AD Therapy Research Articles

N-Propargylamine-hydroxypyridinone hybrids as multitarget agents for the treatment of Alzheimer’s disease

AD is a progressive brain disorder. Because of the lack of remarkable single-target drugs against neurodegenerative disorders, the multitarget-directed ligand strategy has received attention as a promising therapeutic approach. Herein, we rationally designed twenty-nine hybrids of N-propargylamine-hydroxypyridinone. The designed hybrids possessed excellent iron-chelating activity (pFe3+ = 17.09–22.02) and potent monoamine oxidase B inhibitory effects. Various biological evaluations of the optimal compound 6b were performed step by step, including inhibition screening of monoamine oxidase (hMAO-B IC50 = 0.083 ± 0.001 µM, hMAO-A IC50 = 6.11 ± 0.08 µM; SI = 73.5), prediction of blood–brain barrier permeability and mouse behavioral research. All of these favorable results proved that the N-propargylamine-hydroxypyridinone scaffold is a promising structure for the discovery of multitargeted ligands for AD therapy.

Phosphoinositides: Roles in the Development of Microglial-Mediated Neuroinflammation and Neurodegeneration.

Microglia are increasingly recognized as vital players in the pathology of a variety of neurodegenerative conditions including Alzheimer’s (AD) and Parkinson’s (PD) disease. While microglia have a protective role in the brain, their dysfunction can lead to neuroinflammation and contributes to disease progression. Also, a growing body of literature highlights the seven phosphoinositides, or PIPs, as key players in the regulation of microglial-mediated neuroinflammation. These small signaling lipids are phosphorylated derivates of phosphatidylinositol, are enriched in the brain, and have well-established roles in both homeostasis and disease.Disrupted PIP levels and signaling has been detected in a variety of dementias. Moreover, many known AD disease modifiers identified via genetic studies are expressed in microglia and are involved in phospholipid metabolism. One of these, the enzyme PLCγ2 that hydrolyzes the PIP species PI(4,5)P2, displays altered expression in AD and PD and is currently being investigated as a potential therapeutic target.Perhaps unsurprisingly, neurodegenerative conditions exhibiting PIP dyshomeostasis also tend to show alterations in aspects of microglial function regulated by these lipids. In particular, phosphoinositides regulate the activities of proteins and enzymes required for endocytosis, toll-like receptor signaling, purinergic signaling, chemotaxis, and migration, all of which are affected in a variety of neurodegenerative conditions. These functions are crucial to allow microglia to adequately survey the brain and respond appropriately to invading pathogens and other abnormalities, including misfolded proteins. AD and PD therapies are being developed to target many of the above pathways, and although not yet investigated, simultaneous PIP manipulation might enhance the beneficial effects observed. Currently, only limited therapeutics are available for dementia, and although these show some benefits for symptom severity and progression, they are far from curative. Given the importance of microglia and PIPs in dementia development, this review summarizes current research and asks whether we can exploit this information to design more targeted, or perhaps combined, dementia therapeutics. More work is needed to fully characterize the pathways discussed in this review, but given the strength of the current literature, insights in this area could be invaluable for the future of neurodegenerative disease research.

Functional nanoassemblies for the diagnosis and therapy of Alzheimer's diseases.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects populations around the world. Many therapeutics have been investigated for AD diagnosis and/or therapy, but the efficacy is largely limited by the poor bioavailability of drugs and by the presence of the blood-brain barrier. Recently, the development of nanomedicines enables efficient drug delivery to the brain, but the complex pathological mechanism of AD prevents them from successful treatment. As a type of advanced nanomedicine, multifunctional nanoassemblies self-assembled from nanoscale imaging or therapeutic agents can simultaneously target multiple pathological factors, showing great potential in the diagnosis and therapy of AD. To help readers better understand this emerging field, in this review, we first introduce the pathological mechanisms and the potential drug candidates of AD, as well as the design strategies of nanoassemblies for improving AD targeting efficiency. Moreover, the progress of dynamic nanoassemblies that can diagnose and/or treat AD in response to the endogenous or exogenous stimuli will be described. Finally, we conclude with our perspectives on the future development in this field. The objective of this review is to outline the latest progress of using nanoassemblies to overcome the complex pathological environment of AD for improved diagnosis and therapy, in hopes of accelerating the future development of intelligent AD nanomedicines. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging.

In silico Probing Ca2+ And Zn2+ Permeable Transmembrane 4Aβ1-42 Barrel

Alzheimer’s disease is known as one of the most popular forms of dementia affecting numerous people worldwide. The Amyloid beta (Aβ) peptides form to oligomeric conformations that cause the intracellular Ca2+ and Zn2+ abnormality leading to the death of neuron cells. The failure of AD therapy targeting Aβ oligomers probably caused by misunderstanding the ions transport through transmembrane Aβ (tmAβ) ion-like channel since Aβ oligomers transiently exist in a mixture order of Aβ oligomers. The high-resolution of tmAβ peptides are thus unavailable until the date. Fortunately, computational approaches are able to complement the missing experimental structures. The transmembrane 4Aβ1-42 (tm4Aβ1-42) barrel, one of the most neurotoxic elements, was thus predicted in the previous work. Therefore, in this context, the Ca2+/Zn2+ ions transport through the tm4Aβ1-42 barrel was investigated by using the fast pulling of ligand (FPL) and umbrella sampling (US) methods. Good consistent results were obtained implying that Ca2+ ion transport through tm4Aβ1-42 barrel with a lower free energy barrier compared with Zn2+ ion. The obtained results about Ca2+/Zn2+ transport across tmAβ1-42 barrel probably enhances the AD therapy

Multifunctional peptide-assembled micelles for simultaneously reducing amyloid-β and reactive oxygen species.

The excessive production and deposition of amyloid-β (Aβ) is one of the most important etiologies of Alzheimer's disease (AD). The interaction between Aβ and metal ions produces aberrant reactive oxygen species (ROS), which induce oxidative stress and accelerate the progression of AD. To reduce Aβ plaques and ROS to maintain their homeostasis is an emerging and ingenious strategy for effective treatment of AD. Herein, we report the rational design of multifunctional micelles (MPGLT) based on a polymer-grafted peptide to simultaneously clear Aβ and ROS for AD therapy. The MPGLT integrating three functional peptides as a ROS scavenger (tk-GSH), β-sheet breaker (LP) and an autophagy activator (TK) respectively, could capture and degrade Aβ. Meanwhile, the tk-GSH on the surface of MPGLT effectively scavenges the intracellular ROS. Consequently, MPGLT reduced the cytotoxicity of Aβ and ROS. In vivo animal studies using an AD mouse model further showed that MPGLT could transport across the blood–brain barrier for decreasing the Aβ plaque and eliminating ROS in vivo. This peptide micelle-based synergistic strategy may provide novel insight for AD therapy.

A novel inducible complement C3 conditional knockout mouse model: Generation and characterization

AbstractBackgroundThe classical complement pathway is a complex process involved in the elimination of dead cells, debris, and pathogens, and as well as brain wiring during development. Complement protein C3 is an innate immune molecule central in the complement pathway. It participates in removing pathogens and eliminating synapses, and is elevated with aging and neurodegenerative diseases, including Alzheimer’s Disease. Previously, we showed that lifelong, germline C3‐deficiency protected aged male wild‐type and APPswe/PS1dE9 mice against hippocampal neuronal dysfunction and cognitive decline, despite increasing the Aβ plaque load. However, it remains unknown whether suppressing complement C3 signaling during early stages of AD pathogenesis, when relevant therapeutic interventions might be considered, would confer neuroprotection.MethodTo address this question, we generated the first‐ever C3 floxed (C3fl/fl) mouse line, and then crossed the C3fl/fl mice with an inducible, global Cre line (Rosa26‐Cre‐ERT2+/‐) for 2 generations to generate novel inducible C3 conditional knockout C3fl/fl; Rosa26‐Cre‐ERT2+/‐ mice. Mice aged 2‐3 months received intraperitoneal injections of either corn oil or tamoxifen (75 mg/kg) once a day for 5 consecutive days. We analyzed the C3 serum levels at 7, 14, 30, 60, and 90 days post‐tamoxifen treatment. We also analyzed the mRNA expression of complement C1q and C3 in the brain and liver 60 days following tamoxifen treatment.ResultC3fl/fl;Rosa26‐cre‐ERT2+/‐ mice had a significant 70% reduction in serum C3 levels compared to controls, which was consistent at all timepoints analyzed. We also showed that C3 expression in the liver, the main source of complement proteins, as well as in the brain was reduced, demonstrating effective recombinase activity in these organs. Intriguingly, C1q mRNA expression was increased in the brain and liver following tamoxifen treatment; further studies are underway.ConclusionIn conclusion, we present a novel mouse model in which tamoxifen treatment resulted in sustained lowering of C3 in the serum, liver, and brain. We will next cross this model with AD‐like mouse models of amyloidosis and tau pathology to evaluate whether global C3 lowering in early stages AD pathogenesis is protective and if so, our data would support targeting complement as a therapy for AD.

Deep learning detection of informative features in tau PET for Alzheimer\u2019s disease classification

BackgroundAlzheimer’s disease (AD) is the most common type of dementia, typically characterized by memory loss followed by progressive cognitive decline and functional impairment. Many clinical trials of potential therapies for AD have failed, and there is currently no approved disease-modifying treatment. Biomarkers for early detection and mechanistic understanding of disease course are critical for drug development and clinical trials. Amyloid has been the focus of most biomarker research. Here, we developed a deep learning-based framework to identify informative features for AD classification using tau positron emission tomography (PET) scans.ResultsThe 3D convolutional neural network (CNN)-based classification model of AD from cognitively normal (CN) yielded an average accuracy of 90.8% based on five-fold cross-validation. The LRP model identified the brain regions in tau PET images that contributed most to the AD classification from CN. The top identified regions included the hippocampus, parahippocampus, thalamus, and fusiform. The layer-wise relevance propagation (LRP) results were consistent with those from the voxel-wise analysis in SPM12, showing significant focal AD associated regional tau deposition in the bilateral temporal lobes including the entorhinal cortex. The AD probability scores calculated by the classifier were correlated with brain tau deposition in the medial temporal lobe in MCI participants (r = 0.43 for early MCI and r = 0.49 for late MCI).ConclusionA deep learning framework combining 3D CNN and LRP algorithms can be used with tau PET images to identify informative features for AD classification and may have application for early detection during prodromal stages of AD.

Advances in Drug Therapy for Alzheimer\u2019s Disease

SummaryAlzheimer’s disease (AD) is a chronic neurodegenerative disease that mainly causes dementia. It is a serious threat to the health of the global elderly population. Considerable money and effort has been invested in the development of drug therapy for AD worldwide. Many drug therapies are currently under development or in clinical trials, based on two known mechanisms of AD, namely, Aβ toxicity and the abnormal Tau hyperphosphorylation. Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation, neurotransmitter imbalance, oxidative damage and mitochondrial dysfunction, neuron loss and degeneration. Even so, the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited. However, multi-drug combinations may provide a new avenue for drug therapy for AD. In addition, early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.

An Assay for Screening Potential Drug Candidates for Alzheimer's Disease That Act as Chaperones of the Transthyretin and Amyloid-β Peptides Interaction.

The protein transthyretin (TTR) modulates amyloid-β (Aβ) peptides deposition and processing and this physiological effect is further enhanced by treatment with iododiflunisal (IDIF), a small-molecule compound (SMC) with TTR tetramer stabilization properties, which behaves as chaperone of the complex. This knowledge has prompted us to design and optimize a rapid and simple high-throughput assay that relies on the ability of test compounds to form ternary soluble complexes TTR/Aβ/SMC that prevent Aβ aggregation. The method uses the shorter Aβ(12-28) sequence which is cheaper and simpler to use while retaining the aggregation properties of their parents Aβ(1-40) and Aβ(1-42). The test is carried out in 96-plate wells that are UV monitored for turbidity during 6 h. Given its reproducibility, we propose that this test can be a powerful tool for efficient screening of SMCs that act as chaperones of the TTR/Aβ interaction that may led to potential AD therapies.

Anti-Neuroinflammatory Potential of Polyphenols by Inhibiting NF-κB to Halt Alzheimer's Disease.

Alzheimer's disease (AD) is an irrevocable chronic brain disorder featured by neuronal loss, microglial accumulation, and progressive cognitive impairment. The proper pathophysiology of this life-threatening disorder is not completely understood and no exact remedies have been found yet. Over the last few decades, research on AD has mainly highlighted pathomechanisms linked to a couple of the major pathological hallmarks, including extracellular senile plaques made of amyloid-β (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs) made of tau proteins. Aβ can induce apoptosis, trigger an inflammatory response, and inhibit the synaptic plasticity of the hippocampus, which ultimately contributes to reducing cognitive functions and memory impairment. Recently, a third disease hallmark, the neuroinflammatory reaction that is mediated by cerebral innate immune cells, has become a spotlight in the current research area, assured by pre-clinical, clinical, and genetic investigations. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a cytokine producer, is significantly associated with physiological inflammatory proceedings and thus shows a promising candidate for inflammation- based AD therapy. Recent data reveal that phytochemicals, mainly polyphenol compounds, exhibit potential neuroprotective functions and these may be considered as a vital resource for discovering several drug candidates against AD. Interestingly, phytochemicals can easily interfere with the signaling pathway of NF-κB. This review represents the anti-neuroinflammatory potential of polyphenols as inhibitors of NF-κB to combat AD pathogenesis.

Targeting isoaspartate-modified A\u03b2 rescues behavioral deficits in transgenic mice with Alzheimer\u2019s disease-like pathology

BackgroundAmyloid β (Aβ)-directed immunotherapy has shown promising results in preclinical and early clinical Alzheimer’s disease (AD) trials, but successful translation to late clinics has failed so far. Compelling evidence suggests that post-translationally modified Aβ peptides might play a decisive role in onset and progression of AD and first clinical trials targeting such Aβ variants have been initiated. Modified Aβ represents a small fraction of deposited material in plaques compared to pan-Aβ epitopes, opening up pathways for tailored approaches of immunotherapy. Here, we generated the first monoclonal antibodies that recognize l-isoaspartate-modified Aβ (isoD7-Aβ) and tested a lead antibody molecule in 5xFAD mice.MethodsThis work comprises a combination of chemical and biochemical techniques as well as behavioral analyses. Aβ peptides, containing l-isoaspartate at position 7, were chemically synthesized and used for immunization of mice and antibody screening methods. Biochemical methods included anti-isoD7-Aβ monoclonal antibody characterization by surface plasmon resonance, immunohistochemical staining of human and transgenic mouse brain, and the development and application of isoD7-Aβ ELISA as well as different non-modified Aβ ELISA. For antibody treatment studies, 12 mg/kg anti-isoD7-Aβ antibody K11_IgG2a was applied intraperitoneally to 5xFAD mice for 38 weeks. Treatment controls implemented were IgG2a isotype as negative and 3D6_IgG2a, the parent molecule of bapineuzumab, as positive control antibodies. Behavioral studies included elevated plus maze, pole test, and Morris water maze.ResultsOur advanced antibody K11 showed a KD in the low nM range and > 400fold selectivity for isoD7-Aβ compared to other Aβ variants. By using this antibody, we demonstrated that formation of isoD7-Aβ may occur after formation of aggregates; hence, the presence of the isoD7-modification differentiates aged Aβ from newly formed peptides. Importantly, we also show that the Tottori mutation responsible for early-onset AD in a Japanese pedigree is characterized by massively accelerated formation of isoD7-Aβ in cell culture. The presence of isoD7-Aβ was verified by K11 in post mortem human cortex and 5xFAD mouse brain tissue. Passive immunization of 5xFAD mice resulted in a significant reduction of isoD7-Aβ and total Aβ in brain. Amelioration of cognitive impairment was demonstrated by Morris water maze, elevated plus maze, pole, and contextual fear conditioning tests. Interestingly, despite the lower abundance of the isoD7-Aβ epitope, the application of anti-isoD7-Aβ antibodies showed comparable treatment efficacy in terms of reduction of brain amyloid and spatial learning but did not result in an increase of plasma Aβ concentration as observed with 3D6 treatment.ConclusionsThe present study demonstrates, for the first time, that the antibody-mediated targeting of isoD7-modified Aβ peptides leads to attenuation of AD-like amyloid pathology. In conjunction with previously published data on antibodies directed against pGlu-modified Aβ, the results highlight the crucial role of modified Aβ peptides in AD pathophysiology. Hence, the results also underscore the therapeutic potential of targeting modified amyloid species for defining tailored approaches in AD therapy.

Medical algorithm: Diagnosis of atopic dermatitis in early childhood (part I).

Atopic dermatitis (AD, atopic eczema) is a chronic, relapsing, pruritic, non-communicable inflammatory skin disease that affects children and adults1 . It almost always has its debut in early life2,3 , therefore this medical algorithm focuses on diagnosis (part I) and therapy (part II4 ) of AD in early childhood, which is defined by UNESCO as 'the period from birth to eight years old'.

Imbalance of Endocannabinoid/Lysophosphatidylinositol Receptors Marks the Severity of Alzheimer's Disease in a Preclinical Model: A Therapeutic Opportunity.

Simple SummaryAlzheimer’s disease (AD) remains a major challenge for the healthcare system worldwide and, to date, no curative treatment is available. This disease is an irreversible progressive dementia that harms memory and cognitive functions, weakening the ability to carry out tasks by themselves. Among the potential targets for developing innovative therapies for AD, the endocannabinoid system has aroused much interest in the scientific community, since it is involved in multiple processes related to AD pathology. A major challenge to understand the role of the cannabinoid system in AD is to characterize how it contributes to the expression of a specific phenotype, from neuropathology to behavior. In the present study, we addressed this challenge by evaluating the expression of the endocannabinoid system in a transgenic mouse model of AD, bearing five familial AD mutations. Our data suggest that there is an association between the cannabinoid receptors and both the cognitive function and inflammatory response characterizing the disease. Moreover, this association is aggravated by genetic factors. From these data, the expression of endocannabinoid and G protein-coupled 55 receptors (GPR55), and endocannabinoid-related enzymes might be candidate markers for the detection of the severity of this neurodegenerative disease, eventually arising as potential therapeutic targets capable of modifying the course of this incapacitating dementia.Alzheimer’s disease (AD) is the most common form of neurodegeneration and dementia. The endocannabinoid (ECB) system has been proposed as a novel therapeutic target to treat AD. The present study explores the expression of the ECB system, the ECB-related receptor GPR55, and cognitive functions (novel object recognition; NOR) in the 5xFAD (FAD: family Alzheimer’s disease) transgenic mouse model of AD. Experiments were performed on heterozygous (HTZ) and homozygous (HZ) 11 month old mice. Protein expression of ECB system components, neuroinflammation markers, and β-amyloid (Aβ) plaques were analyzed in the hippocampus. According to the NOR test, anxiety-like behavior and memory were altered in both HTZ and HZ 5xFAD mice. Furthermore, both animal groups displayed a reduction of cannabinoid (CB1) receptor expression in the hippocampus, which is related to memory dysfunction. This finding was associated with indirect markers of enhanced ECB production, resulting from the combination of impaired monoacylglycerol lipase (MAGL) degradation and increased diacylglycerol lipase (DAGL) levels, an effect observed in the HZ group. Regarding neuroinflammation, we observed increased levels of CB2 receptors in the HZ group that positively correlate with Aβ’s accumulation. Moreover, HZ 5xFAD mice also exhibited increased expression of the GPR55 receptor. These results highlight the importance of the ECB signaling for the AD pathogenesis development beyond Aβ deposition.

The Neuropeptide Kyotorphin as a Possible Biomarker and Neuroprotective Agent in Alzheimer’s Disease

Summary Alzheimer’s disease (AD) is an age-related neurodegenerative disorder clinically characterized by memory impairment, disorientation, cognitive deficits, and behavioral disturbances. The neuropathological features are amyloid plaques containing aggregated amyloid-beta (Aβ) peptide, neurofibrillary tangles composed of the hyperphosphorylated form of the microtubule protein tau (HP-tau), and loss of neurons and synapses in the brain. There are no effective strategies for the prevention or treatment of the disease, leading to an increased need for AD biomarkers to improve early detection, accurate diagnosis, and accelerate drug development in this field. Recently, increasing attention has been dedicated to neuropeptides in searching for new drug targets in the treatment of nervous system disorders. Available data suggest that many neuropeptides may be associated with the pathophysiology and potential therapy of AD because of their wide distribution in brain areas responsible for learning and memory processes and their predominately neuroprotective actions. This short review aimed to briefly describe the neuropathology of AD and summarize the data related to one of its recently proposed biomarker - kyotorphin (KTP) neuropeptide. Our previous experiments showed moderate and selective protective effects of KTP against the late consequences of the intracerebroventricular streptozotocin-induced AD model.

Repurposed agents in the Alzheimer\u2019s disease drug development pipeline

BackgroundTreatments are needed to address the growing prevalence of Alzheimer’s disease (AD). Clinical trials have failed to produce any AD drugs for Food and Drug Administration (FDA) approval since 2003, and the pharmaceutical development process is both time-consuming and costly. Drug repurposing provides an opportunity to accelerate this process by investigating the AD-related effects of agents approved for other indications. These drugs have known safety profiles, pharmacokinetic characterization, formulations, doses, and manufacturing processes.MethodsWe assessed repurposed AD therapies represented in Phase I, Phase II, and Phase III of the current AD pipeline as registered on ClinicalTrials.gov as of February 27, 2020.ResultsWe identified 53 clinical trials involving 58 FDA-approved agents. Seventy-eight percent of the agents in trials had putative disease-modifying mechanisms of action. Of the repurposed drugs in the pipeline 20% are hematologic-oncologic agents, 18% are drugs derived from cardiovascular indications, 14% are agents with psychiatric uses, 12% are drug used to treat diabetes, 10% are neurologic agents, and the remaining 26% of drugs fall under other conditions. Intellectual property strategies utilized in these programs included using the same drug but altering doses, routes of administration, or formulations. Most repurposing trials were supported by Academic Medical Centers and were not funded through the biopharmaceutical industry. We compared our results to a European trial registry and found results similar to those derived from ClinicalTrials.gov.ConclusionsDrug repurposing is a common approach to AD drug development and represents 39% of trials in the current AD pipeline. Therapies from many disease areas provide agents potentially useful in AD. Most of the repurposed agents are generic and a variety of intellectual property strategies have been adopted to enhance their economic value.

Selection of mutant \xb5plasmin for amyloid-\u03b2 cleavage in vivo

One of the main culprits of Alzheimer’s disease (AD) is the formation of toxic amyloid-β (Aβ) peptide polymers and the aggregation of Aβ to form plaques in the brain. We have developed techniques to purify the catalytic domain of plasmin, micro-plasmin (µPlm), which can be used for an Aβ-clearance based AD therapy. However, in serum, µPlm is irreversibly inhibited by its principal inhibitor α2-antiplasmin (α2-AP). In this study, we engineered and selected mutant forms of µPlm that are both catalytically active and insensitive to α2-AP inhibition. We identified surface residues of μPlm that might interact and bind α2-AP, and used an alanine-scanning mutagenesis method to select residues having higher activity but lower α2-AP inhibition. Then we employed saturation mutagenesis for further optimize both properties. Modeled complex structure of µPlm/α2-AP shows that F587 is a critical contact residue, which can be used as a starting position for further investigation.

What are the sociodemographic and gender determinants of non-fatal self-harm in older adult users and non-users of antidepressants? A national population-based study

BackgroundLate-life self-harm (SH) is often linked to depression. However, very few studies have explored the role of other factors and their interaction with depression in the occurrence of late-life SH. The objective of this research was to examine sociodemographic and gender factors associated with non-fatal SH, in older adults with and without antidepressant therapy.MethodsWe used national longitudinal register data from a total cohort of all Swedish residents aged ≥75 years between 2006 and 2014 (N = 1,413,806). Using personal identity numbers, we linked individuals’ data from numerous national registers. We identified all those with at least one episode of non-fatal self-harm (regardless of level of intent to die) and matched 50 controls to each case. A nested case–control design was used to investigate sociodemographic factors associated with non-fatal SH in the total cohort and among antidepressant users and non-users. Risk factors were analysed in adjusted conditional logistic regression models for the entire cohort and by gender.ResultsIn all, 2242 individuals had at least one episode of a non-fatal SH (980 men and 1262 women). Being unmarried was a risk factor for non-fatal SH in men but not in women. Among users of antidepressants, higher non-fatal SH risk was observed in those born outside the Nordic countries (IRR: 1.44; 95% CI: 1.11–1.86), whereas in AD non-users increased risk was seen in those from Nordic countries other than Sweden (IRR: 1.58; 95% CI: 1.08–2.29). Antidepressant users with higher education had an increased risk of non-fatal SH (IRR: 1.34; 95% CI: 1.12–1.61), in both men and women.ConclusionsForeign country of birth was associated with increased risk for non-fatal SH in older adults with and without AD therapies. Being married was a protective factor for non-fatal SH in men. The complex association between sociodemographic factors and use of antidepressants in the occurrence of self-harm in older men and women indicates the need for multifaceted tailored preventive strategies including healthcare and social services alike.

Characterization of lactic acid bacteria derived exopolysaccharides for use as a defined neuroprotective agent against amyloid beta1\u201342-induced apoptosis in SH-SY5Y cells

Alzheimer’s disease (AD) is a disease characterized by cerebral neuronal degeneration and loss in a progressive manner. Amyloid beta (Aβ) in the brain is toxic to neurons, being a main risk factor for initiation and continuation of cognitive deterioration in AD. Neurotoxicity of Aβ origin is also linked to oxidative stress characterized by excessive lipid peroxidation, protein oxidation, changes in antioxidant systems, and cerebral DNA damage in AD. Furthermore, Aβ can induce oxidative neuronal cell death by a mitochondrial dysfunction. Cellular injury caused by oxidative stress can be possibly prevented by boosting or promoting bodily oxidative defense system by supplying antioxidants in diet or as medications. However, most synthetic antioxidants are found to have cytotoxicity, which prevents their safe use, and limits their administration. For this reason, more attention has been paid to the natural non-toxic antioxidants. One of the most promising groups of non-toxic antioxidative compounds is thought to be polysaccharides. This study investigated the characterization and protective action exerted by exopolysaccharides (EPSs) originated from Lactobacillus delbrueckii ssp. bulgaricus B3 and Lactobacillus plantarum GD2 to protect from apoptotic activity exerted by Aβ1-42 among SH-SY5Y cells. We characterized EPSs by elemental analysis, FTIR, AFM, SEM, and XRD. The antioxidant effects of EPSs were determined by the DPPH free radical scavenging activity, hydroxyl radical scavenging activity, metal ion chelating activity, lipid peroxidation inhibitory activity, and superoxide anion scavenging activity method. The protective effects of EPSs were determined by flow cytometry and RT-PCR. Mannose ratio, molecular weight, functional groups, surface morphology, and amorphous character structure of EPSs are thought to play a role in the protective effect of EPSs. EPSs reduced apoptotic activity of Aβ1-42 in addition to their depolarizing effect on mitochondrial membrane potential in concentration-dependent manner. These observations contribute the inclusion of EPSs among the therapeutic options used to manage various neurological disorders in the traditional medicine in a scientific manner, indicating that EPSs may be promising natural chemical constituents that need advanced research and development for pharmacological therapy of AD.

Dehydroepiandrosterone (DHEA) and its Sulphate (DHEAS) in Alzheimer’s Disease

Neurosteroids Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulphate (DHEAS) are involved in many important brain functions, including neuronal plasticity and survival, cognition and behavior, demonstrating preventive and therapeutic potential in different neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease. The aim of the article was to provide a comprehensive overview of the literature on the involvement of DHEA and DHEAS in Alzheimer's disease. PubMed and MEDLINE databases were searched for relevant literature. The articles were selected considering their titles and abstracts. In the selected full texts, lists of references were searched manually for additional articles. We performed a systematic review of the studies investigating the role of DHEA and DHEAS in various in vitro and animal models, as well as in patients with Alzheimer's disease, and provided a comprehensive discussion on their potential preventive and therapeutic applications. Despite mixed results, the findings of various preclinical studies are generally supportive of the involvement of DHEA and DHEAS in the pathophysiology of Alzheimer's disease, showing some promise for potential benefits of these neurosteroids in the prevention and treatment. However, so far small clinical trials brought little evidence to support their therapy in AD. Therefore, large-scale human studies are needed to elucidate the specific effects of DHEA and DHEAS and their mechanisms of action, prior to their applications in clinical practice.

Dynamics of plasma biomarkers in Down syndrome: the relative levels of A\u03b242 decrease with age, whereas NT1 tau and NfL increase

BackgroundDown syndrome (DS) is the most common genetic cause of Alzheimer’s disease (AD), but diagnosis of AD in DS is challenging due to the intellectual disability which accompanies DS. When disease-modifying agents for AD are approved, reliable biomarkers will be required to identify when and how long people with DS should undergo treatment. Three cardinal neuropathological features characterize AD, and AD in DS—Aβ amyloid plaques, tau neurofibrillary tangles, and neuronal loss. Here, we quantified plasma biomarkers of all 3 neuropathological features in a large cohort of people with DS aged from 3 months to 68 years. Our primary aims were (1) to assess changes in the selected plasma biomarkers in DS across age, and (2) to compare biomarkers measured in DS plasma versus age- and sex-matched controls.MethodsUsing ultra-sensitive single molecule array (Simoa) assays, we measured 3 analytes (Aβ42, NfL, and tau) in plasmas of 100 individuals with DS and 100 age- and sex-matched controls. Tau was measured using an assay (NT1) which detects forms of tau containing at least residues 6–198. The stability of the 3 analytes was established using plasma from ten healthy volunteers collected at 6 intervals over a 5-day period.ResultsHigh Aβ42 and NT1 tau and low NfL were observed in infants. Across all ages, Aβ42 levels were higher in DS than controls. Levels of Aβ42 decreased with age in both DS and controls, but this decrease was greater in DS than controls and became prominent in the third decade of life. NT1 tau fell in adolescents and young adults, but increased in older individuals with DS. NfL levels were low in infants, children, adolescents, and young adults, but thereafter increased in DS compared to controls.ConclusionsHigh levels of Aβ42 and tau in both young controls and DS suggest these proteins are produced by normal physiological processes, whereas the changes seen in later life are consistent with emergence of pathological alterations. These plasma biomarker results are in good agreement with prior neuropathology studies and indicate that the third and fourth decades (i.e., 20 to 40 years of age) of life are pivotal periods during which AD processes manifest in DS. Application of the assays used here to longitudinal studies of individuals with DS aged 20 to 50 years of age should further validate the use of these biomarkers, and in time may allow identification and monitoring of people with DS best suited for treatment with AD therapies.