression remains controversial. Analyses of tau animal ...models suggest that phenotypes coincide with accumulation of soluble aggregated tau species but not the accumulation of NFTs. The pathological role of prefilamentous tau aggregates, e.g., tau oligomeric intermediates, is poorly understood, in part because of methodological challenges. Here, we engineered a novel tau oligomer‐specific antibody, T22, and used it to elucidate the temporal course and biochemical features of oligomers during NFT development in AD brain. We found that tau oligomers in human AD brain samples were 4‐fold higher than those in the controls. We also revealed the role of oligomeric tau conformers in pretangles, neuritic plaques, and neuropil threads in the frontal cortex tissue from AD brains; this analysis uncovers a consistent code that governs tau oligomerization with regard to degree of neuronal cytopathology. These data are the first to characterize the role of tau oligomers in the natural history of NFTs, and they highlight the suitability of tau oligomers as therapeutic targets in AD and related tauopathies.—Lasagna‐Reeves, C. A., Castillo‐Carranza, D. L., Sengupta, U., Troncoso, J., Jackson, G. R., Kayed, R. Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. FASEB J. 26, 1946‐1959 (2012). www.fasebj.org
The pathological hallmark of synucleinopathies, including Parkinson’s disease (PD), is the aggregation of α-synuclein (α-Syn) protein. Even so, tau protein pathology is abundantly found in these ...diseases. Both α-Syn and tau can exist as polymorphic aggregates, a phenomenon that has been widely studied, mostly in their fibrillar assemblies. We have previously discovered that in addition to α-Syn oligomers, oligomeric tau is also present in the brain tissues of patients with PD and dementia with Lewy bodies (DLB). However, the effect of interaction between polymorphic α-Syn oligomers and tau has not been scrupulously studied. Here, we have explored the structural and functional diversity of distinct α-Syn oligomers, prepared by modifying the protein with dopamine (DA) and docosahexaenoic acid (DHA). The two α-Syn oligomers differed in aggregate size, conformation, sensitivity to proteinase K digestion, tryptic digestion, and toxicity, suggesting them as distinct α-Syn oligomeric strains. We examined their internalization mechanisms in primary neurons and seeding propensity in inducing α-Syn aggregation. Using a combined approach of molecular and cellular techniques, we observed that the tau aggregates cross-seeded with the individual α-Syn oligomeric strains differed in their biochemical and biological properties, suggesting two distinct tau strains. The tau aggregate cross-seeded with the DA-modified α-Syn oligomeric strain possessed a potent intracellular tau seeding propensity. This study provides a comprehensive analysis of unique strain-specific interaction between oligomeric α-Syn and tau. Furthermore, this study allows us to speculate that distinct α-Syn-tau interactions inducing tau aggregation might be an underlying mechanism of neurodegeneration in PD.
Kathmandu is a unique city, not only because of its urban landscape set in a mountain basin with intense agricultural use, but also for the urban culture that has helped to produce distinctive ...architecture and built form. The book is not just about documentary evidence; it is also about stirring contemporary debate on town planning issues.
Tau aggregates propagate in brain cells and transmit to neighboring cells as well as anatomically connected brain regions by prion-like mechanisms. Soluble tau aggregates (tau oligomers) are the most ...toxic species that initiate neurodegeneration in tauopathies, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Exogenous tau aggregates have been shown to be internalized by brain cells; however, the precise cellular and molecular mechanisms that underlie the internalization of tau oligomers (TauO) remain elusive. Using brain-derived tau oligomers (BDTOs) from AD, PSP, and DLB patients, we investigated neuronal internalization mechanisms of BDTOs, including the heparan sulfate proteoglycan (HSPG)-mediated pathway, clathrin-mediated pathway, and caveolae-mediated pathway. Here, we demonstrated that the HSPG-mediated pathway regulates internalization of BDTOs from AD and DLB, while HSPG-mediated and other alternative pathways are involved in the internalization of PSP-derived tau oligomers. HSPG antagonism significantly reduced the internalization of TauO, prevented tau translocation to the endosomal-lysosomal system, and decreased levels of hyperphosphorylated tau in neurons, the well-known contributor for neurofibrillary tangles (NFT) accumulation, degeneration of neurons, and cognitive decline. Furthermore, siRNA-mediated silencing of heparan sulfate (HS)-synthesizing enzyme, exostosin-2, leads to decreased internalization of BDTOs, prevented tau-induced autophagy-lysosomal pathway impairment, and decreased hyperphosphorylated tau levels. Collectively, these findings suggest that HSPG-mediated endocytosis and exostsin-2 are involved in neuronal internalization of TauO and subsequent tau-dependent neuropathology in AD and DLB.
Proteinaceous aggregates are major hallmarks of several neurodegenerative diseases. Aggregates of post-translationally modified transactive response (TAR)-DNA binding protein 43 (TDP-43) in ...cytoplasmic inclusion bodies are characteristic features in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent studies have also reported TDP-43 aggregation in Alzheimer's disease (AD). TDP-43 is an RNA/DNA binding protein (RBP) mainly present in the nucleus. In addition to several RBPs, TDP-43 has also been reported in stress granules in FTD and ALS pathologies. Despite knowledge of cytoplasmic mislocalization of TDP-43, the cellular effects of TDP-43 aggregates and their cytotoxic mechanism(s) remain to be clarified. We hypothesize that TDP-43 forms oligomeric assemblies that associate with tau, another key protein involved in ALS and FTD. However, no prior studies have investigated the interactions between TDP-43 oligomers and tau. It is therefore important to thoroughly investigate the cross-seeding properties and cellular localization of both TDP-43 and tau oligomers in neurodegenerative diseases. Here, we demonstrate the effect of tau on the cellular localization of TDP-43 in WT and P301L tau-inducible cell models (iHEK) and in WT HEK-293 cells treated exogenously with soluble human recombinant tau oligomers (Exo-rTauO). We observed cytoplasmic TDP-43 accumulation o in the presence of tau in these cell models. We also studied the occurrence of TDP-43 oligomers in AD, ALS, and FTD human brain tissue using novel antibodies generated against TDP-43 oligomers as well as generic TDP-43 antibodies. Finally, we examined the cross-seeding property of AD, ALS, and FTD brain-derived TDP-43 oligomers (BDT43Os) on tau aggregation using biochemical and biophysical assays. Our results allow us to speculate that TDP-43/tau interactions might play a role in AD, ALS, and FTD.
•TDP-43 oligomers occur in AD, ALS and FTD pathologies.•Tau modulates TDP-43 cellular localization and oligomerization.•Brain-derived TDP-43 oligomers can act as seeds for tau oligomerization in vitro.
With increasing age, as the incidence of Alzheimer's disease is increasing, finding a therapeutic intervention is becoming critically important to either prevent or slow down the progression of the ...disease. Passive immunotherapy has been demonstrated as a successful way of reducing large aggregates and improving cognition in animal models of both tauopathies and Alzheimer's disease. However, with all the continuous attempts and significant success of immunotherapy in preclinical studies, finding a successful clinical therapy has been a great challenge, possibly indicating a lack of accuracy in targeting the toxic species. Both active and passive immunotherapy approaches in transgenic animals have been demonstrated to have pros and cons. Passive immunotherapy has been favored and many mechanisms have been shown to clear toxic amyloid and tau aggregates and improve memory. These mechanisms may differ depending on the antibodie's' target and administration route. In this regard, deciding on affinity vs. specificity of the antibodies plays a significant role in terms of avoiding the clearance of the physiological forms of the targeted proteins and reducing adverse side effects. In addition, knowing that a single protein can exist in different conformational states, termed as strains, with varying degrees of neurotoxicity and seeding properties, presents an additional level of complexity. Therefore, immunotherapy targeting specifically the toxic strains will aid in developing potential strategies for intervention. Moreover, an approach of combinatorial immunotherapies against different amyloidogenic proteins, at distinct levels of the disease progression, might offer an effective therapy in many neurodegenerative diseases.
Abstract
The microtubule-associated protein tau is implicated in the formation of oligomers and fibrillar aggregates that evade proteostasis control and spread from cell-to-cell. Tau pathology is ...accompanied by sustained neuroinflammation and, while the release of alarmin mediators aggravates disease at late stages, early inflammatory responses encompass protective functions. This is the case of the Ca
2+
-binding S100B protein, an astrocytic alarmin which is augmented in AD and which has been recently implicated as a proteostasis regulator, acting over amyloid β aggregation. Here we report the activity of S100B as a suppressor of tau aggregation and seeding, operating at sub-stoichiometric conditions. We show that S100B interacts with tau in living cells even in microtubule-destabilizing conditions. Structural analysis revealed that tau undergoes dynamic interactions with S100B, in a Ca
2+
-dependent manner, notably with the aggregation prone repeat segments at the microtubule binding regions. This interaction involves contacts of tau with a cleft formed at the interface of the S100B dimer. Kinetic and mechanistic analysis revealed that S100B inhibits the aggregation of both full-length tau and of the microtubule binding domain, and that this proceeds through effects over primary and secondary nucleation, as confirmed by seeding assays and direct observation of S100B binding to tau oligomers and fibrils. In agreement with a role as an extracellular chaperone and its accumulation near tau positive inclusions, we show that S100B blocks proteopathic tau seeding. Together, our findings establish tau as a client of the S100B chaperone, providing evidence for neuro-protective functions of this inflammatory mediator across different tauopathies.
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