Loss of vesicular dopamine release precedes tauopathy in degenerative dopaminergic neurons in a Drosophila model expressing human tau.

While a number of genome-wide association studies have identified microtubule-associated protein tau as a strong risk factor for Parkinson's disease (PD), little is known about the mechanism through which human tau can predispose an individual to this disease. Here, we demonstrate that expression of human wild-type tau is sufficient to disrupt the survival of dopaminergic neurons in a Drosophila model. Tau triggers a synaptic pathology visualized by vesicular monoamine transporter-pHGFP that precedes both the age-dependent formation of tau-containing neurofibrillary tangle-like pathology and the progressive loss of DA neurons, thereby recapitulating the pathological hallmarks of PD. Flies overexpressing tau also exhibit progressive impairments of both motor and learning behaviors. Surprisingly, contrary to common belief that hyperphosphorylated tau could aggravate toxicity, DA neuron degeneration is alleviated by expressing the modified, hyperphosphorylated tau(E14). Together, these results show that impairment of VMAT-containing synaptic vesicle, released to synapses before overt tauopathy may be the underlying mechanism of tau-associated PD and suggest that correction or prevention of this deficit may be appropriate targets for early therapeutic intervention

Economic Reforms and Growth in Franco’s Spain

This paper is an attempt at assessing the economic impact of market-oriented reforms undertaken during General Franco’s dictatorship, in particular, the 1959 Stabilization and Liberalization Plan. Using an index of macroeconomic distortions (IMD) the relationship between economic policies and the growth record is examined. Although a gradual reduction in macroeconomic distortions was already in motion during the 1950s, the 1959 Plan opened the way to a new institutional design that favoured a free-market allocation of resources and allowed Spain to accelerate growth and catch up with Western Europe. Without the 1950s reforms and, especially, the 1959 Plan, per capita GDP would have been significantly lower in 1975Spain, Franco’s dictatorship, Economic reforms, Stabilization, Liberalization, Growth

Infinite compressibility states in the Hierarchical Reference Theory of fluids. II. Numerical evidence

Continuing our investigation into the Hierarchical Reference Theory of fluids for thermodynamic states of infinite isothermal compressibility kappa[T] we now turn to the available numerical evidence to elucidate the character of the partial differential equation: Of the three scenarios identified previously, only the assumption of the equations turning stiff when building up the divergence of kappa[T] allows for a satisfactory interpretation of the data. In addition to the asymptotic regime where the arguments of part I (cond-mat/0308467) directly apply, a similar mechanism is identified that gives rise to transient stiffness at intermediate cutoff for low enough temperature. Heuristic arguments point to a connection between the form of the Fourier transform of the perturbational part of the interaction potential and the cutoff where finite difference approximations of the differential equation cease to be applicable, and they highlight the rather special standing of the hard-core Yukawa potential as regards the severity of the computational difficulties.Comment: J. Stat. Phys., in press. Minor changes to match published versio

Convergence of Amyloid-β and Tau Pathologies on Mitochondria In Vivo

The histopathological characteristics of Alzheimer's disease (AD) are amyloid-β (Aβ) containing plaques and neurofibrillary tangles (NFTs) as well as neuronal and synaptic loss. Until today, the underlying mechanisms of the interplay of plaques and tangles remained unresolved. There is increasing evidence that mitochondrial dysfunction might be a possible link, as revealed by studies in several APP and tau transgenic mouse models. Recently, we examined mitochondrial function in a novel triple transgenic mouse model (pR5/APP/PS2)—tripleAD mice—that combines both pathologic features of the disease in brain. Using comparative, quantitative proteomics (iTRAQ) and mass spectroscopy, we found a massive deregulation of 24 proteins, of which one third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Remarkably, deregulation of complex I was related to tau, whereas deregulation of complex IV was Aβ dependent, both at the protein and activity levels. The tripleAD mice showed synergistic effects of Aβ and tau already at the age of 8months, resulting in a depolarized mitochondrial membrane potential. At 12months, the strongest defects on OXPHOS, synthesis of ATP and reactive oxygen species, were exhibited in the tripleAD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in impairing mitochondria. This review highlights the convergence of Aβ and tau on mitochondria and establishes a molecular link in AD pathology in viv

Convergence of Amyloid-β and Tau Pathologies on Mitochondria In Vivo

The histopathological characteristics of Alzheimer’s disease (AD) are amyloid-β (Aβ) containing plaques and neurofibrillary tangles (NFTs) as well as neuronal and synaptic loss. Until today, the underlying mechanisms of the interplay of plaques and tangles remained unresolved. There is increasing evidence that mitochondrial dysfunction might be a possible link, as revealed by studies in several APP and tau transgenic mouse models. Recently, we examined mitochondrial function in a novel triple transgenic mouse model (pR5/APP/PS2)—tripleAD mice—that combines both pathologic features of the disease in brain. Using comparative, quantitative proteomics (iTRAQ) and mass spectroscopy, we found a massive deregulation of 24 proteins, of which one third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Remarkably, deregulation of complex I was related to tau, whereas deregulation of complex IV was Aβ dependent, both at the protein and activity levels. The tripleAD mice showed synergistic effects of Aβ and tau already at the age of 8 months, resulting in a depolarized mitochondrial membrane potential. At 12 months, the strongest defects on OXPHOS, synthesis of ATP and reactive oxygen species, were exhibited in the tripleAD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in impairing mitochondria. This review highlights the convergence of Aβ and tau on mitochondria and establishes a molecular link in AD pathology in vivo

Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

Frontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC)-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies

Probiotics for Preventing Cognitive Impairment in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disease that results in gradual cognitive impairment and eventually leads to dementia. However, despite AD being one of the most prevalent neurodegenerative diseases in aging societies, no clinically successful therapeutic strategies for its treatment or prevention have been reported to date. Studies have indicated that gut microbial alterations are linked to AD. Probiotics are living microorganisms that are known to confer health benefits to the host when ingested in adequate amounts. Certain strains of probiotics appear to influence the central nervous system (CNS) and behavior via the microbiota-gut-brain axis. Increasing evidence from preclinical and clinical studies has demonstrated that probiotics possess preventive as well as therapeutic potential for AD. It is speculated that probiotics could ameliorate the progression of AD by modulating the inflammatory process, counteracting oxidative stress, and other possible mechanisms, although further studies are needed to understand the details. In this chapter, we will highlight the current understandings of the effects as well as the possible mechanisms of action of probiotics for preventing cognitive impairment in AD

Chemical underpinning of the tea bag index: An examination of the decomposition of tea leaves

Decomposition is a key flux of terrestrial carbon to the atmosphere. Therefore, gaining a better understanding of how plant litter decomposes in soil, and what governs this process, is vital for global climate models. The Tea Bag Index (TBI) was introduced by Keuskamp et al. (2013) as a novel method for measuring litter decomposition rate and stabilisation. The TBI uses two types of tea bags representing fast (green tea) and slow (rooibos tea) decomposition substrates as standardised litter bags. To date, the TBI method has been used in over 2000 locations across the globe. However, before now, there has been no information on how the composition of the tea leaves change during incubation. These data are crucial in determining the validity of the use of the TBI method globally, to ensure the tea leaves decompose in a way that is representative of so-called “native” litters. To provide chemical underpinning of the TBI method, a laboratory incubation of the tea bags was conducted with destructive sampling at 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, and 91 d. The incubated tea was analysed for total C and N. In addition, C was characterised as alkyl, O-alkyl, aromatic, or carbonyl C using solid-state 13C nuclear magnetic resonance spectroscopy with cross-polarization and magic angle spinning (CPMAS NMR). The results suggest that changes in carbon in both tea types are comparable to other litter studies, with a net decrease in total C and relative proportion of O-alkyl C fraction, which contains carbohydrates and cellulose. We conclude that the decomposition of tea leaves in the bags used in the TBI is representative of other litters

Tau inhibits mitochondrial calcium efflux and makes neurons vulnerable to calciuminduced cell death

Aggregation or phosphorylation of the microtubule-associated protein tau is the pathological hallmark in a number of diseases termed tauopathies, which include the most common neurodegenerative disorder, Alzheimer’s disease; or frontotemporal dementia, linked to mutations in the gene MAPT encoding tau. Although misfolded tau has strong familial and histopathological (as in intracellular tangles) association with neurodegenerative disorders, the cellular mechanism of tau-induced pathology remains to be controversial. Here we studied the effect of tau on the cytosolic and mitochondrial calcium homeostasis using primary cortical cultures treated with the protein and iPSC-derived neurons bearing the 10 + 16 MAPT mutation linked to frontotemporal dementia. We found that incubation of the primary cortical co-cultures of neurons and astrocytes with tau induced spontaneous Ca2+ oscillations in the neurons, which were also observed in iPSC-neurons with the 10 + 16 MAPT mutation. Importantly, tau inhibited mitochondrial calcium efflux via the mitochondrial Na+/Ca2+ exchanger (NCLX) in both neurons and astrocytes. This inhibition led to mitochondrial depolarisation in response to physiological and pathological calcium stimuli and made these cells vulnerable to calcium-induced caspase 3 activation and cell death. Thus, inhibition of the mitochondrial NCLX in neurons with misfolded or mutated tau can be involved in the mechanism of neurodegeneration.EB was supported with an EMBO short-term fellowship (number 7834) for the development of this project. The work was supported by EPSRC grant EP/R024898/1

ER stress and UPR in Alzheimer's disease : mechanisms, pathogenesis, treatments

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by gradual loss of memory and cognitive function, which constitutes a heavy burden on the healthcare system globally. Current therapeutics to interfere with the underlying disease process in AD is still under development. Although many efforts have centered on the toxic forms of A beta to effectively tackle AD, considering the unsatisfactory results so far it is vital to examine other targets and therapeutic approaches as well. The endoplasmic reticulum (ER) stress refers to the build-up of unfolded or misfolded proteins within the ER, thus, perturbing the ER and cellular homeostasis. Emerging evidence indicates that ER stress contributes to the onset and development of AD. A thorough elucidation of ER stress machinery in AD pathology may help to open up new therapeutic avenues in the management of this devastating condition to relieve the cognitive dementia symptoms. Herein, we aim at deciphering the unique role of ER stress in AD pathogenesis, reviewing key findings, and existing controversy in an attempt to summarize plausible therapeutic interventions in the management of AD pathophysiology.Peer reviewe