Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2), the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.

The Effects of Microglia on Tauopathy Progression Can Be Quantified Using Nexopathy in Silico (Nexis) Models

The prion-like transsynaptic propagation of misfolded tau along the brain’s connectome has previously been modeled using connectome-based network diffusion models. In addition to the connectome, interactions between the general neurological ‘milieu’ in the neurodegenerative brain and proteinopathic species can also contribute to pathology propagation. Such a molecular nexopathy framework posits that the distinct characteristics of neurodegenerative disorders stem from interactions between the network and surrounding molecular players. However, the effects of these modulators remain unquantified. Here, we present Nexopathy in silico (‘Nexis’), a quantitative model of tau progression augmenting earlier models by including parameters of pathology propagation defined by the molecular modulators of connectome-based spread. Our Nexis:microglia model provides the first quantitative characterization of this effect on the whole brain by expanding previous models of neuropathology progression by incorporating microglial influence. We show that Trem2, but not microglial homeostasis genes, significantly improved the model’s predictive power. Trem2 appears to reduce tau accumulation rate while increasing its interregional spread from the hippocampal seed area, causing higher tau burden in the striatum, pallidum, and contralateral hippocampus. Nexis thus provides an improved understanding and quantification of microglial contribution to tau propagation and can be flexibly modified to include other modulators of progressive neurodegeneration.

Natural product-based nanomedicine: Recent advances and issues for the treatment of Alzheimer's disease

: Alzheimer's disease (AD) affects the elderly and is characterized by progressive neurodegeneration caused by different pathologies. The most significant challenges in treating AD include the inability of medications to reach the brain because of its poor solubility, low bioavailability, and the presence of the blood-brain barrier (BBB). Additionally, current evidence suggests the disruption of BBB plays an important role in the pathogenesis of AD. One of the critical challenges in treating AD is the ineffective treatments and its severe adverse effects. Nanotechnology offers an alternative approach to facilitate the treatment of AD by overcoming the challenges in drug transport across the BBB. Various nanoparticles (NP) loaded with natural products were reported to aid in drug delivery for the treatment of AD. The nano- sized entities of NP are great platforms for incorporating active materials from natural products into formulations that can be delivered effectively to the intended action site without compromising the material’s bioactivity. The review highlights the applications of medicinal plants, their derived components, and various nanomedicine-based approaches for the treatment of AD. The combination of medicinal plants and nanotechnology may lead to new theragnostic solutions for the treatment of AD in the future.

Niemann–Pick type C disease with a novel intronic mutation: three Turkish cases from the same family

Objectives Niemann–Pick type C (NPC) disease is a rare progressive neurodegenerative condition that is characterized by the accumulation of cholesterol, glycosphingolipids, and sphingosine in lysosomes. Patients have various systemic and neurological findings depending on their age at onset. This disease is caused by the autosomal recessive transmission of mutations in the NPC1 and NPC2 genes; patients have mutations mainly in the NPC1 gene (95%) and the majority of them are point mutations located in the exonic regions. Case presentation Here, we presented three cousins with hepatosplenomegaly and progressive neurodegeneration who were diagnosed with visceral-neurodegenerative NPC disease. Their parents were relatives, and they had a history of sibling death with similar complaints. Bone marrow smear showed foamy cells in patient 1. Vertical supranuclear gaze palsy was not present in all cases. Sphingomyelinase (SM) activities were almost normal to exclude NPA or NPB. Filipin staining was performed in patient 2 and showed a massive accumulation of unesterified cholesterol The NPC1 gene analysis of the three patients showed a novel homozygous c.1553+5G>A intronic mutation. cDNA analysis was performed from the patient 3 and both parents. It was observed that exon 9 was completely skipped in the homozygous mutant baby. Both the normal and the exon 9-skipped transcripts have been detected in the parents. Conclusions When combined with the filipin staining and the patients’ clinical outcomes, this mutation is likely to be deleterious. Moreover, cDNA sequencing supports the pathogenicity of this novel variant.

A Revisit to Etiopathogenesis and Therapeutic Strategies in Alzheimer’s Disease

: Dementia is a cluster of brain abnormalities that trigger progressive memory deficits and other cognitive abilities such as skills, language, or executive function. Alzheimer’s disease (AD) is the foremost type of age-associated dementia that involves progressive neurodegeneration accompanied by profound cognitive deficits in advanced stages that severely hamper social or occupational abilities with or without the involvement of any other psychiatric condition. The last two decades witnessed a sharp increase (~123%) in mortality due to AD type dementia, typically owing to a very low disclosure rate (~45%) and hence, the prophylactic, as well as the therapeutic cure of AD, has been a huge challenge. Although understanding of AD pathogenesis has witnessed a remarkable growth (e.g., tauopathy, oxidative stress, lipid transport, glucose uptake, apoptosis, synaptic dysfunction, inflammation, and immune system), still a dearth of an effective therapeutic agent in the management of AD prompts the quest for newer pharmacological targets in the purview of its growing epidemiological status. Most of the current therapeutic strategies focus on modulation of a single target, e.g., inhibition of acetylcholinesterase, glutamate excitotoxicity (memantine), or nootropics (piracetam), even though AD is a multifaceted neurological disorder. There is an impedance urgency to find not only symptomatic but effective disease-modifying therapies. The present review focuses on the risk / protective factors and pathogenic mechanisms involved in AD. In addition to the existing symptomatic therapeutic approach, a diverse array of possible targets linked to pathogenic cascades have been re-investigated to envisage the pharmacotherapeutic strategies in AD.

Alterations of Plasma Galectin-3 and C3 Levels in Patients with Parkinson’s Disease

Parkinson’s disease (PD) is characterized by progressive neurodegeneration of dopaminergic neurons in the ventral midbrain. The complement-phagosome pathway is involved in the pathogenesis of PD. Here we measured levels of complement-phagocytosis molecules, including galectin-3, C3, C4, and cathepsin D, in the plasma of 56 patients with PD, and 46 normal controls (NCs). Plasma levels of galectin-3 (9.93 ± 3.94 ng/mL) were significantly higher in PD patients compared with NCs (8.39 ± 1.95 ng/mL, p = 0.012), and demonstrated a positive correlation with Hoehn and Yahr stages in PD patients (R2 = 0.218, p < 0.001). On the other hand, plasma C3 levels were significantly lower in PD patients (305.27 ± 205.16 μg/mL) compared with NCs (444.34 ± 245.54 μg/mL, p = 0.002). However, the levels did not correlate with Hoehn and Yahr stages (R2 = 0.010, p = 0.469). Plasma levels of C4 and cathepsin D in PD patients were similar to those in NCs. Our results show possible altered complement-phagocytosis signals in the peripheral blood of PD patients, highlighting the potential of galectin-3 as a biomarker of PD.

L-Arginine Ameliorates Defective Autophagy in GM2 Gangliosidoses by mTOR Modulation

Aims: Tay–Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by β-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay–Sachs and Sandhoff diseases. Results: Pathological autophagosomes with impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities. Innovation: Our data provide a novel molecular mechanism underlying GM2 gangliosidosis. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for these diseases. Conclusions: We contend that the expression of autophagy/lysosome/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy.

Oxidative Stress Caused by Ozone Exposure Induces Changes in P2X7 Receptors, Neuroinflammation, and Neurodegeneration in the Rat Hippocampus

Low-ozone doses cause alterations in the oxidation-reduction mechanisms due to the increase in reactive oxygen species, alter cell signaling, and produce deleterious metabolic responses for cells. Adenosine 5 ′ triphosphate (ATP) can act as a mediator in intercellular communication between neurons and glial cells. When there is an increase in extracellular ATP, a modification is promoted in the regulation of inflammation, energy metabolism, by affecting the intracellular signaling pathways that participate in these processes. The objective of this work was to study changes in the P2X7 receptor, and their relationship with the inflammatory response and energy metabolism, in a model of progressive neurodegeneration in the hippocampus of rats chronically exposed to low-ozone doses. Therefore, 72 male rats were exposed to low-ozone doses for different periods of time. After exposure to ozone was finished, rats were processed for immunohistochemical techniques, western blot, quantitative polymerase chain reaction (qPCR), and histological techniques for periodic acid-Schiff staining. The results showed immunoreactivity changes in the amount of the P2X7 protein. There was an increase in phosphorylation for glycogen synthase kinase 3-β (GSK3-β) as treatment continued. There were also increases in 27 interleukin 1 beta (IL-1 β) and interleukin 17 (IL-17) and a decrease in interleukin 10 (IL-10). Furthermore, neuronal glycogen was found at 30 and 60 days, and an increase in caspase 3. An increase in mRNA was also shown for the P2X7 gene at 60 days, and GSK3-β at 90 days of exposure. In conclusion, these results suggest that repeated exposure to low-ozone doses, such as those that can occur during highly polluted days, causes a state of oxidative stress, leading to alterations in the P2X7 receptors, which promote changes in the activation of signaling pathways for inflammatory processes and cell death, converging at a progressive neurodegeneration process, as may be happening in Alzheimer’s disease.

Treatment of Multiple Sclerosis

A comprehensive and ideal approach to treatment of multiple sclerosis (MS) has 5 levels of intervention. They are 1) prevention of active disease (clinical or subclinical relapses) in the first place, to prevent cumulative relapse-associated disability burden; 2) shortening the duration of active inflammatory demyelination associated with relapses, to limit the extent of irreversible central nervous system injury; 3) induction of more complete recovery after a relapse, to prevent or delay an ensuing chronic progressive neurodegeneration; 4) slowing the progressive phase of MS after progression ensues; and 5) treatment of symptoms and complications. The ultimate combined goal of these intervention levels is to alter the natural history of MS and prevent progression responsible for the main quantity of disability in MS, thereby improving the quality of life for patients with MS. Currently, treating physicians can accomplish levels 1, 2, and 5. Level 3 and level 4 interventions are yet to be developed sufficiently to affect the disease course meaningfully.

Advancement of PD Is Reflected by White Matter Changes in Olfactory Areas: A Pilot Study

Loss of sense of smell is a well-known non-motor symptom of Parkinson’s disease (PD). Here, we present insight into the association between PD advancement and equivalents of smell loss in olfactory-eloquent brain areas, such as the posterior cortex and orbitofrontal cortex. Twelve PD patients in different Hoehn and Yahr stages and 12 healthy normosmic individuals were examined with diffusion tensor imaging. Tract-based spatial statistics were used to analyze microstructural changes in white matter adjacent to the bilateral posterior and orbitofrontal cortex. Axial diffusivity, mean diffusivity, and radial diffusivity were significantly higher in olfactory ROIs in advanced PD patients. The results of this preliminary study indicate that PD advancement is associated with progressive neurodegeneration in olfactory-related brain areas.