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[...]a substantial increase in long-term funding for multidisciplinary research programmes is absolutely essential to reduce the burden of individual suffering and the enormous societal cost of AD. In 2015, almost 47 million people worldwide were estimated to be affected by dementia, and the numbers are expected to reach 75 million by 2030, and 131 million by 2050, with the greatest increase expected in low-income and middle-income countries.2 In 2012 and 2015, the World Health Organization (WHO) presented reports in which it acknowledged this trend--sometimes described in terms of a fast-growing epidemic--and concluded that AD and other dementias should be regarded as a global public health priority.3,4 Similar policy declarations have been made by the European Union5 (EU) and by some individual countries. Care for people with dementia is provided by several sectors in society, with the social-care (long-term care and home services) and informal-care (provided by non-professional caregivers) sectors accounting for the greatest proportion of costs--even greater than the cost of direct medical care.6 In cost-of-illness studies, total societal cost estimates for dementia in Europe in 2010 were between $238·6 billion6 and [euro]105·6 billion.7 The economic costs of caring for a growing number of people with AD and other dementias are formidable, but the combined economic and societal burden of dementia is more daunting still, corresponding to the aggregate burden of people with dementia and their next of kin.

Topological crystalline insulators are a novel state of matter in which the topological features of the electronic structure have been predicted to originate from crystal symmetries. Now an experimental realization of a topological crystalline insulator is reported, in the form of Pb 1− x Sn x Se. Topological insulators are a class of quantum materials in which time-reversal symmetry, relativistic effects and an inverted band structure result in the occurrence of electronic metallic states on the surfaces of insulating bulk crystals. These helical states exhibit a Dirac-like energy dispersion across the bulk bandgap, and they are topologically protected. Recent theoretical results have suggested the existence of topological crystalline insulators (TCIs), a class of topological insulators in which crystalline symmetry replaces the role of time-reversal symmetry in ensuring topological protection 1 , 2 . In this study we show that the narrow-gap semiconductor Pb 1− x Sn x Se is a TCI for x = 0.23. Temperature-dependent angle-resolved photoelectron spectroscopy demonstrates that the material undergoes a temperature-driven topological phase transition from a trivial insulator to a TCI. These experimental findings add a new class to the family of topological insulators, and we anticipate that they will lead to a considerable body of further research as well as detailed studies of topological phase transitions.

Since the advent of topological insulators hosting Dirac surface states, efforts have been made to gap these states in a controllable way. A new route to accomplish this was opened up by the discovery of topological crystalline insulators where the topological states are protected by crystal symmetries and thus prone to gap formation by structural changes of the lattice. Here we show a temperature-driven gap opening in Dirac surface states within the topological crystalline insulator phase in (Pb,Sn)Se. By using angle-resolved photoelectron spectroscopy, the gap formation and mass acquisition is studied as a function of composition and temperature. The resulting observations lead to the addition of a temperature- and composition-dependent boundary between massless and massive Dirac states in the topological phase diagram for (Pb,Sn)Se (001). Overall, our results experimentally establish the possibility to tune between massless and massive topological states on the surface of a topological system. The opening of a Dirac point gap in topologically non-trivial materials is key to potential applications. Here, the authors use photoelectron spectroscopy to study gap formation and carrier mass acquisition in a topological crystalline insulator as a function of composition and temperature.

The minimal ingredients to explain the essential physics of layered copper-oxide (cuprates) materials remains heavily debated. Effective low-energy single-band models of the copper–oxygen orbitals are widely used because there exists no strong experimental evidence supporting multi-band structures. Here, we report angle-resolved photoelectron spectroscopy experiments on La-based cuprates that provide direct observation of a two-band structure. This electronic structure, qualitatively consistent with density functional theory, is parametrised by a two-orbital ( d x 2 - y 2 and d z 2 ) tight-binding model. We quantify the orbital hybridisation which provides an explanation for the Fermi surface topology and the proximity of the van-Hove singularity to the Fermi level. Our analysis leads to a unification of electronic hopping parameters for single-layer cuprates and we conclude that hybridisation, restraining d -wave pairing, is an important optimisation element for superconductivity. The essential physics of cuprate superconductors is often described by single-band models. Here, Matt et al. report direct observation of a two-band electronic structure in La-based cuprates.

Background Increased levels of the pathogenic amyloid β-peptide (Aβ), released from its precursor by the transmembrane protease γ-secretase, are found in Alzheimer disease (AD) brains. Interestingly, monoamine oxidase B (MAO-B) activity is also increased in AD brain, but its role in AD pathogenesis is not known. Recent neuroimaging studies have shown that the increased MAO-B expression in AD brain starts several years before the onset of the disease. Here, we show a potential connection between MAO-B, γ-secretase and Aβ in neurons. Methods MAO-B immunohistochemistry was performed on postmortem human brain. Affinity purification of γ-secretase followed by mass spectrometry was used for unbiased identification of γ-secretase-associated proteins. The association of MAO-B with γ-secretase was studied by coimmunoprecipitation from brain homogenate, and by in-situ proximity ligation assay (PLA) in neurons as well as mouse and human brain sections. The effect of MAO-B on Aβ production and Notch processing in cell cultures was analyzed by siRNA silencing or overexpression experiments followed by ELISA, western blot or FRET analysis. Methodology for measuring relative intraneuronal MAO-B and Aβ42 levels in single cells was developed by combining immunocytochemistry and confocal microscopy with quantitative image analysis. Results Immunohistochemistry revealed MAO-B staining in neurons in the frontal cortex, hippocampus CA1 and entorhinal cortex in postmortem human brain. Interestingly, the neuronal staining intensity was higher in AD brain than in control brain in these regions. Mass spectrometric data from affinity purified γ-secretase suggested that MAO-B is a γ-secretase-associated protein, which was confirmed by immunoprecipitation and PLA, and a neuronal location of the interaction was shown. Strikingly, intraneuronal Aβ42 levels correlated with MAO-B levels, and siRNA silencing of MAO-B resulted in significantly reduced levels of intraneuronal Aβ42. Furthermore, overexpression of MAO-B enhanced Aβ production. Conclusions This study shows that MAO-B levels are increased not only in astrocytes but also in pyramidal neurons in AD brain. The study also suggests that MAO-B regulates Aβ production in neurons via γ-secretase and thereby provides a key to understanding the relationship between MAO-B and AD pathogenesis. Potentially, the γ-secretase/MAO-B association may be a target for reducing Aβ levels using protein–protein interaction breakers.

In Alzheimer's disease (AD), tau undergoes abnormal post‐translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy – targeted protein degradation – recently emerged as a modality in drug discovery where bifunctional molecules bring the target protein close to the degradation machinery to promote clearance. Since 2016, this strategy has been applied to tau pathologies and attracted broad interest in academia and the pharmaceutical industry. However, a systematic review of recent studies on tau degradation mechanisms is lacking. Here we review tau degradation mechanisms (the ubiquitin–proteasome system and the autophagy–lysosome pathway), their dysfunction in AD, and tau‐targeted degraders, such as proteolysis‐targeting chimeras and autophagy‐targeting chimeras. We emphasize the need for a continuous exploration of tau degradation mechanisms and provide a future perspective for developing tau‐targeted degraders, encouraging researchers to work on new treatment options for AD patients. Highlights Post‐translational modifications, aggregation, and mutations affect tau degradation. A vicious circle exists between impaired degradation pathways and tau pathologies. Ubiquitin plays an important role in complex degradation pathways. Tau‐targeted degraders provide promising strategies for novel AD treatment.

Background In Alzheimer’s disease (AD), amyloid-β 1–42 (Aβ42) neurotoxicity stems mostly from its soluble oligomeric aggregates. Studies of such aggregates have been hampered by the lack of oligomer-specific research tools and their intrinsic instability and heterogeneity. Here, we developed a monoclonal antibody with a unique oligomer-specific binding profile (ALZ-201) using oligomer-stabilising technology. Subsequently, we assessed the etiological relevance of the Aβ targeted by ALZ-201 on physiologically derived, toxic Aβ using extracts from post-mortem brains of AD patients and controls in primary mouse neuron cultures. Methods Mice were immunised with stable oligomers derived from the Aβ42 peptide with A21C/A30C mutations (AβCC), and ALZ-201 was developed using hybridoma technology. Specificity for the oligomeric form of the Aβ42CC antigen and Aβ42 was confirmed using ELISA, and non-reactivity against plaques by immunohistochemistry (IHC). The antibody’s potential for cross-protective activity against pathological Aβ was evaluated in brain tissue samples from 10 individuals confirmed as AD ( n =7) and non-AD ( n =3) with IHC staining for Aβ and phosphorylated tau (p-Tau) aggregates. Brain extracts were prepared and immunodepleted using the positive control 4G8 antibody, ALZ-201 or an isotype control to ALZ-201. Fractions were biochemically characterised, and toxicity assays were performed in primary mouse neuronal cultures using automated high-content microscopy. Results AD brain extracts proved to be more toxic than controls as demonstrated by neuronal loss and morphological determinants (e.g. synapse density and measures of neurite complexity). Immunodepletion using 4G8 reduced Aβ levels in both AD and control samples compared to ALZ-201 or the isotype control, which showed no significant difference. Importantly, despite the differential effect on the total Aβ content, the neuroprotective effects of 4G8 and ALZ-201 immunodepletion were similar, whereas the isotype control showed no effect. Conclusions ALZ-201 depletes a toxic species in post-mortem AD brain extracts causing a positive physiological and protective impact on the integrity and morphology of mouse neurons. Its unique specificity indicates that a low-abundant, soluble Aβ42 oligomer may account for much of the neurotoxicity in AD. This critical attribute identifies the potential of ALZ-201 as a novel drug candidate for achieving a true, clinical therapeutic effect in AD.

Background Synaptic degeneration and accumulation of amyloid β-peptides (Aβ) are hallmarks of the Alzheimer diseased brain. Aβ is synaptotoxic and produced by sequential cleavage of the amyloid precursor protein (APP) by the β-secretase BACE1 and by γ-secretase. If APP is instead cleaved by the α-secretase ADAM10, Aβ will not be generated. Although BACE1 is considered to be a presynaptic protein and ADAM10 has been reported to mainly localize to the postsynaptic density, we have previously shown that both ADAM10 and BACE1 are highly enriched in synaptic vesicles of rat brain and mouse primary hippocampal neurons. Results Here, using brightfield proximity ligation assay, we expanded our previous result in primary neurons and investigated the in situ synaptic localization of ADAM10 and BACE1 in rat and human adult brain using both pre- and postsynaptic markers. We found that ADAM10 and BACE1 were in close proximity with both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. The substrate APP was also detected both pre- and postsynaptically. Subcellular fractionation confirmed that ADAM10 and BACE1 are enriched to a similar degree in synaptic vesicles and as well as in the postsynaptic density. Conclusions We show that the α-secretase ADAM10 and the β-secretase BACE1 are located in both the pre- and postsynaptic compartments in intact brain sections. These findings increase our understanding of the regulation of APP processing, thereby facilitating development of more specific treatment strategies.

High-temperature superconductivity emerges from an un-conventional metallic state. This has stimulated strong efforts to understand exactly how Fermi liquids breakdown and evolve into an un-conventional metal. A fundamental question is how Fermi liquid quasiparticle excitations break down in momentum space. Here we show, using angle-resolved photoemission spectroscopy, that the Fermi liquid quasiparticle excitations of the overdoped superconducting cuprate La 1.77 Sr 0.23 CuO 4 is highly anisotropic in momentum space. The quasiparticle scattering and residue behave differently along the Fermi surface and hence the Kadowaki–Wood's relation is not obeyed. This kind of Fermi liquid breakdown may apply to a wide range of strongly correlated metal systems where spin fluctuations are present. An outstanding question regarding cuprate superconductors is how the Fermi liquid behaviour of their normal state breaks down. Chang et al . conduct a systematic ARPES study of how the Fermi liquid quasiparticle excitations break down in momentum space, and find it to be highly anisotropic in La 2− x Sr x CuO 4 .

The amyloid-cascade hypothesis posits that the role of amyloid β-peptide (Aβ) in Alzheimer disease (AD) involves polymerization into structures that eventually are deposited as amyloid plaques. During this process, neurotoxic oligomers are formed that induce synaptic loss and neuronal death. Several different isoforms of Aβ are produced, of which the 40 and 42 residue variants (Aβ40 and Aβ42) are the most common. Aβ42 has a strong tendency to form neurotoxic aggregates and is involved in AD pathogenesis. Longer Aβ isoforms, like the less studied Aβ43, are gaining attention for their higher propensity to aggregate into neurotoxic oligomers. To further investigate Aβ43 in AD, we conducted a quantitative study on Aβ43 levels in human brain. We homogenized human brain tissue and prepared fractions of various solubility; tris buffered saline (TBS), sodium dodecyl sulfate (SDS) and formic acid (FA). Levels of Aβ43, as well as Aβ40 and Aβ42, were quantified using ELISA. We compared quantitative data showing Aβ levels in occipital and frontal cortex from sporadic (SAD) and familial (FAD) AD cases, as well as non-demented (ND) controls. Results showed Aβ43 present in each fraction from the SAD and FAD cases, while its level was lower than the detection limit in the majority of the ND-cases. Aβ42 and Aβ43 were enriched in the less soluble fractions (SDS and FA) of SAD and FAD cases in both occipital and frontal cortex. Thus, although the total levels of Aβ43 in human brain are low compared to Aβ40 and Aβ42, we suggest that Aβ43 could initiate the formation of oligomers and amyloid plaques and thereby be crucial to AD pathogenesis.