The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects

The Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimer’s disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to human BIN1 isoform8 (BIN1iso8) and human BIN1 isoform9 (BIN1iso9), induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.

Thiamine as a Possible Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Encephalopathy

On the basis that similar biochemical and histological sequences of events occur in the brain during thiamine deficiency and hypoxia/ischemia related brain damage, we have planned this review to discuss the possible therapeutic role of thiamine and its derivatives in the management of neonatal hypoxic-ischemic encephalopathy (HIE). Among the many benefits, thiamine per se as antioxidant, given intravenously (IV) at high doses, defined as dosage greater than 100 mg IV daily, should counteract the damaging effects of reactive oxygen and nitrogen species in the brain, including the reaction of peroxynitrite with the tyrosine residues of the major enzymes involved in intracellular glucose metabolism, which plays a key pathophysiological role in HIE in neonates. Accordingly, it is conceivable that, in neonatal HIE, the blockade of intracellular progressive oxidative stress and the rescue of mitochondrial function mediated by thiamine and its derivatives can lead to a definite neuroprotective effect. Because therapeutic hypothermia and thiamine may both act on the latent period of HIE damage, a synergistic effect of these therapeutic strategies is likely. Thiamine treatment may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment.

Striatonigrostriatal Spirals in Addiction

A biological reward system is integral to all animal life and humans are no exception. For millennia individuals have investigated this system and its influences on human behavior. In the modern day, with the US facing an ongoing epidemic of substance use without an effective treatment, these investigations are of paramount importance. It is well known that basal ganglia contribute to rewards and are involved in learning, approach behavior, economic choices, and positive emotions. This review aims to elucidate the physiological role of striatonigrostriatal (SNS) spirals, as part of basal ganglia circuits, in this reward system and their pathophysiological role in perpetuating addiction. Additionally, the main functions of neurotransmitters such as dopamine and glutamate and their receptors in SNS circuits will be summarized. With this information, the claim that SNS spirals are crucial intermediaries in the shift from goal-directed behavior to habitual behavior will be supported, making this circuit a viable target for potential therapeutic intervention in those with substance use disorders.

Physiological and Pathophysiological Role of Cysteine Metabolism in Human Metabolic Syndrome

: Cysteine is one of the major intermediate products of cellular amino-acid metabolism. It is a semi-essential amino acid for protein synthesis. Besides, it is also employed in the regulation of major endogenous anti-oxidant molecules i.e., reduced glutathione (GSH). Further, it is a precursor of multiple sulfur-containing molecules like hydrogen sulfide, lanthionine, taurine, coenzyme A and biotin. It is also one of the key molecules for post-translational modifications of various cellular proteins. In physiological conditions, it is employed in the sulfhydration process and plays a key role in the physiology modification of the inflammatory process in various organs, including the neurological system. The catabolism of cysteine is regulated by cysteine dioxygenase enzyme activity. The dysregulated conditions of cysteine and cysteine-associated hydrogen sulfide metabolism are widely employed in the acceleration of the neurodegenerative process. Moreover, the upregulation of cysteine and hydrogen sulfide synthesis occurs via the reverse trans-sulfuration process. This process helps to manage the worsening of a pathological condition of a cellular system. Moreover, it is also employed in the accumulation of homocysteine contents. Further, both cysteine and homocysteine molecules are widely accepted as biomarkers for various types of diseases. Therefore, the targets involved in the regulation of cysteine have been considered as valid targets to treat various disorders like cardiac disease, ischemic stroke, diabetes, cancer, and renal dysfunction.

Evidence for infection in intervertebral disc degeneration: a systematic review

Purpose Back pain is a major problem worldwide and is linked to intervertebral disc degeneration and Modic change. Several studies report growth of bacteria following extraction of degenerate discs at spine surgery. A pathophysiological role for infection in back pain has been proposed. Method We conducted a PRISMA systematic review. MEDLINE, PubMed, Scopus and Web of Science were searched with the terms Modic change, intervertebral dis*, bacteria, microb*, and infect*. Date limits of 2001–2021 were set. Human studies investigating the role of bacteria in disc degeneration or Modic change in vertebrae were included. Results Thirty-six articles from 34 research investigations relating to bacteria in human degenerate discs were found. Cutibacterium acnes was identified in pathological disc material. A ‘candidate bacterium’ approach has been repeatedly adopted which may have biased results to find species a priori, with disc microbial evidence heavily weighted to find C. acnes. Conclusion Evidence to date implicates C. acnes identified through culture, microscopy and sequencing, with some suggestion of diverse bacterial colonisation in the disc. This review found studies which used culture methods and conventional PCR for bacterial detection. Further agnostic investigation using newer methods should be undertaken.

Postoperative proliferative vitreoretinopathy development is linked to vitreal CXCL5 concentrations

The specific changes linked to de novo development of postoperative PVR have remained elusive and were the object of the underlying study. Vitreous fluid (VF) was obtained at the beginning of vitrectomy from 65 eyes that underwent vitrectomy for primary rhegmatogenous retinal detachment (RRD) without preoperative PVR. Eyes developing postoperative PVR within 6 months after re-attachment surgery were compared to those which did not regarding the preoperative concentrations of 43 cytokines and chemokines in the VF, using multiplex beads analysis. For all comparisons Holm’s correction was applied in order to control for multiple comparisons. Twelve out of 65 eyes (18.5%) developed PVR postoperatively. While 12 of the chemokines and cytokines presented concentration differences on a statistical level of p < 0.05 (CXCL5, CCL11, CCL24, CCL26, GM-CSF, IFN-γ, CCL8, CCL7, MIF, MIG/CXCL9, CCL19, and CCL25), CXCL5 was the only cytokine with sufficiently robust difference in its VF concentrations to achieve significance in eyes developing postoperative PVR compared to eyes without PVR. CXCL5 may represent a potent biomarker for the de novo development of postoperative PVR. In line with its pathophysiological role in the development of PVR, it might serve as a basis for the development of urgently needed preventive options.

Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.

Zinc Finger Proteins in Neuro-Related Diseases Progression

Zinc finger proteins (ZNF) are among the most abundant proteins in eukaryotic genomes. It contains several zinc finger domains that can selectively bind to certain DNA or RNA and associate with proteins, therefore, ZNF can regulate gene expression at the transcriptional and translational levels. In terms of neurological diseases, numerous studies have shown that many ZNF are associated with neurological diseases. The purpose of this review is to summarize the types and roles of ZNF in neuropsychiatric disorders. We will describe the structure and classification of ZNF, then focus on the pathophysiological role of ZNF in neuro-related diseases and summarize the mechanism of action of ZNF in neuro-related diseases.