Neurodegenerative Brain Research Articles

From Controversy to Consensus: Neurogenesis and Neuroplasticity

More and more research in recent years has focused on neurogenesis and neuroplasticity. The hippocampus is a key location of adult neurogenesis. Because this part of the brain is regulated by environmental variables, it must be mentioned the therapeutic potential for neurodegenerative illnesses and brain injuries. Furthermore, this information challenges the historical concept of a static brain and tries to demonstrate its flexibility, adaptability, and possibility for regeneration. Those mechanisms which are found in a variety of mammalian species, including humans, are important when it comes to adaptive learning and memory, thus providing insights into cognitive well-being and mental health. The discovery of the brain's dynamic nature represented by new neurons, marks a shift in the field of neurology with far-reaching potentials. This paper highlights the significant potential of adult neurogenesis when it comes to clinical applications such as Alz-heimer’s disease.

Unraveling the thrombin–Alzheimer’s connection: Oral anticoagulants as potential neuroprotective therapeutics

In Alzheimer’s disease (AD), toxic amyloids formed by amyloid-β (Aβ) proteins and tau are implicated in the development of inflammatory, vascular, and neurodegenerative brain disorders. Thrombin has also been recognized as a proteopathic factor involved in Aβ-induced neurovascular dysfunction. Vascular Aβ activates the contact system in the blood, stimulating the production of inflammatory bradykinin and procoagulant thrombin. Thrombin, in turn, triggers inflammation, platelet activation, and the formation of fibrinolysis-resistant, Aβ-containing fibrin clots, leading to Aß-type cerebral amyloid angiopathy and associated neuropathology. Targeting thrombin with oral anticoagulants can normalize proinflammatory and prothrombotic states, counteracting the neurovascular consequences of AD. Pre-clinical studies have shown that such interventions preserve vascular and blood–brain barrier integrity, improve cerebral blood flow and brain perfusion, and reduce parenchymal accumulations of toxic Aβ, tau, fibrin(ogen), and thrombin. These effects mitigate neuroinflammatory and neurodegenerative processes, ultimately preserving cognitive functions for a longer period. Recent observational clinical studies in patients with atrial fibrillation (AF) demonstrated that treatment with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) reduced the risk of dementia by up to 48% compared to non-users. The anti-dementia effects were most prominent in elderly patients but were also observed in individuals with low AF risk or newly diagnosed AF. In addition, DOACs reduced the risk of intracranial hemorrhage by approximately 50% compared to VKAs. The current review highlights the potential neuroprotective role of DOACs in AD. By preventing excessive thrombin generation caused by Aβ pathology, DOACs could protect vascular and neuronal functions, thereby slowing cognitive decline. DOACs, such as dabigatran, apixaban, and rivaroxaban, warrant further clinical investigation for their potential repurposing as disease-modifying therapeutics in AD.

Neurodegenerative fluid biomarkers are enriched in human cervical lymph nodes.

In animal models, brain neurodegeneration biomarkers drain into cervical lymph nodes (CLNs), and this drainage function is reduced with ageing. If this occurred in humans, CLNs may provide a readily accessible measure of this aspect of protein clearance. We tested this hypothesis in people using ultrasound-guided fine needle aspiration (FNA). We measured amyloid-beta 40 and 42, phospho-Tau-181, glial-fibrillary-acidic-protein, and neurofilament-light using single molecule array in CLN aspirates and plasma from: i) a discovery cohort of 25 autoimmune patients, and from ii) plasma, CLNs and capillary blood in four healthy volunteers, an optimisation cohort. FNA was well-tolerated by all participants. In both cohorts, all biomarkers were detected in all plasma and CLN samples, other than neurofilament-light (8/17 of discovery cohort). CLN biomarker concentrations were significantly greater than plasma concentrations for all except neurofilament-light, most markedly for phospho-Tau-181 (266-fold; P<0.02), whose CLN concentrations decreased with age (Spearman r=-0.66, P=0.001). This study presents the first evidence that neurodegenerative biomarkers are detectable in human CLNs. Raised CLN:plasma biomarker ratios suggest their concentration in CLNs may offer a distinct compartment for minimally-invasive measurement of brain clearance and lymphatic drainage, with potential applicability to study of ageing and future clinical trials.

Associations Between High-Density Lipoprotein Cholesterol Efflux and Brain Grey Matter Volume.

Objective: High-density lipoprotein cholesterol efflux function may prevent brain amyloid beta deposition and neurodegeneration. However, the relevance of this finding has not been established in the diverse middle-aged population. Methods: We examined 1826 adults (47% Black adults) who participated in the Dallas Heart Study to determine associations between high-density lipoprotein (HDL) measures and brain structure and function. White matter hyperintensities (WMH) and whole-brain grey matter volume (GMV) were measured using brain MRI, and the Montreal Cognitive Assessment (MoCA) was used to measure neurocognitive function. HDL cholesterol efflux capacity (HDL-CEC) was assessed using fluorescence-labeled cholesterol efflux from J774 macrophages, and HDL particle size measures were assessed using nuclear magnetic resonance (NMR) spectroscopy (LipoScience). Multivariable linear regressions were performed to elucidate associations between HDL-CEC and brain and cognitive phenotypes after adjustment for traditional risk factors such as age, smoking status, time spent in daily physical activity, and education level. Results: Higher HDL-CEC and small HDL particle (HDL-P) concentration were positively associated with higher GMV normalized to total cranial volume (TCV) (GMV/TCV) after adjustment for relevant risk factors (β = 0.078 [95% CI: 0.029, 0.126], p = 0.002, and β = 0.063 [95% CI: 0.014, 0.111], p = 0.012, respectively). Conversely, there were no associations between HDL measures and WMH or MoCA (all p > 0.05). Associations of HDL-CEC and small HDL-P with GMV/TCV were not modified by ApoE-ε4 status or race/ethnicity. Interpretation: Higher HDL cholesterol efflux and higher plasma concentration of small HDL-P were associated with higher GMV/TCV. Additional studies are needed to explore the potential neuroprotective functions of HDL.

Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models.

Parkinson's disease (PD) is characterized by age-dependent neurodegeneration and the accumulation of toxic phosphorylated α-synuclein (pS129-α-syn). The mechanisms underlying these crucial pathological changes remain unclear. Mutations in parkin RBR E3 ubiquitin protein ligase (PARK2), the gene encoding parkin that is phosphorylated by PTEN-induced putative kinase 1 (PINK1) to participate in mitophagy, cause early onset PD. However, current parkin-KO mouse and pig models do not exhibit neurodegeneration. In the current study, we utilized CRISPR/Cas9 technology to establish parkin-deficient monkey models at different ages. We found that parkin deficiency leads to substantia nigra neurodegeneration in adult monkey brains and that parkin phosphorylation decreases with aging, primarily due to increased insolubility of parkin. Phosphorylated parkin is important for neuroprotection and the reduction of pS129-α-syn. Consistently, overexpression of WT parkin, but not a mutant form that cannot be phosphorylated by PINK1, reduced the accumulation of pS129-α-syn. These findings identify parkin phosphorylation as a key factor in PD pathogenesis and suggest it as a promising target for therapeutic interventions.

Agmatine Improves Oxidative Stress Profiles in Rat Brain Tissues Induced by Sodium Azide

Introduction: The brain is highly susceptible to oxidative damage due to excessive oxygen tension, a high concentration of oxidizable substrates, and low antioxidant capacity. Consequently, oxidative stress is linked to several brain disorders and neurodegeneration. Sodium azide is a cytochrome oxidase inhibitor that promotes neurodegeneration by enhancing the release of excitotoxins and inducing oxidative stress through the peroxidation of membrane lipids. This process results in the release of intra-mitochondrial Ca+2 and H2O2 (ROS Dependent-Ca+2 release). Agmatine, a biogenic amine, is also referred to as a free radical scavenger, protecting the brain from membrane collapse, apoptosis, and mitochondrial swelling. Objective: This study was designed to identify the antioxidative effects of agmatine on sodium azide- induced oxidative stress in brain tissues. Methodology: Twenty-four male albino Wistar rats were allocated into two groups: a control group receiving water and a test group administered sodium azide (5 mg/kg, intraperitoneally) for a duration of 14 days. Subsequently, the animals were further subdivided and treated for an additional two weeks with either water or agmatine (100 mg/kg). Behavioral assessments were performed onehour post-agmatine administration, and brain homogenates were prepared for biochemical analyses. Results: The agmatine-treated group exhibited a significant increase (P&lt;0.01) in both the number of entries and the time spent in the light box and the open arms of the light/dark transition box and elevated plus maze tests, respectively. Additionally, agmatine administration significantly enhanced (P&lt;0.01) the total number of squares crossed in the open field test. Biochemical assessments revealed that agmatine treatment significantly reduced (P&lt;0.01) the levels of reactive oxygen species and malondialdehyde. Moreover, it significantly increased (P&lt;0.01) the levels of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and glutathione compared to the control group. Conclusion: The present study revealed that agmatine has substantial effects on oxidative and antioxidant enzyme levels in sodium azide-induced oxidative stress. Agmatine-treated rats exhibited decreased reactive oxygen species levels and improvements in behavioral impairments resulting from sodium azide administration.

Modelling human neuronal catecholaminergic pigmentation in rodents recapitulates age-related neurodegenerative deficits

One key limitation in developing effective treatments for neurodegenerative diseases is the lack of models accurately mimicking the complex physiopathology of the human disease. Humans accumulate with age the pigment neuromelanin inside neurons that synthesize catecholamines. Neurons reaching the highest neuromelanin levels preferentially degenerate in Parkinson’s, Alzheimer’s and apparently healthy aging individuals. However, this brain pigment is not taken into consideration in current animal models because common laboratory species, such as rodents, do not produce neuromelanin. Here we generate a tissue-specific transgenic mouse, termed tgNM, that mimics the human age-dependent brain-wide distribution of neuromelanin within catecholaminergic regions, based on the constitutive catecholamine-specific expression of human melanin-producing enzyme tyrosinase. We show that, in parallel to progressive human-like neuromelanin pigmentation, these animals display age-related neuronal dysfunction and degeneration affecting numerous brain circuits and body tissues, linked to motor and non-motor deficits, reminiscent of early neurodegenerative stages. This model could help explore new research avenues in brain aging and neurodegeneration.

Symposium: What Does the Microbiome Tell Us about Prevention and Treatment of AD/ADRD?

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) are broad-impact multifactorial neurodegenerative diseases. Their complexity presents unique challenges for developing effective therapies. This review highlights research presented at the 2024 Society for Neuroscience meeting which emphasized the gut microbiome's role in AD pathogenesis by influencing brain function and neurodegeneration through the microbiota-gut-brain axis. This emerging evidence underscores the potential for targeting the gut microbiota to treat AD/ADRD.

Bisphenol F-induced precocious genesis of aggressive neurobehavioral response is associated with heightened monoamine oxidase activity and neurodegeneration in zebrafish brain

The production and use of plastics and plastics products has increased dramatically in recent decades. Moreover, their unprotected disposal into ambient life sustaining environment poses a significant health risk. Bisphenol F (BPF) an alternative to bisphenol A (BPA) has been extensively employed for making of plastics. Recent reports have documented the neurotoxic potential of BPF through induction of altered neurochemical profile, microglia-astrocyte-mediated neuroinflammation, oxidative stress, transformed neurobehavioral response, cognitive dysfunction, etc. In the present study, our approach was to understand the underlying mechanism of BPF-persuaded genesis of aggressive neurobehavioral response in zebrafish. The basic findings advocated a temporal transformation in native explorative behaviour and progressive induction of aggressive behavioural response in zebrafish following exposure to BPF. Our neurobehavioral findings supported the argument of oxidative stress-mediated neuromorphological transformation in the periventricular grey zone (PGZ) of the zebrafish brain. In line with earlier reports, our findings also showed that heightened monoamine oxidase (MAO) activity and downregulation in tyrosine hydroxylase expression in the zebrafish brain is associated with the precocious genesis of aggressive neurobehavioral response in zebrafish brain. Our findings also shed light on BPF-instigated apoptotic neuronal death as revealed by augmented chromatin condensation and cleaved caspase-3 expression. Further observation showed that the downregulation of NeuN (a marker of post-mitotic mature neuron) expression provided substantial neurotoxicity, leading to neurodegeneration in the PGZ region of the zebrafish brain. These basic findings grossly advocate that BPF acts as a potent neurotoxicant in transmuting native neurobehavioral response through the induction of oxidative stress, heightened MAO activity and neuromorphological transformation in the zebrafish brain.

Interferon Signature's Members, a Novel Altered Correlation upon Interferon-β Treatment in Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system and is characterized by extensive brain damage and neurodegeneration. Immunological, genetic, and histological analyses of MS patients provide data in support of the concept that autoimmunity plays a crucial role in the condition's course. It has been proposed that MS may be treated with interferon (IFN)-β and other members of the type I family. Low levels of type I IFN in MS patients may affect immunological control, establish the threshold for an IFN therapeutic response, and be"primed" or "fixed" by IFN therapy. This study was conducted as a cross-sectional study. qRT-PCR was used to examine the expression of two critical IFN regulatory genes, IFI44 and MX1, in MS patients receiving IFN-β treatment. The findings demonstrated a considerable rise in the expression of both genes in MS patients treated with IFN-β compared to those newly diagnosed with the illness. In addition, IFI44 and MX1 might be positively associated with their expression after IFN-β therapy and be regarded as IFN-β responsiveness indicators. The IFI44/MX1 axis could act as one of the crucial regulators of the disease following IFN-β treatment.

A timeline study on vascular co-morbidity induced cerebral endothelial dysfunction assessed by perfusion MRI

Endothelial dysfunction is considered a key element in the early pathogenesis of neurodegenerative disorders. Dysfunction of the cerebral endothelial cells can result in dysregulation of cerebral perfusion and disruption of the Blood Brain Barrier (BBB), leading to brain damage, neurodegeneration and cognitive decline. It has been shown that the presence of modifiable risk factors exacerbates endothelial dysfunction. This study primarily aimed to identify which among various perfusion MRI methodologies could be effectively utilized to non-invasively identify early pathological alterations as a result of endothelial dysfunction. We compared these perfusion MRI measurements to invasive immunohistochemistry to detect early pathological alterations in the cerebral vasculature of a rat model of multiple cardiovascular co-morbidities (the ZSF1 Obese rat) at several stages of the cerebrovascular pathology. We observed cerebral hyperperfusion, expressed by increased Cerebral Blood Flow (CBF) and increased BBB permeability in the ZSF1 Obese rats, at an early stage of disease development. The increase in CBF observed with Arterial Spin Labeling (ASL) was lost during later stages of disease progression. These findings are in line with recent clinical findings in early stages of Alzheimer's disease (AD), that also show early increases in CBF.

Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid β (Aβ) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheseshave been proposed, including the cholinergic, Aβ, tau, oxidative stress, and the metal-ion hypothesis. Among these, the cholinergic and Aβ hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.

PRECLINICAL EVALUATION OF POLYHERBAL AS AN ANTI- ALZHEIMERS, BY USING IN-VITRO ANTICHOLINESTERASE ENZYME MODEL

Background: Alzheimers disease is a neurodegenerative brain condition that causes mild cognitive impairment and memory loss, eventually leading to dementia. With developments in medicine, there are now more people in the world trying to treat a wider range of illnesses. It has been discovered that traditional herbal treatment works well with little or no adverse effects. Materials &amp; Methods: There are certain chemical components in the polyherbal extract of liquorice, ginger, and hibiscus sabadariffa that have anti-Alzheimers properties. Results &amp; Discussion: The polyherbal extract of liquorice, ginger, and hibiscus sabadariffa has been shown to have significant inhibition up to 44.02% in the group treated with it, which supports the extracts anti-Alzheimers activity. This was determined through a dose-dependent study and statistical comparison using Graph Pad Prism, version 10.2.2 by two-way ANOVA.

Gene deletion of Pregnancy-associated Plasma Protein-A (PAPP-A) improves pathology and cognition in an Alzheimer's disease mouse model

Alzheimer's disease (AD) is a progressive neurodegenerative disease of age with no effective preventative or treatment approaches. Deeper understanding of the mechanisms underlying the accumulation of toxic β-amyloid oligopeptides and the formation of amyloid plaque in AD has the potential to identify new therapeutic targets. Prior research links the insulin-like growth factor (IGF) system to pathologic mechanisms underlying AD. Suppression of local IGF-I receptor (IGFIR) signaling in AD mice has been shown to reduce plaque formation in the brain and delay neurodegeneration and behavioral changes. However, direct inhibitors of IGFIR signaling are not a viable treatment option for AD due to the essentiality of the IGFIR in physiological growth and metabolism. We have previously demonstrated a more selective means to reduce local IGFIR signaling through inhibition of PAPP-A, a novel zinc metalloprotease that regulates local IGF-I bioavailability through cleavage of inhibitory IGF binding proteins. Here we tested if deletion of PAPP-A in a mouse model of AD provides protection against pathology and behavioral changes. We show that compared to AD mice, AD/PAPP-A KO mice had significantly less plaque burden, reduced astrocytic activation, decreased IGF-IR activity, and improved cognition. Human senile AD plaques showed specific immunostaining for PAPP-A. Thus, inhibition of PAPP-A expression or activity may represent a novel treatment strategy for AD.

Gene-variant specific effects of plasma amyloid-β levels in Swedish autosomal dominant Alzheimer disease

BackgroundSeveral blood-based biomarkers offer the opportunity of in vivo detection of brain pathology and neurodegeneration in Alzheimer disease with high specificity and sensitivity, but the performance of amyloid-β (Aβ) measurements remains under evaluation. Autosomal dominant Alzheimer disease (ADAD) with mutations in PSEN1, PSEN2 and APP can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the Aβ-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma Aβ concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease.Methods92 plasma samples were collected from at-risk individuals (n = 47) in a Swedish cohort of ADAD, including 18 mutation carriers (13 APPswe (p.KM670/671NL) MC), 5 PSEN1 (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of Aβ1–38, Aβ1–40 and Aβ1–42 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models.ResultsCross-sectional analysis at baseline showed more than a 3-fold increase in all plasma Aβ peptides in APPswe MC, regardless of clinical status, compared to controls (p < 0.01). PSEN1 (p.H163Y) presymptomatic MC had a decrease of plasma Aβ1–38 compared to controls (p < 0.05). There was no difference in Aβ1–42/1–40 ratio between APPswe MC (PMC and SMC), PSEN1 MC (PMC) and controls at baseline. Notably, both cross-sectional data and repeated-measures analysis suggested that APPswe MC have a stable Aβ1–42/1–40 ratio with increasing age, in contrast to the decrease seen with aging in both controls and PSEN1 (p.H163Y) MC.ConclusionThese data show very strong mutation-specific effects on Aβ profiles in blood, most likely due to a ubiquitous production outside of the CNS. Hence, analyses in an unselected clinical setting might unintentionally disclose genetic status. Furthermore, our findings suggest that the Aβ ratio might be a poor indicator of brain Aβ pathology in selected genetic cases. The very small sample size is a limitation that needs to be considered but reflects the scarcity of longitudinal in vivo data from genetic cohorts.

Whole-Body Vibration Affects Hippocampal Choline Acetyltransferase and Synaptophysin Expression and Improves Spatial Memory in Young Adult Mice.

Beneficial effects of whole-body vibration (WBV) on brain and musculoskeletal health in mice have been demonstrated, but underlying mechanisms remain relatively unrevealed. WBV improves attention and memory performance in mice, putatively through stimulation of the cholinergic system. Here, we investigated the effects of WBV on the septo-hippocampal cholinergic system. Young C57BL/6 mice (8 weeks old) were subjected to 10 min WBV/day (mechanical vibration: 30 Hz; ~0.1-μm peak-to-peak displacement), 5X/week for 5 weeks. In Experiment 1, choline acetyltransferase (ChAT)-immunoreactivity in the septum and hippocampus was analyzed either 2 or 24 h after the last WBV session. Pseudo-WBV-treated mice (same handling procedure as WBV, but no vibrations) served as controls. In Experiment 2, the longitudinal profile of ChAT-immunoreactivity was analyzed in the hippocampus after 1, 2, 3, 4, or 5 weeks of WBV. In addition, synaptophysin immunostaining was performed at either 2 and 5 weeks of WBV. Mice housed 1/cage during the entire experiment served as controls. The balance-beam test was used to monitor the functional impact of WBV. In Experiment 3, a Y-maze reference-memory test was performed after 5 weeks of WBV to obtain a functional cognitive outcome measure of WBV. Pseudo-WBV treated mice served as controls. In Experiment 1, ChAT-immunoreactivity was significantly enhanced after the last WBV session of the 5-week period. This was found in the septum, Cornu Ammonis 1 (CA1), CA3, and dentate gyrus, and was dependent on layer and time-point (2 or 24 h). Experiment 2 revealed that, ChAT-immunoreactivity was lower after 2 weeks of WBV, whereas it was significantly higher after 5 weeks (similar to in Experiment 1). Immunostaining for synaptophysin, a marker for synaptic density, was also significantly higher after 5 weeks of WBV, but not significantly lower after 2 weeks, as was ChAT. WBV-treated groups performed significantly better than did controls on the balance beam from week 3 onwards. Experiment 3 showed that WBV-treated mice had better spatial-reference memory performance in the Y-maze test than did pseudo-WBV controls. Our results indicate that WBV stimulates the septo-hippocampal cholinergic system in a gradual and dynamic way that may contribute to improved spatial-memory performance. This finding suggests that WBV, by upregulation of the septo-hippocampal cholinergic system, may be considered a valuable therapeutic strategy to enhance brain functions in aging, neurodegenerative, and other brain diseases.

Hallmarks of aging in age-related macular degeneration and age-related neurological disorders: novel insights into common mechanisms and clinical relevance.

Age-related macular degeneration (AMD) and age-related neurological diseases (ANDs), such as Alzheimer's and Parkinson's Diseases, are increasingly prevalent conditions that significantly contribute to global morbidity, disability, and mortality. The retina, as an accessible part of the central nervous system (CNS), provides a unique window to study brain aging and neurodegeneration. By examining the associations between AMD and ANDs, this review aims to highlight novel insights into fundamental mechanisms of aging and their role in neurodegenerative disease progression. This review integrates knowledge from the emerging field of aging research, which identifies common denominators of biological aging, specifically loss of proteostasis, impaired macroautophagy, mitochondrial dysfunction, and inflammation. Finally, we emphasize the clinical relevance of these pathways and the potential for cross-disease therapies that target common aging hallmarks. Identifying these shared pathways could open avenues to develop therapeutic strategies targeting mechanisms common to multiple degenerative diseases, potentially attenuating disease progression and promoting the healthspan.

Effectiveness of Tri-Kaysorn-Mas Extract in Ameliorating Cognitive-like Behavior Deficits in Ovariectomized Mice via Activation of Multiple Mechanisms.

Postmenopausal women have a higher probability of experiencing cognitive alterations compared to men, suggesting that the decline in female hormones may contribute to cognitive deterioration. Thailand traditionally uses Tri-Kaysorn-Mas (TKM), a blend of three medicinal herbs, as a tonic to stimulate appetite and relieve dyspepsia. Due to its antioxidant and anti-acetylcholinesterase activities, we investigated the effects of TKM (50 and 100 mg/kg/day, p.o., for 8 weeks) on cognitive deficits and their underlying causes in an ovariectomized (OVX) mouse model of menopause. OVX mice showed cognitive impairment in the Y-maze, novel object recognition task (NORT), and Morris water maze (MWM) behavioral tests, along with atrophic changes to the uterus, altered levels of serum 17β-estradiol, and down-regulated expression of estrogen receptors (ERα and ERβ). These behavioral effects were reversed by TKM. TKM decreased malondialdehyde (MDA) levels and mitigated oxidative stress in the brain by enhancing the activity of superoxide dismutase (SOD) and catalase (CAT) and by up-regulating the antioxidant-related gene Nrf2 while down-regulating Keap1. TKM also counteracted OVX-induced neurodegeneration by enhancing the expression of the neurogenesis-related genes BDNF and CREB. The results indicate that TKM extract alleviates oxidative brain damage and neurodegeneration while enhancing cognitive behavior in OVX mice, significantly improving cognitive deficiencies related to menopause/ovariectomy through multiple targets.

Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism

TMEM106B is an endolysosomal transmembrane protein not only associated with multiple neurological disorders including frontotemporal dementia, Alzheimer’s disease, and hypomyelinating leukodystrophy but also potentially involved in COVID-19. Additionally, recent studies have identified amyloid fibrils of C-terminal TMEM106B in both aged healthy and neurodegenerative brains. However, so far little is known about physiological functions of TMEM106B in the endolysosome and how TMEM106B is involved in a wide range of human conditions at molecular levels. Here, we performed lipidomic analysis of the brain of TMEM106B-deficient mice. We found that TMEM106B deficiency significantly decreases levels of two major classes of myelin lipids, galactosylceramide and its sulfated derivative sulfatide. Subsequent co-immunoprecipitation assay showed that TMEM106B physically interacts with galactosylceramidase. We also found that galactosylceramidase activity was significantly increased in TMEM106B-deficient brains. Thus, our results suggest that TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism and have implications for TMEM106B-associated diseases.

Unveiling citicoline's mechanisms and clinical relevance in the treatment of neuroinflammatory disorders.

Citicoline, a compound produced naturally in small amounts in the human body, assumes a pivotal role in phosphatidylcholine synthesis, a dynamic constituent of membranes of neurons. Across diverse models of brain injury and neurodegeneration, citicoline has demonstrated its potential through neuroprotective and anti-inflammatory effects. This review aims to elucidate citicoline's anti-inflammatory mechanism and its clinical implications in conditions such as ischemic stroke, head trauma, glaucoma, and age-associated memory impairment. Citicoline's anti-inflammatory prowess is rooted in its ability to stabilize cellular membranes, thereby curbing the excessive release of glutamate-a pro-inflammatory neurotransmitter. Moreover, it actively diminishes free radicals and inflammatory cytokines productions, which could otherwise harm neurons and incite neuroinflammation. It also exhibits the potential to modulate microglia activity, the brain's resident immune cells, and hinder the activation of NF-κB, a transcription factor governing inflammatory genes. Clinical trials have subjected citicoline to rigorous scrutiny in patients grappling with acute ischemic stroke, head trauma, glaucoma, and age-related memory impairment. While findings from these trials are mixed, numerous studies suggest that citicoline could confer improvements in neurological function, disability reduction, expedited recovery, and cognitive decline prevention within these cohorts. Additionally, citicoline boasts a favorable safety profile and high tolerability. In summary, citicoline stands as a promising agent, wielding both neuroprotective and anti-inflammatory potential across a spectrum of neurological conditions. However, further research is imperative to delineate the optimal dosage, treatment duration, and underlying mechanisms. Moreover, identifying specific patient subgroups most likely to reap the benefits of citicoline as a new therapy remains a critical avenue for exploration.