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Alzheimer's disease (AD) is the most prevalent form of dementia and is characterised by a progressive loss of neurons, which manifests as gradual memory decline, followed by cognitive loss. Despite the significant progress in identifying novel biomarkers and understanding the prodromal pathology and symptomatology, AD remains a significant unmet clinical need. Lecanemab and aducanumab, the only Food and Drug Administration approved drugs to exhibit some disease-modifying clinical efficacy, target Aβ amyloid, underscoring the importance of this protein in disease aetiology. Nevertheless, in the absence of a definitive cure, the utilisation of preclinical models remains imperative for the identification of novel therapeutic targets and the evaluation of potential therapeutic agents. Drosophila melanogaster is a model system that can be used as a research tool to investigate neurodegeneration and therapeutic interventions. The short lifespan, low price and ease of husbandry/rearing make Drosophila an advantageous model organism from a practical perspective. However, it is the highly conserved genome and similarity of Drosophila and human neurobiology which make flies a powerful tool to investigate neurodegenerative mechanisms. In addition, the ease of transgenic modifications allows for early proof of principle studies for future therapeutic approaches in neurodegenerative research. This mini review will specifically focus on utilising Drosophila as an in vivo model of amyloid toxicity in AD., (© 2024 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.)

The excitation-inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1-type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co-morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists. Our results show that neither the D1-like dopamine receptor antagonist SCH23390 nor the D2-like dopamine receptor antagonist haloperidol reduces the frequency of epileptic activities. While requiring further investigation, our results indicate that on a systemic level, dopamine receptors are not significantly contributing to epilepsy observed in vivo in this mouse model of Alzheimer's disease., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The relationship between amyloid beta and cognitive dysfunction in mouse models of Alzheimer's disease has been evaluated predominantly with the spatial reference memory version of the water maze task. However, as Alzheimer's disease encompasses decline in multiple memory systems, it is important to also utilize non-spatial tasks to fully characterize the role of amyloid on behaviour in animal models. We used the TgCRND8 mouse model of Alzheimer's disease to evaluate the effect of amyloid on spatial reference memory, as well as on the non-spatial task of acquisition of conditioned taste aversion, and on the procedural task of swimming to a visible platform. We demonstrate that 8- to 12-month-old TgCRND8 mice are significantly impaired in all three tasks, and that the levels of soluble amyloid beta are significantly correlated with impairment in spatial reference memory, but not with impairment in conditioned taste aversion or swimming to a visible platform. Insoluble fractions of amyloid, which correspond closely to amyloid plaque burden in the brain, are not associated with any behavioural measure. Our study extends the characterization of the model to stages of advanced amyloid pathology and demonstrates that older TgCRND8 mice are impaired in multiple memory systems, including procedural tasks, which are spared at younger ages. The lack of association between amyloid plaques and memory decline supports clinical findings in Alzheimer's patients. [ABSTRACT FROM AUTHOR]

Ecosystem function is maintained in part by direct species interactions, but indirect interactions and non‐consumptive effects may be of equal ecological importance. Along the west coast of North America, the recent population collapse of the predatory sunflower sea star Pycnopodia helianthoides has been implicated in the proliferation of the purple sea urchin Strongylocentrotus purpuratus, and a concurrent decline in kelp canopy cover in several locales. Recent work began to quantify the predation rates effects (i.e., direct consumptive effects) of Pycnopodia on sea urchins that may lead to density‐mediated indirect effects on kelp. However, the importance of non‐consumptive effects on urchin behavior and the possible trait‐mediated indirect effects of Pycnopodia on kelp are not well understood. This leaves a critical gap in our knowledge about how these predators may be controlling grazer populations and, indirectly, primary production by macroalgae in nearshore habitats. We measured the non‐consumptive behavioral effects of Pycnopodia on S. purpuratus in the laboratory including grazing rates, feeding behavior, and movement of starved versus fed urchins, the latter simulating urchin metabolic conditions within urchin barrens. We found that the presence of a waterborne Pycnopodia cue reduced the grazing rate of fed urchins by 50% over short (~24 h) time scales. In contrast, starved urchins consumed kelp and did not exhibit an escape response in the presence of a Pycnopodia cue. This study highlights a trait‐mediated indirect interaction between Pycnopodia, S. purpuratus, and kelp, showing how the urchin response to a predator cue may differ based on urchin metabolic conditions or ecosystem state, and helps clarify the positive role of Pycnopodia on kelp forest health. [ABSTRACT FROM AUTHOR]

Cerebrovascular dysfunction has been implicated as a major contributor to Alzheimer's Disease (AD) pathology, with cerebral endothelial cell (cEC) stress promoting ischemia, cerebral‐blood flow impairments and blood–brain barrier (BBB) permeability. Recent evidence suggests that cardiovascular (CV)/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear. Our lab has demonstrated that amyloid beta 40 (Aβ40) species, and particularly Aβ40‐E22Q (AβQ22; vasculotropic Dutch mutant), promote death receptor 4 and 5 (DR4/DR5)‐mediated apoptosis in human cECs, barrier permeability, and angiogenic impairment. Previous studies show that Hhcy also induces EC dysfunction, but it remains unknown whether Aβ and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates Aβ‐induced cEC DR4/5‐mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates AβQ22‐mediated activation of the DR4/5‐mediated extrinsic apoptotic pathway in cECs, including DR4/5 expression, caspase 8/9/3 activation, cytochrome‐c release and DNA fragmentation. Additionally, we revealed that Hhcy intensifies the deregulation of the same cEC junction proteins mediated by Aβ, precipitating BBB permeability. Furthermore, Hhcy and AβQ22, impairing VEGF‐A/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC angiogenic capabilities. Overall, these results show that the presence of the CV risk factor Hhcy exacerbates Aβ‐induced cEC apoptosis, barrier dysfunction, and angiogenic impairment. This study reveals specific mechanisms through which amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD/CAA and Hhcy conditions. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), a progressive neurodegenerative disorder, has emerged as the most common form of dementia in the elderly. Two major pathological hallmarks have been identified for AD: extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT). Recently, dynamin-related protein 1 (Drp1) was recognized to contribute significantly towards the pathogenesis of AD. Drp1 is primarily located in the cytosol, from where it translocates to the mitochondrial outer membrane and drives the mitochondrial fission via GTP hydrolysis. Drp1 interacts with Aβ and phosphorylated tau, leading to excessive mitochondrial fragmentation, which in turn results in synaptic dysfunction, neuronal damage and cognitive decline. Several studies suggest an increase in the level of Drp1 in the post-mortem brain specimen collected from the AD patients and murine models of AD. Interestingly, heterozygous deletion of Drp1 in the transgenic murine model of AD ameliorates the mitochondrial dysfunction, improving learning and memory. The current review article discusses the possible mechanistic pathways by which Drp1 can influence the pathogenesis of AD. Besides, it will describe various inhibitors for Drp1 and their potential role as therapeutics for AD in the future., (© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease with multifaceted neuropathological disorders. AD is characterized by intracellular accumulation of phosphorylated tau proteins and extracellular deposition of amyloid beta (Aβ). Various protease enzymes, including neprilysin (NEP), are concerned with the degradation and clearance of Aβ. Indeed, a defective neuronal clearance pathway due to the dysfunction of degradation enzymes might be a possible mechanism for the accumulation of Aβ and subsequent progression of AD neuropathology. NEP is one of the most imperative metalloproteinase enzymes involved in the clearance of Aβ. This review aimed to highlight the possible role of NEP inhibitors in AD. The combination of sacubitril and valsartan which is called angiotensin receptor blocker and NEP inhibitor (ARNI) may produce beneficial and deleterious effects on AD neuropathology. NEP inhibitors might increase the risk of AD by the inhibition of Aβ clearance, and increase brain bradykinin (BK) and natriuretic peptides (NPs), which augment the pathogenesis of AD. These verdicts come from animal model studies, though they may not be applied to humans. However, clinical studies revealed promising safety findings regarding the use of ARNI. Moreover, NEP inhibition increases various neuroprotective peptides involved in inflammation, glucose homeostasis and nerve conduction. Also, NEP inhibitors may inhibit dipeptidyl peptidase 4 (DPP4) expression, ameliorating insulin and glucagon‐like peptide 1 (GLP‐1) levels. These findings proposed that NEP inhibitors may have a protective effect against AD development by increasing GLP‐1, neuropeptide Y (NPY) and substance P, and deleterious effects by increasing brain BK. Preclinical and clinical studies are recommended in this regard. [ABSTRACT FROM AUTHOR]

Moyamoya disease (MMD) is a rare disorder of the cerebrovascular system. It is a steno‐occlusive disease that involves angiogenesis and blood–brain barrier (BBB) disruption. Bradykinin (BK), its metabolite des‐Arg9‐BK, and receptor (B1R) affect angiogenesis and BBB integrity. In this study, we aimed to investigate the changes in BK, B1R and des‐Arg9‐BK levels in the serum and brain tissues of patients with MMD and explore the underlying mechanism of these markers in MMD. We obtained the serum samples and superficial temporal artery (STA) tissue of patients with MMD from the Department of Neurosurgery of the Jining First People's Hospital. First, we measured BK, des‐Arg9‐BK and B1R levels in the serum of patients by means of ELISA. Next, we performed immunofluorescence to determine B1R expression in STA tissues. Finally, we determined the underlying mechanism through Western blot, angiogenesis assay, immunofluorescence, transendothelial electrical resistance and transcytosis assays. Our results demonstrated a significant increase in the BK, des‐Arg9‐BK and B1R levels in the serum of patients with MMD compared to healthy controls. Furthermore, an increase in the B1R expression level was observed in the STA tissues of patients with MMD. BK and des‐Arg9‐BK could promote the migratory and proliferative abilities of bEnd.3 cells and inhibited the formation of bEnd.3 cell tubes. In vitro BBB model showed that BK and des‐Arg9‐BK could reduce claudin‐5, ZO‐1 and occluding expression and BBB disruption. To the best of our knowledge, our results show an increase in BK and B1R levels in the serum and STA tissues of patients with MMD. BK and Des‐Arg9‐BK could inhibit angiogenesis, promote migratory and proliferative capacities of cells, and disrupt BBB integrity. Therefore, regulating BK, des‐Arg9‐BK and B1R levels in the serum and the brain could be potential strategies for treating patients with MMD. [ABSTRACT FROM AUTHOR]

Although insulin resistance increases the risk of Alzheimer's disease (AD), the mechanisms remain unclear, partly because no animal model exhibits the insulin‐resistant phenotype without persistent hyperglycemia. Here we established an AD model with whole‐body insulin resistance without persistent hyperglycemia (APP/IR‐dKI mice) by crossbreeding constitutive knock‐in mice with P1195L‐mutated insulin receptor (IR‐KI mice) and those with mutated amyloid precursor protein (AppNL‐G‐F mice: APP‐KI mice). APP/IR‐dKI mice exhibited cognitive impairment at an earlier age than APP‐KI mice. Since cholinergic dysfunction is a major characteristic of AD, pharmacological interventions on the cholinergic system were performed to investigate the mechanism. Antagonism to a nicotinic acetylcholine receptor α7 (nAChRα7) suppressed cognitive function and cortical blood flow (CBF) response to cholinergic‐regulated peripheral stimulation in APP‐KI mice but not APP/IR‐dKI mice. Cortical expression of Chrna7, encoding nAChRα7, was downregulated in APP/IR‐dKI mice compared with APP‐KI. Amyloid β burden did not differ between APP‐KI and APP/IR‐dKI mice. Therefore, insulin resistance, not persistent hyperglycemia, induces the earlier onset of cognitive dysfunction and CBF deregulation mediated by nAChRα7 downregulation. Our mouse model will help clarify the association between type 2 diabetes mellitus and AD. [ABSTRACT FROM AUTHOR]

Genetic disruption of glycosyltransferases has provided clear information on the roles of their reaction products in the body. Our group has studied the function of glycosphingolipids by genetic engineering of glycosyltransferases in cell culture and in mice, which has demonstrated both expected and unexpected results. Among these findings, aspermatogenesis in ganglioside GM2/GD2 synthase knockout mice was one of the most surprising and intriguing results. There were no sperms in testis, and multinuclear giant cells were detected instead of spermatids. Although serum levels of testosterone in the male mice were extremely low, testosterone accumulated in the interstitial tissues, including Leydig cells, and seemed not to be transferred into the seminiferous tubules or vascular cavity from Leydig cells. This was considered to be the cause of aspermatogenesis and low serum levels of testosterone. Patients with a mutant GM2/GD2 synthase gene (SPG26) showed similar clinical signs, not only in terms of the neurological aspects, but also in the male reproductive system. The mechanisms for testosterone transport by gangliosides are discussed here based on our own results and reports from other laboratories. [ABSTRACT FROM AUTHOR]

Misfolded Aβ is involved in the progression of Alzheimer's disease (AD). However, the role of its polymorphic variants or conformational strains in AD pathogenesis is not fully understood. Here, we study the seeding properties of two structurally defined synthetic misfolded Aβ strains (termed 2F and 3F) using in vitro and in vivo assays. We show that 2F and 3F strains differ in their biochemical properties, including resistance to proteolysis, binding to strain‐specific dyes, and in vitro seeding. Injection of these strains into a transgenic mouse model produces different pathological features, namely different rates of aggregation, formation of different plaque types, tropism to specific brain regions, differential recruitment of Aβ40/Aβ42 peptides, and induction of microglial and astroglial responses. Importantly, the aggregates induced by 2F and 3F are structurally different as determined by ssNMR. Our study analyzes the biological properties of purified Aβ polymorphs that have been characterized at the atomic resolution level and provides relevant information on the pathological significance of misfolded Aβ strains. Synopsis: Two structurally defined Aβ conformational variants differ in their biochemical properties in vitro and induce different pathological features in a transgenic mouse model. Amyloid pathology induced by different Aβ strains is characterized by different tropism, morphology, and tinctorial properties.Synthetic Aβ fibrils (2F and 3F) preferentially seed Aβ40 while in vivo‐derived seeds have a preference to recruit Aβ42.Neuroinflammation induced in treated mice is Aβ strain specific.Seeded aggregates induced by structurally different Aβ strains in mice display different conformations. [ABSTRACT FROM AUTHOR]

The E4 allele of apolipoprotein E (ApoE4) is a key genetic risk factor for late‐onset Alzheimer's disease (AD), increasing the risk of developing the disease by up to three‐fold. However, the mechanisms by which ApoE4 contributes to AD pathogenesis are poorly understood. Here, we utilize a mouse model expressing either human ApoE3 or human ApoE4 to examine the effects of the E4 allele on a wide range of genetic and molecular pathways that are altered in early AD pathology. We demonstrate that ApoE4‐expressing mice begin to show early differential expression of multiple genes, leading to alterations in downstream pathways related to neural cell maintenance, insulin signaling, amyloid processing and clearance, and synaptic plasticity. These alterations may result in the earlier accumulation of pathological proteins such as β‐amyloid that may build up within cells, leading to the accelerated degeneration of neurons and astrocytes as observed in ApoE4‐positive individuals. We also examine the metabolic effects associated with a high‐fat diet (HFD) in male ApoE4‐expressing mice compared with regular chow diet (RD) fed mice at different ages. We found that young ApoE4‐expressing mice fed HFD developed metabolic disturbances, such as elevated weight gain, blood glucose, and plasma insulin levels that cumulatively have been observed to increase the risk of AD in humans. Taken together, our results reveal early pathways that could mediate ApoE4‐related AD risk and may help identify more tractable therapeutic targets for treating ApoE4‐associated AD. [ABSTRACT FROM AUTHOR]

Astrocytes associate with amyloid plaques in Alzheimer's disease (AD). Astrocytes react to changes in the brain environment, including increasing concentrations of amyloid‐β (Aβ). However, the precise response of astrocytes to soluble small Aβ oligomers at concentrations similar to those present in the human brain has not been addressed. In this study, we exposed astrocytes to media from neurons that express the human amyloid precursor protein (APP) transgene with the double Swedish mutation (APPSwe), and which contains APP‐derived fragments, including soluble human Aβ oligomers. We then used proteomics to investigate changes in the astrocyte secretome. Our data show dysregulated secretion of astrocytic proteins involved in the extracellular matrix and cytoskeletal organization and increase secretion of proteins involved in oxidative stress responses and those with chaperone activity. Several of these proteins have been identified in previous transcriptomic and proteomic studies using brain tissue from human AD and cerebrospinal fluid (CSF). Our work highlights the relevance of studying astrocyte secretion to understand the brain response to AD pathology and the potential use of these proteins as biomarkers for the disease. [ABSTRACT FROM AUTHOR]

The renin‐angiotensin system (RAS) plays essential roles in maintaining peripheral cardiovascular homeostasis, with its potential roles in the brain only being recognized more recently. Angiotensin‐I‐converting enzyme (ACE) is the main component of the RAS, and it has been implicated in various disorders of the brain. ACE and other RAS components, including the related enzyme ACE2, angiotensin peptides and their respective receptors, can participate in the pathological state, as well as with potential to contribute to neuroprotection and/or to complement existing treatments for psychiatric illness. In this narrative review, we aimed to identify the main studies describing the functions of the RAS and ACEs in the brain and their association with brain disorders. These include neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, psychiatric illnesses such as schizophrenia, bipolar disorder, and depression. We also discuss the possible association of a functional polymorphism of the ACE gene with these brain diseases and the relevance of the neuroprotective and anti‐inflammatory properties of ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs). Based on this, we conclude that there is significant potential value to the inclusion of ACEis and/or ARBs as a novel integrated approach for the treatment of various disorders of the brain, and particularly for psychiatric illness. [ABSTRACT FROM AUTHOR]

During protein folding and misfolding, structural properties and aggregation tendency can be significantly influenced by histidine behaviors (tautomeric behaviors and protonation behaviors). The original reasons were derived from the net charge changes and the various N/N−H orientation on imidazole rings. In the current study, total 18 independent REMD simulations were performed to investigate the histidine behaviors on four Tau peptide fragments (MBD, including R1, R2, R3, and R4 fragments). We found that, compared to R1, R2, R3 except (ϵδ), and R4 systems with flexible structural features, only R3(ϵδ) has dominating conformational structure (possibility of 81.3 %) with three β‐strand structures in parallel β‐sheet structures at I4‐K6 and I24‐H26, as well as antiparallel β‐sheet structure at G19‐L21. Importantly, the H25 and H26 residues (in R3(ϵδ) system) are directly involved in the sheet structure formations and strong H‐bonded interactions (possibility range of 31.3 %–44.7 %). Furthermore, the donors and acceptors analysis confirmed that only R3(ϵδ) shows faraway amino acids interaction features in both H25 and H26 residues, and such cooperation effects of two histidine residues contribute to current structural features. The current study will be helpful to further enrichment of the histidine behavior hypothesis, it provides new insight for understanding protein folding and misfolding. [ABSTRACT FROM AUTHOR]

Ageing is the main risk factor common to most primary neurodegenerative disorders. Indeed, age‐related brain alterations have been long considered to predispose to neurodegeneration. Although protein misfolding and the accumulation of toxic protein aggregates have been considered as causative events in neurodegeneration, several other biological pathways affected by brain ageing also contribute to pathogenesis. Here, we discuss the evidence showing the involvement of the mechanisms controlling neuronal structure, gene expression, autophagy, cell metabolism and neuroinflammation in the onset and progression of neurodegenerative disorders. Furthermore, we review the therapeutic strategies currently under development or as future approaches designed to normalize these pathways, which may then increase brain resilience to cope with toxic protein species. In addition to therapies targeting the insoluble protein aggregates specifically associated with each neurodegenerative disorder, these novel pharmacological approaches may be part of combined therapies designed to rescue brain function. [ABSTRACT FROM AUTHOR]

Aggregation and accumulation of amyloid‐β peptide (Aβ) are a critical trigger for the onset of Alzheimer's disease (AD). While the plaques are the most outstanding Aβ pathological feature, much of the recent research emphasis has been on soluble Aβ species because of their diffusible, proinflammatory, and toxic properties. The focus on soluble aggregated Aβ species has also increased the interest in antibodies that are selective for different Aβ conformations. In the current study, we developed and characterized a new class of monoclonal antibodies (referred to as mAbSL) that are selective for Aβ protofibrils. Cloning and sequencing of the heavy and light chain variable regions for multiple antibodies identified sequence characteristics that may impart the conformational selectivity by the antibodies. Transfection of FreeStyle 293F cells with the plasmids permitted in‐house expression and purification of mAbSL antibodies along with non‐conformation‐selective Aβ monoclonal antibodies (Aβ mAbs). Several of the purified mAbSL antibodies demonstrated significant affinity and selectivity for Aβ42 protofibrils compared with Aβ42 monomers and Aβ42 fibrils. Competition ELISA assays assessing the best overall antibody, mAbSL 113, yielded affinity constants of 7 nM for the antibody‐Aβ42 protofibril interaction, while the affinity for either Aβ42 monomers or Aβ42 fibrils was roughly 80 times higher. mAbSL 113 significantly inhibited Aβ42 monomer aggregation by a unique mechanism compared with the inhibition displayed by Aβ mAb 513. Aβ42 protofibril dynamics were also markedly altered in the presence of mAbSL 113, whereby insoluble complex formation and protofibril deposition were stimulated by the antibody at low substoichiometric molar ratios. As the field contemplates the therapeutic effectiveness of Aβ conformation‐selective antibodies, the findings presented here demonstrate new information on a monoclonal antibody that selectively targets Aβ protofibrils and impacts Aβ dynamics. [ABSTRACT FROM AUTHOR]

In restoration ecology, the Field of Dreams hypothesis posits that restoration efforts that create a suitable environment could lead to the eventual recovery of the remaining aspects of the ecosystem through natural processes. Natural processes following partial restoration has led to ecosystem recovery in both terrestrial and aquatic systems. However, understanding the efficacy of a "Field of Dreams" approach requires a comparison of different approaches to partial restoration in terms of spatial, temporal, and ecological scale with what would happen given more comprehensive restoration efforts. We explore the relative effect of partial restoration and ongoing recovery on restoration efficacy with a dynamical model based on temperate rocky reefs in Northern California. We analyze our model for both the ability and rate of bull kelp forest recovery under different restoration strategies. We compare the efficacy of a partial restoration approach with a more comprehensive restoration effort by exploring how kelp recovery likelihood and rate change with varying intensities of urchin removal and kelp outplanting over different time periods and spatial scales. We find that, in the case of bull kelp forests, setting more favorable initial conditions for kelp recovery by implementing both urchin harvesting and kelp outplanting at the start of the restoration project has a bigger impact on the kelp recovery rate than applying restoration efforts through a longer period of time. Therefore, partial restoration efforts, in terms of spatial and temporal scale, can be significantly more effective when applied across multiple ecological scales in terms of both the capacity and rate for achieving the target outcomes. [ABSTRACT FROM AUTHOR]

Enhancing protein O‐GlcNAcylation by pharmacological inhibition of the enzyme O‐GlcNAcase (OGA), which removes the O‐GlcNAc modification from proteins, has been explored in mouse models of amyloid‐beta and tau pathology. However, the O‐GlcNAcylation‐dependent link between gene expression and neurological behavior remains to be explored. Using chronic administration of Thiamet G (TG, an OGA inhibitor) in vivo, we used a protocol designed to relate behavior with the transcriptome and selected biochemical parameters from the cortex of individual animals. TG‐treated mice showed improved working memory as measured using a Y‐maze test. RNA sequencing analysis revealed 151 top differentially expressed genes with a Log2fold change >0.33 and adjusted p‐value <0.05. Top TG‐dependent upregulated genes were related to learning, cognition and behavior, while top downregulated genes were related to IL‐17 signaling, inflammatory response and chemotaxis. Additional pathway analysis uncovered 3 pathways, involving gene expression including 14 cytochrome c oxidase subunits/regulatory components, chaperones or assembly factors, and 5 mTOR (mechanistic target of rapamycin) signaling factors. Multivariate Kendall correlation analyses of behavioral tests and the top TG‐dependent differentially expressed genes revealed 91 statistically significant correlations in saline‐treated mice and 70 statistically significant correlations in TG‐treated mice. These analyses provide a network regulation landscape that is important in relating the transcriptome to behavior and the potential impact of the O‐GlcNAC pathway. [ABSTRACT FROM AUTHOR]

Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism of neuronal damage during ischemic stroke remains unclear; therefore, the effective treatment of post‐ischemic stroke remains a critical challenge. Recently, iron has emerged as a crucial factor in post‐reperfusion injuries, participating in cell peroxidation, excitotoxicity, and a distinctive cell death pathway, namely, ferroptosis. Since iron is tightly regulated in the brain and important for brain functions, the imbalance of its metabolism, including its overload and deficiency, has been shown to impact ischemic stroke outcomes. This review summarizes the current understanding of pathological events associated with iron in ischemic stroke and discusses relevant drug development. [ABSTRACT FROM AUTHOR]

Heat shock factor 1 (HSF1) is a master stress‐responsive transcriptional factor, protecting cells from death. However, its gene regulation in vivo in the brain in response to neuronal stimuli remains elusive. Here, we investigated its direct regulation of the brain‐derived neurotrophic factor (BDNF) gene (Bdnf) in response to acute neuronal stress stimuli in the brain. The results of immunohistochemistry and chromatin immunoprecipitation quantitative PCR (ChIP‐qPCR) showed that administration of kainic acid (a glutamate receptor agonist inducing excitotoxity) to young adult mice induced HSF1 nuclear translocation and its binding to multiple Bdnf promoters in the hippocampus. Footshock, a physical stressor used for learning, also induced HSF1 binding to selected Bdnf promoters I and IV. This is, to our knowledge, the first demonstration of HSF1 gene regulation in response to neuronal stimuli in the hippocampus in vivo. HSF1 binding sites (HSEs) in Bdnf promoters I and IV were also detected when immunoprecipitated by an antibody of phosphorylated (p)CREB (cAMP‐responsive element‐binding protein), suggesting their possible interplay in acute stress‐induced Bdnf transcription. Interestingly, their promoter binding patterns differed by KA and footshock, suggesting that HSF1 and pCREB orchestrate to render fine‐tuned promoter control depending on the types of stress. Further, HSF1 overexpression increased Bdnf promoter activity in a luciferase assay, while virus infection of constitutively active‐form HSF1 increased levels of BDNF mRNA and protein in vitro in primary cultured neurons. These results indicated that HSF1 activation of Bdnf promoter was sufficient to induce BDNF expression. Taken together, these results suggest that HSF1 promoter‐specific control of Bdnf gene regulation plays an important role in neuronal protection and plasticity in the hippocampus in response to acute stress, possibly interplaying with pCREB. [ABSTRACT FROM AUTHOR]

The most common transport route of biologically active compounds or drugs involves the absorption of the respective compounds across cell membranes via passive diffusion. In this context, biologically active compounds must have sufficient lipophilic character for their penetration through cell membranes. On the other hand, it is a very important task to be able to derivatize the existing compounds with effective and practical transformations to increase their biological activities. Accordingly, the free amino group in the structures of thiadiazolines can be functionalized and their biological activities can be further improved. In the present study, for the first time, several novel lipophilic 5‐substituted 4‐acyl‐2‐(acylamino)‐Δ2‐1,3,4‐thiadiazolines as potential biologically active agents were synthesized and selectively deacylated with the assistance of urotropin based cationic surfactant to afford the corresponding 5‐substituted 4‐acyl‐2‐amino‐Δ2‐1,3,4‐thiadiazolines with moderate to good isolated yields. The surfactant catalyzed eco‐friendly method developed in this study greatly facilitated the regioselective deacylation of the thiadiazoline ring system at the N2 position. [ABSTRACT FROM AUTHOR]

The mechanisms of amyloid accumulation in familial Alzheimer's disease (FAD) and sporadic AD (SAD) are controversial. In FAD, mutations in presenilin (PSEN) impair γ‐secretase activity and lead to abnormal amyloid β–protein (Aβ) production, thereby increasing the Aβ42/40 ratio. SAD is postulated to be caused by decreased Aβ clearance of apolipoprotein E4 (APOE4), the strongest risk factor for SAD. However, whether intracellular APOE4 affects Aβ production is unclear. Using APOE3 and APOE4 knock‐in (KI) mouse brain and primary cultured fibroblasts from these mice, in this study, we demonstrated that APOE3 and APOE4 bind to the γ‐secretase complex and isoform‐dependently regulate its activity and Aβ production. We found that Aβ40 levels and γ‐secretase activity were higher in APOE knockout mouse brain than in wild‐type mouse brain. APOE4‐KI fibroblasts had significant lower Aβ levels and γ‐secretase activity but higher Aβ42/40 ratio compared with APOE3‐KI cells, indicating that APOE4‐KI reduces Aβ production by inhibiting γ‐secretase activity. Interestingly, the levels of γ‐secretase complex bound to APOE4 are higher than those bound to APOE3, and the levels of γ‐secretase complex in the brain and fibroblasts of APOE4‐KI mice were higher than those of APOE3‐KI mice. Taken together, our findings demonstrate that intracellular APOE4 inhibits Aβ production, more preferentially inhibits Aβ40 production, and thereby induces an increase in the Aβ42/40 ratio via binding to the γ‐secretase complex. These results suggest a novel mechanism in which intracellular APOE4 contributes to the pathogenesis of SAD by inhibiting γ‐secretase activity. [ABSTRACT FROM AUTHOR]

Cerebral clearance of amyloid β‐protein (Aβ) is decreased in early‐onset and late‐onset Alzheimer's disease (AD). Aβ is cleared from the brain by enzymatic degradation and by transport out of the brain. More than 20 Aβ‐degrading enzymes have been described. Increasing the degradation of Aβ offers an opportunity to decrease brain Aβ levels in AD patients. This review discusses the direct and indirect approaches which have been used in experimental systems to alter the expression and/or activity of Aβ‐degrading enzymes. Also discussed are the enzymes' regulatory mechanisms, the conformations of Aβ they degrade, where in the scheme of Aβ production, extracellular release, cellular uptake, and intracellular degradation they exert their activities, and changes in their expression and/or activity in AD and its animal models. Most of the experimental approaches require further confirmation. Based upon each enzyme's effects on Aβ (some of the enzymes also possess β‐secretase activity and may therefore promote Aβ production), its direction of change in AD and/or its animal models, and the Aβ conformation(s) it degrades, investigating the effects of increasing the expression of neprilysin in AD patients would be of particular interest. Increasing the expression of insulin‐degrading enzyme, endothelin‐converting enzyme‐1, endothelin‐converting enzyme‐2, tissue plasminogen activator, angiotensin‐converting enzyme, and presequence peptidase would also be of interest. Increasing matrix metalloproteinase‐2, matrix metalloproteinase‐9, cathepsin‐B, and cathepsin‐D expression would be problematic because of possible damage by the metalloproteinases to the blood brain barrier and the cathepsins' β‐secretase activity. Many interventions which increase the enzymatic degradation of Aβ have been shown to decrease AD‐type pathology in experimental models. If a safe approach can be found to increase the expression or activity of selected Aβ‐degrading enzymes in human subjects, then the possibility that this approach could slow the AD progression should be examined in clinical trials. [ABSTRACT FROM AUTHOR]

Cholesterol‐24‐hydroxylase (CYP46), a member of the cytochrome P450 superfamily of enzymes, is selectively expressed in the brain and is mainly responsible for cholesterol turnover in the central nervous system. Although increased cyp46A1 gene expression has been linked to cognitive alterations in aging and observed in neurodegenerative diseases and after traumatic brain injury, a detailed characterization of the brain regions and cell types in which CYP46 is expressed in old individuals has not been performed. Using immunohistochemistry and immunofluorescence, we investigated the specific regions and cell populations in the brain, in which cyp46A1 is expressed in 24‐month‐old mice. We found that CYP46 is localized in the same neuronal populations in young and old brains, mainly in the hippocampus, in cortical layers, and in Purkinje neurons of the cerebellum. No increase in CYP46 levels was found in astrocytes in old mice brains, in primary astrocyte‐neuron cocultures aged in vitro, or in primary cultures of senescent astrocytes. However, interleukin‐6 treatment strongly induced cyp46A1 expression in reactive astrocytes characterized by high GFAP levels but had no effect in nonactivated astrocytes. Our data suggest that cholesterol‐24‐hydroxylase expression is triggered in reactive astrocytes in response to proinflammatory signals, probably as part of a response mechanism to injury. [ABSTRACT FROM AUTHOR]

The two hallmarks of Alzheimer's disease (AD) are amyloid‐β (Aβ) plaques and neurofibrillary tangles marked by phosphorylated tau. Increasing evidence suggests that aggregating Aβ drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely, there is a realization that non‐fibrillar (oligomeric) forms of Aβ mediate toxicity in AD. Fibrillar (filamentous) aggregates of proteins across the spectrum of the primary and secondary tauopathies were the focus of recent structural studies with a filament structure‐based nosologic classification, but less emphasis was given to non‐filamentous co‐aggregates of insoluble proteins in the fractions derived from post‐mortem human brains. Here, we revisited sarkosyl‐soluble and ‐insoluble extracts to characterize tau and Aβ species by quantitative targeted mass spectrometric proteomics, biochemical assays, and electron microscopy. AD brain sarkosyl‐insoluble pellets were greatly enriched with Aβ42 at almost equimolar levels to N‐terminal truncated microtubule‐binding region (MTBR) isoforms of tau with multiple site‐specific post‐translational modifications (PTMs). MTBR R3 and R4 tau peptides were most abundant in the sarkosyl‐insoluble materials with a 10‐fold higher concentration than N‐terminal tau peptides. This indicates that the major proportion of the enriched tau was the aggregation‐prone N‐terminal and proline‐rich region (PRR) of truncated mixed 4R and 3R tau with more 4R than 3R isoforms. High concentration and occupancies of site‐specific phosphorylation pT181 (~22%) and pT217 (~16%) (key biomarkers of AD) along with other PTMs in the PRR and MTBR indicated a regional susceptibility of PTMs in aggregated tau. Immunogold labelling revealed that tau may exist in globular non‐filamentous form (N‐terminal intact tau) co‐localized with Aβ in the sarkosyl‐insoluble pellets along with tau filaments (N‐truncated MTBR tau). Our results suggest a model that Aβ and tau interact forming globular aggregates, from which filamentous tau and Aβ emerge. These characterizations contribute towards unravelling the sequence of events which lead to end‐stage AD changes. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) could be considered a potential neuroprotective therapy in amyloid beta (Aβ)-associated retinal and optic nerve degeneration. Hence, in this study we investigated the neuroprotective effect of BDNF against Aβ1-40-induced retinal and optic nerve injury. In this study, exposure to Aβ1-40 was associated with retinal and optic nerve injury. TUNEL staining showed significant reduction in the apoptotic cell count in the BDNF-treated group compared with Aβ1-40 group. H&E-stained retinal sections also showed a striking reduction in neuronal cells in the ganglion cell layer (GCL) of retinas fourteen days after Aβ1-40 exposure. By contrast, number of retinal cells was preserved in the retinas of BDNF-treated animals. After Aβ1-40 exposure, visible axonal swelling was observed in optic nerve sections. However, the BDNF-treated group showed fewer changes in optic nerve; axonal swelling was less frequent and less marked. In the present study, exposure to Aβ was associated with oxidative stress, whereas levels of retinal glutathione (GSH), superoxide dismutase (SOD) and catalase were significantly increased in BDNF-treated than in Aβ1-40-treated rats. Both visual object recognition tests using an open-field arena and a Morris water maze showed that BDNF improved rats' ability to recognise visual cues (objects with different shapes) after Aβ1-40 exposure, thus demonstrating that the visual performance of rats was relatively preserved following BDNF treatment. In conclusion, intravitreal treatment with BDNF prevents Aβ1-40-induced retinal cell apoptosis and axon loss in the optic nerve of rats by reducing retinal oxidative stress and restoring retinal BDNF levels., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: To test the hypothesis that high‐frequency oscillations (HFOs) between 250 and 500 Hz occur in mouse models of Alzheimer's disease (AD) and thus are not unique to epilepsy. Methods: Experiments were conducted in three mouse models of AD: Tg2576 mice that simulate a form of familial AD, presenilin 2 knock‐out (PS2KO) mice, and the Ts65Dn model of Down's syndrome. We recorded HFOs using wideband (0.1–500 Hz, 2 kHz) intra‐hippocampal and cortical surface electroencephalography (EEG) at 1 month until 24 months of age during wakefulness, slow wave sleep (SWS), and rapid eye movement (REM) sleep. In addition, interictal spikes (IISs) and seizures were analyzed for the possible presence of HFOs. Comparisons were made to the intra‐hippocampal kainic acid and pilocarpine models of epilepsy. Results: We describe for the first time that hippocampal and cortical HFOs are a new EEG abnormality in AD mouse models. HFOs occurred in all transgenic mice but no controls. They were also detectable as early as 1 month of age and prior to amyloid beta plaque neuropathology. HFOs were most frequent during SWS (vs REM sleep or wakefulness). Notably, HFOs in the AD and epilepsy models were indistinguishable in both spectral frequency and duration. HFOs also occurred during IISs and seizures in the AD models, although with altered spectral properties compared to isolated HFOs. Significance: Our data demonstrate that HFOs, an epilepsy biomarker with high translational value, are not unique to epilepsy and thus not disease specific. Our findings also strengthen the idea of hyperexcitability in AD and its significant overlap with epilepsy. HFOs in AD mouse models may serve as an EEG biomarker, which is detectable from the scalp and thus amenable to noninvasive detection in people at risk for AD. [ABSTRACT FROM AUTHOR]

Inflammation associated with viral infection of the nervous system has been involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis. Polyinosinic:polycytidylic acid (poly[I:C]) is a Toll‐like receptor 3 (TLR3) agonist that mimics the inflammatory response to systemic viral infections. Despite growing recognition of the role of glial cells in AD pathology, their involvement in the accumulation and clearance of amyloid β (Aβ) in the brain of patients with AD is poorly understood. Neprilysin (NEP) and insulin‐degrading enzyme (IDE) are the main Aβ‐degrading enzymes in the brain. This study investigated whether poly(I:C) regulated Aβ degradation and neurotoxicity by modulating NEP and IDE protein levels through TLR3 in astrocytes. To this aim, primary rat primary astrocyte cultures were treated with poly(I:C) and inhibitors of the TLR3 signaling. Protein levels were assessed by Western blot. Aβ toxicity to primary neurons was measured by lactate dehydrogenase release. Poly(I:C) induced a significant decrease in NEP levels on the membrane of astrocytes as well as in the culture medium. The degradation of exogenous Aβ was markedly delayed in poly(I:C)‐treated astrocytes. This delay significantly increased the neurotoxicity of exogenous Aβ1‐42. Altogether, these results suggest that viral infections induce Aβ neurotoxicity by decreasing NEP levels in astrocytes and consequently preventing Aβ degradation. [ABSTRACT FROM AUTHOR]

Brain perivascular macrophages (PVMs) are attracting increasing attention as this emerging cell population in the brain has multifaced roles in supporting the central nervous system structure, brain development, and maintaining physiological functions. They also widely participate in neurological diseases such as neurodegeneration and ischemic stroke. Moreover, PVMs have been reported to have both beneficial and detrimental effects under different pathological contexts. Advanced research technologies allowed the further in‐depth study of PVMs and revealed novel concepts in their origins, differentiation, and regulatory mechanisms. Deepened understanding of the roles of PVMs in different brain pathological conditions can reveal novel phenotypic changes and regulatory signaling, which might pave the way for the development of novel treatment strategies targeting PVMs. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of cognitive disorder in an elderly population associated with the accumulation of amyloid plaques and neurofibrillary tangles. Nerolidol is assumed to have neuroprotection effects. This study aimed to investigate the therapeutic effects of nerolidol on the Aβ‐induced model of AD in rats. Hippocampal injection of Aβ was used to induce AD. Animals were randomly divided into control, sham (received PBS as Aβ solvent), AD, DNPZ (AD + donepezil, 4 weeks); NRD‐50 (AD + nerolidol, 50 mg/kg, 4 weeks), NRD‐100 (AD + nerolidol, 100 mg/kg, 4 weeks; Prot (rats which received 100 mg/kg nerolidol for two weeks before Aβ administration), and Solv (AD + sunflower oil as nerolidol solvent, 4 weeks) groups. All rats were subjected to a memory behavioral passive avoidance test by shuttle box. Thioflavin‐S staining was performed to confirm Aβ plaque formation and measured using ImageJ analyzing program. BDNF and CREB‐1 expressions were analyzed by immunohistochemistry assay. Aβ induced AD by Aβ plaques formation and increasing step‐through latency time. It reduced the expression of BDNF and CREB‐1 protein. Administration of nerolidol or donepezil improved these features by decreasing Aβ and increasing BDNF and CREB‐1 expression and latency time. Nerolidol is likely to provide protection against AD. It may prevent dementia through the mediation of BDNF‐CREB‐1 expression and cholinergic nerve cells restoring. It seems that the administration of nerolidol before the onset of the disease will be more effective than after. [ABSTRACT FROM AUTHOR]

Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant forms of dementia caused by mutations in the integral membrane protein 2B (ITM2B, also known as BRI2) gene. Secretase processing of mutant BRI2 leads to secretion and deposition of BRI2‐derived amyloidogenic peptides, ABri and ADan that resemble APP/β‐amyloid (Aβ) pathology, which is characteristic of Alzheimer's disease (AD). Amyloid pathology in FBD/FDD manifests itself predominantly in the microvasculature by ABri/ADan containing cerebral amyloid angiopathy (CAA). While ABri and ADan peptide sequences differ only in a few C‐terminal amino acids, CAA in FDD is characterized by co‐aggregation of ADan with Aβ, while in contrast no Aβ deposition is observed in FBD. The fact that FDD patients display an earlier and more severe disease onset than FBD suggests a potential role of ADan and Aβ co‐aggregation that promotes a more rapid disease progression in FDD compared to FBD. It is therefore critical to delineate the chemical signatures of amyloid aggregation in these two vascular dementias. This in turn will increase the knowledge on the pathophysiology of these diseases and the pathogenic role of heterogenous amyloid peptide interactions and deposition, respectively. Herein, we used matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) in combination with hyperspectral, confocal microscopy based on luminescent conjugated oligothiophene probes (LCO) to delineate the structural traits and associated amyloid peptide patterns of single CAA in postmortem brain tissue of patients with FBD, FDD as well as sporadic CAA without AD (CAA+) that show pronounced CAA without parenchymal plaques. The results show that CAA in both FBD and FDD consist of N‐terminally truncated‐ and pyroglutamate‐modified amyloid peptide species (ADan and ABri), but that ADan peptides in FDD are also extensively C‐terminally truncated as compared to ABri in FBD, which contributes to hydrophobicity of ADan species. Further, CAA in FDD showed co‐deposition with Aβ x‐42 and Aβ x‐40 species. CAA+ vessels were structurally more mature than FDD/FBD CAA and contained significant amounts of pyroglutamated Aβ. When compared with FDD, Aβ in CAA+ showed more C‐terminal and less N‐terminally truncations. In FDD, ADan showed spatial co‐localization with Aβ3pE‐40 and Aβ3‐40 but not with Aβx‐42 species. This suggests an increased aggregation propensity of Aβ in FDD that promotes co‐aggregation of both Aβ and ADan. Further, CAA maturity appears to be mainly governed by Aβ content based on the significantly higher 500/580 patterns observed in CAA+ than in FDD and FBD, respectively. Together this is the first study of its kind on comprehensive delineation of Bri2 and APP‐derived amyloid peptides in single vascular plaques in both FDD/FBD and sporadic CAA that provides new insight in non‐AD‐related vascular amyloid pathology. Cover Image for this issue: https://doi.org/10.1111/jnc.15424 [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) commonly co‐occur. T2DM increases the risk for AD by approximately twofold. Animal models provide one means of interrogating the relationship of T2DM to AD and investigating brain insulin resistance in the pathophysiology of AD. Animal models show that persistent hyperglycaemia results in chronic low‐grade inflammation that may contribute to the development of neuroinflammation and accelerate the pathobiology of AD. Epidemiological studies suggest that patients with T2DM who received treatment with specific anti‐diabetic agents have a decreased risk for the occurrence of AD and all‐cause dementia. Agents such as metformin ameliorate T2DM and may have other important systemic effects that lower the risk of AD. Glucagon‐like peptide 1 (GLP‐1) agonists have been associated with a decreased risk for AD in patients with T2DM. Both insulin and non‐insulin anti‐diabetic treatments have been evaluated for the treatment of AD in clinical trials. In most cases, patients included in the trials have clinical features of AD but do not have T2DM. Many of the trials were conducted prior to the use of diagnostic biomarkers for AD. Trials have had a wide range of durations and population sizes. Many of the agents used to treat T2DM do not cross the blood brain barrier, and the effects are posited to occur via lowering of peripheral hyperglycaemia and reduction of peripheral and central inflammation. Clinical trials of anti‐diabetic agents to treat AD are ongoing and will provide insight into the therapeutic utility of these agents. [ABSTRACT FROM AUTHOR]

Dysregulation of insulin signaling in the Alzheimer's disease (AD) brain has been extensively reported. Serine racemase (SR) modulates insulin secretion in pancreatic islets. This study aimed to examine whether SR regulates insulin synthesis and secretion in neurons, thereby modulating insulin signaling in the AD brain. Srr‐knockout (Srr−/−) mice generated with the CRISPR/Cas9 technique were used. Using immunofluorescence and fluorescence in situ hybridization, levels of insulin protein and insulin(ins2) mRNA were significantly increased in the hippocampal but not in hypothalamic sections of Srr−/− mice compared with WT mice. Real‐time quantitative PCR revealed that ins2 mRNA from primary hippocampal neuronal cultures of Srr−/− mice was significantly increased compared with that from cultured neurons of WT mice. Notably, the secretion of proinsulin C‐peptide was increased in Srr−/− neurons relative to WT neurons. By examining membrane fractional proteins with immunoblotting, Srr−/− neurons retained ATP‐dependent potassium channels on plasmalemma and correspondingly contained higher levels of p‐AMPK. After treatment with Aβ42, the phosphorylation levels of insulin receptor substrate at serine 616 636 (p‐IRS1ser616,636) were significantly lower, whereas p‐AKT308 and p‐AKT473 were higher in Srr−/− neurons than in WT neurons, respectively. The phosphorylated form of c‐Jun N‐terminal kinase decreased in the cultured Srr−/− neurons relative to the WT neurons upon Aβ42 treatment. In contrast, phosphorylated protein kinase R remained at the same levels. Further, reactive oxygen species were reduced in cultured Srr−/− neurons under Aβ42 treatment relative to the WT neurons. Collectively, our study indicated that Srr deletion promoted insulin synthesis and secretion of proinsulin C‐peptide, thereby reversing insulin resistance by Aβ42. This study suggests that targeting the neuronal SR may be utilized to enhance insulin signaling which is inhibited at the early stage of the AD brain. [ABSTRACT FROM AUTHOR]

Curcumin, isolated from turmeric (Curcuma longa L.) is one of the broadly studied phytomolecule owing to its strong antioxidant and anti‐inflammatory potential and has been considered a promising therapeutic candidate in a wide range of disorders. Considering, its low bioavailability, different curcumin analogs have been developed to afford desired pharmacokinetic profile and therapeutic outcome in varied pathological states. Several preclinical and clinical studies have indicated that curcumin ameliorates mitochondrial dysfunction, inflammation, oxidative stress apoptosis‐mediated neural cell degeneration and could effectively be utilized in the treatment of different neurodegenerative diseases. Hence, in this review, we have summarized key findings of experimental and clinical studies conducted on curcumin and its analogues with special emphasis on molecular pathways, viz. NF‐kB, Nrf2‐ARE, glial activation, apoptosis, angiogenesis, SOCS/JAK/STAT, PI3K/Akt, ERK1/2 /MyD88 /p38 MAPK, JNK, iNOS/NO, and MMP pathways involved in imparting ameliorative effects in the therapy of neurodegenerative disorders and associated conditions. [ABSTRACT FROM AUTHOR]

The newly constructed time-resolved atomic, molecular and optical science instrument (TMO) is configured to take full advantage of both linear accelerators at SLAC National Accelerator Laboratory, the copper accelerator operating at a repetition rate of 120 Hz providing high per-pulse energy as well as the superconducting accelerator operating at a repetition rate of about 1 MHz providing high average intensity. Both accelerators power a soft X-ray freeelectron laser with the new variable-gap undulator section. With this flexible light source, TMO supports many experimental techniques not previously available at LCLS and will have two X-ray beam focus spots in line. Thereby, TMO supports atomic, molecular and optical, strong-field and nonlinear science and will also host a designated new dynamic reaction microscope with a submicrometer X-ray focus spot. The flexible instrument design is optimized for studying ultrafast electronic and molecular phenomena and can take full advantage of the sub-femtosecond soft X-ray pulse generation program. [ABSTRACT FROM AUTHOR]

Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age‐associated diseases. The ubiquitin–proteasome and autophagy‐lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age‐related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins. Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy‐lysosome and ubiquitin–proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging. Consequently, proteases influence the onset and progression of age‐related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age‐related neurodegeneration. [ABSTRACT FROM AUTHOR]

Background and Purpose: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, and women account for 60% of diagnosed cases. β‐Amyloid (Aβ) oligomers are considered the principal neurotoxic species in AD brains. The M1 muscarinic ACh receptor (M1 mAChR) plays a key role in memory and learning. M1 mAChR agonists show pro‐cognitive activity but cause many adverse off‐target effects. A new orally bioavailable M1 mAChR positive allosteric modulator (PAM), VU0486846, is devoid of direct agonist activity or adverse effects but was not tested for disease‐modifying efficacy in female AD mice. Experimental Approach Nine‐month‐old female APPswe/PSEN1ΔE9 (APPswe) and wildtype mice were treated with VU0486846 in drinking water (10 mg·kg−1·day−1) for 4 or 8 weeks. Cognitive function of mice was assessed after treatment, and brains were harvested for biochemical and immunohistochemical assessment. Key Results: VU0486846 improved cognitive function of APPswe mice when tested in novel object recognition and Morris water maze. This was paralleled by a significant reduction in Aβ oligomers and plaques and neuronal loss in the hippocampus. VU0486846 reduced Aβ oligomer production in APPswe mice by increasing M1 mAChR expression and shifting the processing of amyloid precursor protein from amyloidogenic cleavage to non‐amyloidogenic cleavage. Specifically, VU0486846 reduced the expression of β‐secretase 1 (BACE1), whereas it enhanced the expression of the α‐secretase ADAM10 in APPswe hippocampus. Conclusion and Implications: Using M1 mAChR PAMs can be a viable disease‐modifying approach that should be exploited clinically to slow AD in women. [ABSTRACT FROM AUTHOR]

The multi‐site ubiquitination of Tau protein found in Alzheimer's disease filaments hints at the failed attempt of neurons to remove early toxic species. The ubiquitin‐dependent degradation of Tau is regulated in vivo by the E3 ligase CHIP, a quality controller of the cell proteome dedicated to target misfolded proteins for degradation. In our study, by using site‐resolved NMR, biochemical and computational methods, we elucidate the structural determinants underlying the molecular recognition between the ligase and its intrinsically disordered substrate. We reveal a multi‐domain dynamic interaction that explains how CHIP can direct ubiquitination of Tau at multiple sites even in the absence of chaperones, including its typical partner Hsp70/Hsc70. Our findings thus provide mechanistic insight into the chaperone‐independent engagement of a disordered protein by its E3 ligase. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is a leading cause of intellectual disability that also results in hallmark Alzheimer's disease (AD) pathologies such as amyloid beta (Aβ) plaques and hyperphosphorylated tau. The Ts65Dn mouse model is commonly used to study DS, as trisomic Ts65Dn mice carry 2/3 of the triplicated gene homologues as occur in human DS. The Ts65Dn strain also allows investigation of mechanisms common to DS and AD pathology, with many of these triplicated genes implicated in AD; for example, trisomic Ts65Dn mice overproduce amyloid precursor protein (APP), which is then processed into soluble Aβ40‐42 fragments. Notably, Ts65Dn mice show alterations to the basal forebrain, which parallels the loss of function in this region observed in DS and AD patients early on in disease progression. However, a complete picture of soluble Aβ40‐42 accumulation in a region‐, age‐, and sex‐specific manner has not yet been characterized in the Ts65Dn model. Here, we show that trisomic mice accumulate soluble Aβ40‐42 in the basal forebrain, frontal cortex, hippocampus, and cerebellum in an age‐specific manner, with elevation in the frontal cortex and hippocampus as early as 4 months of age. Furthermore, we detected sex differences in accumulation of Aβ40‐42 within the basal forebrain, with females having significantly higher Aβ40‐42 at 7–8 months of age. Lastly, we show that APP expression in the basal forebrain and hippocampus inversely correlates with Aβ40‐42 levels. This spatial and temporal characterization of soluble Aβ40‐42 in the Ts65Dn model allows for further exploration of the role soluble Aβ plays in the progression of other AD‐like pathologies in these key brain regions. [ABSTRACT FROM AUTHOR]