Endocytic pathways of pathogenic protein aggregates in neurodegenerative diseases

Endocytosis is the fundamental uptake process through which cells internalize extracellular materials and species. Neurodegenerative diseases (NDs) are characterized by a progressive accumulation of intrinsically disordered protein species, leading to neuronal death. Misfolding in many proteins leads to various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other disorders. Despite the significance of disordered protein species in neurodegeneration, their spread between cells and the cellular uptake of extracellular species is not entirely understood. This review discusses the major internalization mechanisms of the different conformer species of these proteins and their endocytic mechanisms. We briefly introduce the broad types of endocytic mechanisms found in cells and then summarize what is known about the endocytosis of monomeric, oligomeric and aggregated conformations of tau, Aβ, α-Syn, Huntingtin, Prions, SOD1, TDP-43 and other proteins associated with neurodegeneration. We also highlight the key players involved in internalizing these disordered proteins and the several techniques and approaches to identify their endocytic mechanisms. Finally, we discuss the obstacles involved in studying the endocytosis of these protein species and the need to develop better techniques to elucidate the uptake mechanisms of a particular disordered protein species.     

Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin

Declining nicotinamide adenine dinucleotide (NAD⁺) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders. Experimental therapies aimed at boosting brain NAD⁺ levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD⁺ precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD⁺ levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD⁺ levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo-controlled crossover trial (NCT02921659) of oral NR supplementation (500 mg, 2x /day, 6 weeks). We demonstrate that oral NR supplementation increases NAD⁺ levels in NEVs and decreases NEV levels of Aβ42, pJNK, and pERK1/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin–Akt signaling proteins and changes in pERK1/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD⁺ levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood-based window into monitoring the physiologic response of NR in the brain.     

N-glycosylation induced changes in tau protein dynamics reveal its role in tau misfolding and aggregation: A microsecond long molecular dynamics study

Various posttranslational modifications like hyperphosphorylation, O-GlcNAcylation, and acetylation have been attributed to induce the abnormal folding in tau protein. Recent in vitro studies revealed the possible involvement of N-glycosylation of tau protein in the abnormal folding and tau aggregation. Hence, in this study, we performed a microsecond long all atom molecular dynamics simulation to gain insights into the effects of N-glycosylation on Asn-359 residue which forms part of the microtubule binding region. Trajectory analysis of the stimulations coupled with essential dynamics and free energy landscape analysis suggested that tau, in its N-glycosylated form tends to exist in a largely folded conformation having high beta sheet propensity as compared to unmodified tau which exists in a large extended form with very less beta sheet propensity. Residue interaction network analysis of the lowest energy conformations further revealed that Phe378 and Lys353 are the functionally important residues in the peptide which helped in initiating the folding process and Phe378, Lys347, and Lys370 helped to maintain the stability of the protein in the folded state.     

Metabolic defects shared by Alzheimer's disease and diabetes: A focus on mitochondria

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two global epidemics that share several metabolic defects, such as insulin resistance, impaired glucose metabolism, and mitochondrial defects. Importantly, strong evidence demonstrates that T2D significantly increases the risk of cognitive decline and dementia, particularly AD. Here, we provide an overview of the metabolic defects that characterize and link both pathologies putting the focus on mitochondria. The biomarker potential of mitochondrial components and the therapeutic potential of some drugs that target and modulate mitochondria are also briefly discussed.     

Individual day-to-day variations in plasma amino acid levels in healthy persons

Summary Fasting plasma levels of the large neutral amino acids (LNAA;l-forms) andl-tryptophan (TRP) ratios were determined in thirteen healthy volunteers (7 males, 6 females) on five consecutive mornings, and the same procedure was repeated for each individual three months later. We found characteristic overall ranges for the parameters studied, and, in addition to certain differences between the sexes, considerable inter- and intraindividual daily variations. Although the individuals showed statistically identifiable mean levels that, in the majority of subjects, were maintained over a period of three months, it is concluded that the degree of intraindividual variability does not allow us to regard a single value as characteristic for a given individual. This should be borne in mind in particular in follow-up studies of plasma LNAA in patients with, for example, depressive disorders.     

Prevalence and trends of common mental disorders from 2007-2009 to 2019-2022: results from the Netherlands Mental Health Survey and Incidence Studies (NEMESIS), including comparison of prevalence rates before vs. during the COVID-19 pandemic

Up-to-date information on the prevalence and trends of common mental disorders is relevant to health care policy and planning, owing to the high burden associated with these disorders. In the first wave of the third Netherlands Mental Health Survey and Incidence Study (NEMESIS-3), a nationally representative sample was interviewed face-to-face from November 2019 to March 2022 (6,194 subjects; 1,576 interviewed before and 4,618 during the COVID-19 pandemic; age range: 18-75 years). A slightly modified version of the Composite International Diagnostic Interview 3.0 was used to assess DSM-IV and DSM-5 diagnoses. Trends in 12-month prevalence rates of DSM-IV mental disorders were examined by comparing these rates between NEMESIS-3 and NEMESIS-2 (6,646 subjects; age range: 18-64 years; interviewed from November 2007 to July 2009). Lifetime DSM-5 prevalence estimates in NEMESIS-3 were 28.6% for anxiety disorders, 27.6% for mood disorders, 16.7% for substance use disorders, and 3.6% for attention-deficit/hyperactivity disorder. Over the last 12 months, prevalence rates were 15.2%, 9.8%, 7.1%, and 3.2%, respectively. No differences in 12-month prevalence rates before vs. during the COVID-19 pandemic were found (26.7% pre-pandemic vs. 25.7% during the pandemic), even after controlling for differences in socio-demographic characteristics of the respondents interviewed in these two periods. This was the case for all four disorder categories. From 2007-2009 to 2019-2022, the 12-month prevalence rate of any DSM-IV disorder significantly increased from 17.4% to 26.1%. A stronger increase in prevalence was found for students, younger adults (18-34 years) and city dwellers. These data suggest that the prevalence of mental disorders has increased in the past decade, but this is not explained by the COVID-19 pandemic. The already high mental disorder risk of young adults has particularly further increased in recent years.     

Substance use disorders: a comprehensive update of classification,epidemiology, neurobiology,clinical aspects,treatment and prevention

Substance use disorders (SUDs) are highly prevalent and exact a large toll on individuals’ health, well-being, and social functioning. Long-lasting changes in brain networks involved in reward, executive function, stress reactivity, mood, and self-awareness underlie the intense drive to consume substances and the inability to control this urge in a person who suffers from addiction (moderate or severe SUD). Biological (including genetics and developmental life stages) and social (including adverse childhood experiences) determinants of health are recognized factors that contribute to vulnerability for or resilience against developing a SUD. Consequently, prevention strategies that target social risk factors can improve outcomes and, when deployed in childhood and adolescence, can decrease the risk for these disorders. SUDs are treatable, and evidence of clinically significant benefit exists for medications (in opioid, nicotine and alcohol use disorders), behavioral therapies (in all SUDs), and neuromodulation (in nicotine use disorder). Treatment of SUDs should be considered within the context of a Chronic Care Model, with the intensity of intervention adjusted to the severity of the disorder and with the concomitant treatment of comorbid psychiatric and physical conditions. Involvement of health care providers in detection and management of SUDs, including referral of severe cases to specialized care, offers sustainable models of care that can be further expanded with the use of telehealth. Despite advances in our understanding and management of SUDs, individuals with these conditions continue to be stigmatized and, in some countries, incarcerated, highlighting the need to dismantle policies that perpetuate their criminalization and instead develop policies to ensure support and access to prevention and treatment.     

The Human Obesity Gene Map: The 1996 Update

An update of the human obesity gene map up to October 1996 is presented. Evidence from Mendelian disorders exhibiting obesity as a clinical feature, single-gene mutation rodent models, quantitative trait loci uncovered in crossbreeding experiments with mouse, rat, and pig models, association and case-control studies with candidate genes, and linkage studies with genes and other markers is reviewed. All chromosomal locations of the animal loci are converted into human genome locations based on syntenic relationships between the genomes. A complete listing of all these loci reveals that only 4 of the 24 human chromosomes are not yet represented, i.e., 9, 18, 21, and Y. Several chromosome arms are characterized by the presence of several putative loci. The following arms include at least three such loci: 1p, 1q, 3p, 4q, 6p, 7q, 8p, 8q, 11p, 11q, 15q, 20q, and Xq. Studies with negative association and linkage results are also reviewed.     

Fatty Acid Composition of Human Myelin Proteolipid Protein in Peroxisomal Disorders

Myelin proteolipid protein (PLP) is an acylated protein which contains approximately 2 mol of ester-bound fatty acids. In this study, the amount and composition of fatty acids covalently bound to human myelin PLP were determined during development and in peroxisomal disorders. Palmitic, oleic, and stearic acids accounted for most of the PLP acyl chains. However, in contrast to PLP in other species, human PLP contains relatively more very long chain fatty acids (VLCFA). The fatty acid composition remained essentially unchanged between 1 day and 74 years of age. The total amount of fatty acid bound to PLP was not altered in any of the pathological cases examined. However, in the peroxisomal disorder adrenoleukodystrophy, the proportions of saturated and, to a lesser extent, monounsaturated VLCFA bound to PLP were increased at the expense of oleic acid. Smaller, but significant, changes were observed in adrenomyeloneuropathy. The reduction in the levels of oleic acid was also observed in two other peroxisomal disorders, the cerebrohepatorenal (Zellweger) syndrome and neonatal adrenoleukodystrophy, as well as in the lysosomal disorder Krabbe globoid cell leukodystrophy. However, in these disorders, the decrease in oleic acid occurred at the expense of stearic acid, and not VLCFA. The results indicate that, although a characteristic PLP fatty acid pattern is normally maintained, changes in the acyl chain pool can ultimately be reflected in the fatty acid composition of the protein. The altered PLP-acyl chain pattern in peroxisomal disorders may contribute to the pathophysiology of these devastating disorders.     

Lipoxygenase activity in apples in relation to storage and physiological disorders

Different methods for the preparation of active lipoxygenase (LOX) extracts from apples were compared. Highest activities were obtained using a 0.25 M phosphate buffer (pH 7) containing 1% Triton X-100 and 10^?2 M metabisulphite as extraction solvent. LOX activity during storage was investigated in the core, flesh, and peel. Activity was always highest in the core and peel. On storage, activity was increased in each part of the fruit but especially in the core and peel. Increase in LOX preceded the browning of the core. LOX may be responsible for the browning and may be concerned in the induction of superficial scald.