Age-related Neurodegenerative Diseases Research Articles

Alzheimer's Disease, Hearing Loss, and Deviance Detection.

Age-related hearing loss is a widespread condition among the elderly, affecting communication and social participation. Given its high incidence, it is not unusual that individuals suffering from age-related hearing loss also suffer from other age-related neurodegenerative diseases, a scenario which severely impacts their quality of life. Furthermore, recent studies have identified hearing loss as a relevant risk factor for the development of dementia due to Alzheimer’s disease, although the underlying associations are still unclear. In order to cope with the continuous flow of auditory information, the brain needs to separate repetitive sounds from rare, unexpected sounds, which may be relevant. This process, known as deviance detection, is a key component of the sensory perception theory of predictive coding. According to this framework, the brain would use the available incoming information to make predictions about the environment and signal the unexpected stimuli that break those predictions. Such a system can be easily impaired by the distortion of auditory information processing that accompanies hearing loss. Changes in cholinergic neuromodulation have been found to alter auditory deviance detection both in humans and animal models. Interestingly, some theories propose a role for acetylcholine in the development of Alzheimer’s disease, the most common type of dementia. Acetylcholine is involved in multiple neurobiological processes such as attention, learning, memory, arousal, sleep and/or cognitive reinforcement, and has direct influence on the auditory system at the levels of the inferior colliculus and auditory cortex. Here we comment on the possible links between acetylcholine, hearing loss, and Alzheimer’s disease, and association that is worth further investigation.

Neuropsychological Assessment in Dementia Diagnosis.

This article discusses the application of neuropsychological evaluation to the workup of individuals with age-related cognitive impairment and suspected dementia. Referral questions, principles of evaluation, and common instruments to detect abnormalities in cognition and behavior in this population are reviewed. The integration of neuropsychological test findings with other clinical and biomarker information enhances early detection, differential diagnosis, and care planning. Life expectancy is increasing in the United States, and, accordingly, the prevalence and incidence of dementia associated with age-related neurodegenerative brain disease are rising. Age is the greatest risk factor for the dementia associated with Alzheimer disease, the most common neurodegenerative cause of dementia in people over 65 years of age; other etiologies, such as the class of frontotemporal lobar degenerations, are increasingly recognized in individuals both younger and older than 65 years of age. The clinical dementia diagnosis, unfortunately, is imperfectly related to disease etiology; however, probabilistic relationships can aid in diagnosis. Further, mounting evidence from postmortem brain autopsies points to multiple etiologies. The case examples in this article illustrate how the neuropsychological evaluation increases diagnostic accuracy and, most important, identifies salient cognitive and behavioral symptoms to target for nonpharmacologic intervention and caregiver education and support. Sharing the diagnosis with affected individuals is also discussed with reference to prognosis and severity of illness. The clinical neuropsychological examination facilitates early detection of dementia, characterizes the level of severity, defines salient clinical features, aids in differential diagnosis, and points to a pathway for care planning and disease education.

Genotype-phenotype correlation of T-cell subtypes reveals senescent and cytotoxic genes in Alzheimer's disease.

Recent studies identifying expression quantitative trait loci (eQTLs) in immune cells have uncovered important links between disease risk alleles and gene expression trends in monocytes, T cells and other cell types. However, these studies are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimer's disease (AD). We have performed RNA sequencing on four T-cell subsets in genome-wide genotyped and well-characterized AD subjects and age- and sex-matched controls from the Religious Orders Study/Memory and Aging Project. We correlated gene expression data with AD neuropathological traits and with single-nucleotide polymorphisms to detect eQTLs. We identified several significant genes involved in T-cell senescence and cytotoxicity, consistent with T-cell RNA sequencing studies in aged/AD cohorts. We identified unexpected eQTLs previously associated with neuropsychiatric disease traits. Finally, we discovered that pathways related to axon guidance and synaptic function were enriched among trans-eQTLs in coding regions of the genome. Our data strengthen the potential link between T-cell senescence and age-related neurodegenerative disease. In addition, our eQTL data suggest that T-cell phenotypes may influence neuropsychiatric disorders and can be influenced by genes involved in neurodevelopmental processes.

Reducing PDK1/Akt Activity: An Effective Therapeutic Target in the Treatment of Alzheimer's Disease.

Alzheimer’s disease (AD) is a common age-related neurodegenerative disease that leads to memory loss and cognitive function damage due to intracerebral neurofibrillary tangles (NFTs) and amyloid-β (Aβ) protein deposition. The phosphoinositide-dependent protein kinase (PDK1)/protein kinase B (Akt) signaling pathway plays a significant role in neuronal differentiation, synaptic plasticity, neuronal survival, and neurotransmission via the axon–dendrite axis. The phosphorylation of PDK1 and Akt rises in the brain, resulting in phosphorylation of the TNF-α-converting enzyme (TACE) at its cytoplasmic tail (the C-terminal end), changing its internalization as well as its trafficking. The current review aimed to explain the mechanisms of the PDK1/Akt/TACE signaling axis that exerts its modulatory effect on AD physiopathology. We provide an overview of the neuropathological features, genetics, Aβ aggregation, Tau protein hyperphosphorylation, neuroinflammation, and aging in the AD brain. Additionally, we summarized the phosphoinositide 3-kinase (PI3K)/PDK1/Akt pathway-related features and its molecular mechanism that is dependent on TACE in the pathogenesis of AD. This study reviewed the relationship between the PDK1/Akt signaling pathway and AD, and discussed the role of PDK1/Akt in resisting neuronal toxicity by suppressing TACE expression in the cell membrane. This work also provides a perspective for developing new therapeutics targeting PDK1/Akt and TACE for the treatment of AD.

RNP components condense into repressive RNP granules in the aging brain

Cytoplasmic RNP condensates enriched in mRNAs and proteins are found in various cell types and associated with both buffering and regulatory functions. While a clear link has been established between accumulation of aberrant RNP aggregates and progression of aging-related neurodegenerative diseases, the impact of physiological aging on neuronal RNP condensates has never been explored. Through high-resolution imaging, we uncover that RNP components progressively cluster into large yet dynamic granules in the aging Drosophila brain. We further show that age-dependent clustering is caused by an increase in the stoichiometry of the conserved helicase Me31B/DDX6, and requires PKA kinase activity. Finally, our functional analysis reveals that mRNA species recruited to RNP condensates upon aging exhibit age-dependent translational repression, indicating that co-clustering of selected mRNAs and translation regulators into repressive condensates may contribute to the specific post-transcriptional changes in gene expression observed in the course of aging.

S-adenosyl methionine improves motor co-ordination with reduced oxidative stress, dopaminergic neuronal loss, and DNA methylation in the brain striatum of 6-hydroxydopamine-induced neurodegeneration in rats.

Parkinson's disease (PD) is the most common age-related neurodegenerative disease worldwide. S-adenosyl methionine (SAMe), a methyl donor that plays an important role in DNA methylation, could replenish the cellular antioxidant glutathione (GSH). Herein, we investigated the neuroprotective effects of SAMe in 6-hydroxydopamine (6-OHDA) rat models of PD and elucidated the underlying mechanism. PD model rats were developed by injecting 6-OHDA stereotaxically into the striatum. In Phase 1 of the study, we performed the neurobehavioral tests, GSH assay, and histopathology to evaluate the neuroprotective effects of SAMe. The animals were treated with SAMe (150 or 300 mg/kg body weight) orally for 28 days. The positive control group received selegiline (5mg/kg), whereas the disease control group received normal saline. In Phase 2, we evaluated the striatal dopamine levels and performed DNA methylation assay to uncover the mechanism of action of SAMe. In this phase, a higher dose of SAMe (300 mg/kg) was used. SAMe (300 mg/kg) treatment for 4 weeks significantly attenuated the abnormal circling behavior in PD rats (p < 0.05). Moreover, SAMe at both doses (150 and 300 mg/kg) enhanced the performance of PD rats in the open field test and stepping test (p < 0.05). SAMe treatment significantly increased the GSH levels, and at high dose, SAMe restricted neuronal loss in the striatum of PD-model rats (p < 0.05). Moreover, SAMe treatment led to a significant recovery in the dopamine levels and improved the DNA methylation status in the dopaminergic neurons (p < 0.05) of PD model rats. SAMe exhibits antioxidant activity and DNA methylation modulating effects in 6-OHDA model PD rats. Moreover, SAMe prevents neuronal loss in PD rats suggesting that SAMe has therapeutic potential in preventing PD development. The neuroprotective potential of SAMe is greater at high doses.

Similarities among Alzheimer's Disease, Parkinson's Disease and Dementia may Call for a Similar Treatment

Alzheimer's Disease (AD), Parkinson's Disease (PD), and Dementia are all age-related neurodegenerative diseases. In the US, AD victims are increasing every year from 5.5 million in 2018 to 13.8 million by 2050. PD patient are calculated to increase from 7K to 1 million by 2030. Results from accumulation of extracellular amyloid-β (Aβ) peptide and deposition of intracellular <em>tau</em> aggregated tangles.

Using a Video Device and a Deep Learning-Based Pose Estimator to Assess Gait Impairment in Neurodegenerative Related Disorders: A Pilot Study

As the world’s population is living longer, age-related neurodegenerative diseases are becoming a more significant global issue. Neurodegenerative diseases cause worsening motor, cognitive and autonomic dysfunction over time and reduce functional abilities required for daily living. Compromised motor performance is one of the first and most evident manifestations. In the case of Parkinson’s disease, these impairments are currently evaluated by experts through the use of rating scales. Although this method is widely used by experts worldwide, it includes subjective and error-prone motor examinations that also fail in the characterization of symptoms’ fluctuations. The aim of this study is to evaluate whether artificial intelligence techniques can be used to objectively assess gait impairment in subjects with Parkinson’s disease. This paper presents the results of a cohort of ten subjects, five with a Parkinson’s disease diagnosis at different degrees of severity. We experimentally demonstrate good effectiveness of the proposed system in extracting the main features concerning people’s gait during the standard tests that clinicians use to assess the burden of disease. This system can offer neurologists, through accurate and objective data, a second opinion or a suggestion to reconsider score assignment. Thanks to its simplicity, tactful and non-intrusive approach and clinical-grade accuracy, it can be adopted on an ongoing basis even in environments where people usually live and work.

Brain‐wide Network Restructuring after Chemogenetic Locus Coeruleus Activation: Implications of Tonic Noradrenergic Activity for Neurodegeneration

Loss of noradrenergic neurons in a small brainstem nucleus, the locus coeruleus (LC), is a common characteristic in the development of age‐related neurodegenerative diseases such as Alzheimer's disease (AD) and other dementias. The noradrenergic system (NS) projects from the locus coeruleus (LC) throughout the brain to modulate neurophysiology for memory, learning and cognition, for regulation of sleep and circadian rhythm, and in response to stress and reward. Thus dysregulation of NS activity, i.e., blunted or tonic firing of LC neurons and its resultant effect on neural activity, is considered a significant factor in development and progression of neurodegenerative diseases as well as of psychiatric disorders. Our hypothesis is that tonic activation of LC neurons acutely discoordinates neuronal firing patterns across the brain, and ultimately provokes a prolonged abnormal brain state. We test this hypothesis via brain‐wide manganese‐enhanced MRI (MEMRI) in parallel with recordings of naturalistic behavior before, during, and long after chemogenetic (hM3Dq) stimulation of LC neurons. After systemic delivery, paramagnetic Mn(II) ions (0.3 mmol/kg, i.p.) accumulate in active neurons of awake‐behaving mice, highlighting neural activity by T1‐weighted MRI. Adult mice (3‐6 months) were subjected either to longitudinal MEMRI (n = 18) or to open field behavior (n = 8), ± hM3Dq expression; and ± designer drug – clozapine‐N‐oxide (CNO). For behavior naïve C57BL/6 mice were video recorded and behavioral parameters tracked by Noldus Ethovision XT15, before and after administration of CNO (5 mg/kg, i.p.). Mice then underwent stereotactic injection of CAV2‐PRS‐hM3D(Gq)‐mCherry targeting the LC (AP = ‐5.4, ML = ±0.80, DV = ‐3.80). At 4‐8 weeks after transfection the effect of CNO ± hM3Dq on LC neurons was monitored in live animals by pupillary light response. Pre‐ and post‐CNO behavior was again recorded. For MEMRI two groups ± hM3Dq were imaged before and after CNO. MEMRI images were analyzed for Mn(II)‐dependent intensity increases by statistical parametric mapping (SPM), segment‐wise cross‐correlation and network analysis. Transgene expression was confirmed post‐mortem by microscopy of mCherry in LC brain sections, which showed transgene expression in bilateral LC. Comparison of MEMRI segment‐wise intensities revealed changes of strength and direction of correlations between time points that also diffed between groups. Hierarchical clustering of these correlations revealed 40% increase in modularity, i.e., the number of distinct clusters, after CNO only in the hM3Dq transfected group. Together our data suggest discoordination of brain regions after LC‐NS activation. In neurodegenerative disease the loss of LC input could result in the opposite effects, while none‐the‐less leading to discoordination of brain‐wide activity underlying sleep disorders and memory disturbance. This brain‐wide imaging strategy with chemogenetic LC manipulation provides critical insight into NS modulation of neural activity under both normal and pathological conditions.

DNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis.

DNA is under constant attack from both endogenous and exogenous sources, and when damaged, specific cellular signalling pathways respond, collectively termed the “DNA damage response.” Efficient DNA repair processes are essential for cellular viability, although they decline significantly during aging. Not surprisingly, DNA damage and defective DNA repair are now increasingly implicated in age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS affects both upper and lower motor neurons in the brain, brainstem and spinal cord, leading to muscle wasting due to denervation. DNA damage is increasingly implicated in the pathophysiology of ALS, and interestingly, the number of DNA damage or repair proteins linked to ALS is steadily growing. This includes TAR DNA binding protein 43 (TDP-43), a DNA/RNA binding protein that is present in a pathological form in almost all (97%) cases of ALS. Hence TDP-43 pathology is central to neurodegeneration in this condition. Fused in Sarcoma (FUS) bears structural and functional similarities to TDP-43 and it also functions in DNA repair. Chromosome 9 open reading frame 72 (C9orf72) is also fundamental to ALS because mutations in C9orf72 are the most frequent genetic cause of both ALS and related condition frontotemporal dementia, in European and North American populations. Genetic variants encoding other proteins involved in the DNA damage response (DDR) have also been described in ALS, including FUS, SOD1, SETX, VCP, CCNF, and NEK1. Here we review recent evidence highlighting DNA damage and defective DNA repair as an important mechanism linked to neurodegeneration in ALS.

ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer's Disease.

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects 50 million people worldwide, with 10 million new cases occurring each year. The emotional and economic impacts of AD on patients and families are devastating. Approved treatments confer modest improvement in symptoms, and recently one treatment obtained accelerated approval from the United States Food and Drug Administration (FDA) and may have modest disease modifying benefit. Research over the past three decades has established a clear causal linkage between AD and elevated brain levels of amyloid β (Aβ) peptide, and substantial evidence now implicates soluble, non-fibrillar Aβ oligomers (AβOs) as the molecular assemblies directly responsible for AD-associated memory and cognitive failure and accompanying progressive neurodegeneration. The widely recognized linkage of elevated Aβ and AD spawned a comprehensive 20-year therapeutic campaign that focused primarily on two strategies – inhibition of the secretase enzymes responsible for Aβ production and clearance of Aβ peptide or amyloid plaques with Aβ-directed immunotherapeutics. Unfortunately, all clinical trials of secretase inhibitors were unsuccessful. Of the completed phase 3 immunotherapy programs, bapineuzumab (targeting amyloid plaque) and solanezumab (targeting Aβ monomers) were negative, and the crenezumab program (targeting Aβ monomers and to a small extent oligomers) was stopped for futility. Aducanumab (targeting amyloid plaques), which recently received FDA accelerated approval, had one positive and one negative phase 3 trial. More than 25 negative randomized clinical trials (RCTs) have evaluated Aβ-targeting therapeutics, yet none has directly evaluated whether selective blockage of disease-relevant AβOs can stop or reverse AD-associated cognitive decline. Here, we briefly summarize studies that establish the AD therapeutic rationale to target AβOs selectively, and we describe ACU193, the first AβO-selective immunotherapeutic to enter human clinical trials and the first positioned to test the AβO hypothesis of AD.

Dual-Functional Antioxidant and Antiamyloid Cerium Oxide Nanoparticles Fabricated by Controlled Synthesis in Water-Alcohol Solutions.

Oxidative stress is known to be associated with a number of degenerative diseases. A better knowledge of the interplay between oxidative stress and amyloidogenesis is crucial for the understanding of both, aging and age-related neurodegenerative diseases. Cerium dioxide nanoparticles (CeO2 NPs, nanoceria) due to their remarkable properties are perspective nanomaterials in the study of the processes accompanying oxidative-stress-related diseases, including amyloid-related pathologies. In the present work, we analyze the effects of CeO2 NPs of different sizes and Ce4+/Ce3+ ratios on the fibrillogenesis of insulin, SOD-like enzymatic activity, oxidative stress, biocompatibility, and cell metabolic activity. CeO2 NPs (marked as Ce1–Ce5) with controlled physical–chemical parameters, such as different sizes and various Ce4+/Ce3+ ratios, are synthesized by precipitation in water–alcohol solutions. All synthesized NPs are monodispersed and exhibit good stability in aqueous suspensions. ThT and ANS fluorescence assays and AFM are applied to monitor the insulin amyloid aggregation and antiamyloid aggregation activity of CeO2 NPs. The analyzed Ce1–Ce5 nanoparticles strongly inhibit the formation of insulin amyloid aggregates in vitro. The bioactivity is analyzed using SOD and MTT assays, Western blot, fluorescence microscopy, and flow cytometry. The antioxidative effects and bioactivity of nanoparticles are size- or valence-dependent. CeO2 NPs show great potential benefits for studying the interplay between oxidative stress and amyloid-related diseases, and can be used for verification of the role of oxidative stress in amyloid-related diseases.

Human IPSC 3D brain model as a tool to study chemical-induced dopaminergic neuronal toxicity

Oxidative stress is caused by an imbalance between the generation and detoxification of reactive oxygen and nitrogen species (ROS/RNS). This imbalance plays an important role in brain aging and age-related neurodegenerative diseases. In the context of Parkinson's disease (PD), the sensitivity of dopaminergic neurons in the substantia nigra pars compacta to oxidative stress is considered a key factor of PD pathogenesis. Here we study the effect of different oxidative stress-inducing compounds (6-OHDA, MPTP or MPP+) on the population of dopaminergic neurons in an iPSC-derived human brain 3D model (aka BrainSpheres). Treatment with 6-OHDA, MPTP or MPP+ at 4 weeks of differentiation disrupted the dopaminergic neuronal phenotype in BrainSpheres at (50, 5000, 1000 μM respectively). 6-OHDA increased ROS production and decreased mitochondrial function most efficiently. It further induced the greatest changes in gene expression and metabolites related to oxidative stress and mitochondrial dysfunction. Co-culturing BrainSpheres with an endothelial barrier using a transwell system allowed the assessment of differential penetration capacities of the tested compounds and the damage they caused in the dopaminergic neurons within the BrainSpheres In conclusion, treatment with compounds known to induce PD-like phenotypes in vivo caused molecular deficits and loss of dopaminergic neurons in the BrainSphere model. This approach therefore recapitulates common animal models of neurodegenerative processes in PD at similarly high doses. The relevance as tool for drug discovery is discussed.

Blood pressure and heart rate responses to orthostatic challenge and Valsalva manoeuvre in mild cognitive impairment with Lewy bodies.

ObjectivesOrthostatic hypotension is a common feature of normal ageing, and age‐related neurodegenerative diseases, in particular the synucleinopathies including dementia with Lewy bodies. Orthostatic hypotension and other abnormal cardiovascular responses may be early markers of Lewy body disease. We aimed to assess whether abnormal blood pressure and heart rate responses to orthostatic challenge and Valsalva manoeuvre would be more common in mild cognitive impairment with Lewy bodies (MCI‐LB) than MCI due to Alzheimer's disease (MCI‐AD).MethodsMCI patients (n = 89) underwent longitudinal clinical assessment with differential classification of probable MCI‐LB, possible MCI‐LB, or MCI‐AD, with objective autonomic function testing at baseline. Blood pressure and heart rate responses to active stand and Valsalva manoeuvre were calculated from beat‐to‐beat cardiovascular data, with abnormalities defined by current criteria, and age‐adjusted group differences estimated with logistic models.ResultsOrthostatic hypotension and abnormal heart rate response to orthostatic challenge were not more common in probable MCI‐LB than MCI‐AD. Heart rate abnormalities were likewise not more common in response to Valsalva manoeuvre in probable MCI‐LB. An abnormal blood pressure response to Valsalva (delayed return to baseline/absence of overshoot after release of strain) was more common in probable MCI‐LB than MCI‐AD. In secondary analyses, magnitude of blood pressure drop after active stand and 10‐s after release of Valsalva strain were weakly correlated with cardiac sympathetic denervation.ConclusionsProbable MCI‐LB may feature abnormal blood pressure response to Valsalva, but orthostatic hypotension is not a clear distinguishing feature from MCI‐AD.

Assessing the Role of Ependymal and Vascular Cells as Sources of Extracellular Cues Regulating the Mouse Ventricular-Subventricular Zone Neurogenic Niche.

Neurogenesis persists in selected regions of the adult mouse brain; among them, the ventricular-subventricular zone (V-SVZ) of the lateral ventricles represents a major experimental paradigm due to its conspicuous neurogenic output. Postnatal V-SVZ neurogenesis is maintained by a resident population of neural stem cells (NSCs). Although V-SVZ NSCs are largely quiescent, they can be activated to enter the cell cycle, self-renew and generate progeny that gives rise to olfactory bulb interneurons. These adult-born neurons integrate into existing circuits to modify cognitive functions in response to external stimuli, but cells shed by V-SVZ NSCs can also reach injured brain regions, suggesting a latent regenerative potential. The V-SVZ is endowed with a specialized microenvironment, which is essential to maintain the proliferative and neurogenic potential of NSCs, and to preserve the NSC pool from exhaustion by finely tuning their quiescent and active states. Intercellular communication is paramount to the stem cell niche properties of the V-SVZ, and several extracellular signals acting in the niche milieu have been identified. An important part of these signals comes from non-neural cell types, such as local vascular cells, ependymal and glial cells. Understanding the crosstalk between NSCs and other niche components may aid therapeutic approaches for neuropathological conditions, since neurodevelopmental disorders, age-related cognitive decline and neurodegenerative diseases have been associated with dysfunctional neurogenic niches. Here, we review recent advances in the study of the complex interactions between V-SVZ NSCs and their cellular niche. We focus on the extracellular cues produced by ependymal and vascular cells that regulate NSC behavior in the mouse postnatal V-SVZ, and discuss the potential implication of these molecular signals in pathological conditions.

Magnesium in aging and aging-related disease

Magnesium (Mg2+) is an essential divalent cation in human body. Its balance is tightly controlled via a balanced interplay among intestinal absorption, storage, and renal excretion, involving multiple transporters across cell membrane that regulate Mg2+ influx and efflux. Mg2+ is involved in a variety of physiological and pathological processes such as enzymatic reactions, energy metabolism, cell proliferation, apoptosis, oxidative stress, and inflammation. In particular, Mg2+ contributes to the molecular hallmarks of aging. Emerging evidence demonstrates that altered Mg2+ status has been associated with many aging-related diseases, including cancer, cardiovascular disease, neurodegenerative disease, musculoskeletal function, metabolic syndrome, and COVID-19. In this review, we focus on Mg2+ and its association with molecular hallmarks of aging. We also summarize recent findings supporting an important role of Mg2+ in aging-related disease including the COVID-19 pandemic.

A Brief Notes on Gene Therapy, Cell Therapy and Cell-Based Gene Therapy for Alzheimer’s Disease

Alzheimer’s disease (AD) is known as an age-related neurodegenerative disease where progressive loss of memory associated with cognition defects has been noticed. Molecular analysis of AD revealed the formation of aggregated amyloid-β protein and hyper phosphorylated tau tangles at the synaptic circuit, which causes the loss of neuronal communication.

Co-treatment with natural HMGB1 inhibitor Glycyrrhizin exerts neuroprotection and reverses Parkinson’s disease like pathology in Zebrafish

Ethnopharmacological relevanceParkinson’s disease (PD) is the second most devastating age-related neurodegenerative diseases after Alzheimer diseases (AD) and is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) and aggregation of α-synuclein (α-syn). The precise etiology of PD is not yet fully understood and lacks the disease-modifying therapeutic strategies that could reverse the ongoing neurodegeneration. In the quest of exploring novel disease modifying therapeutic strategies, natural compounds from plant sources have gained much attention in recent days. Glycyrrhizin (GL) is the main active ingredient of the roots and rhizomes of licorice (Glycyrrhiza glabra L), which are generally used in the treatment of inflammatory diseases or as a tonifying herbal medicine. In Persia, GL is a conventional neuroprotective agent that are used to treat neurological disorders. The traditional use of GL in Japan is to treat chronic hepatitis B. In addition, GL is a natural inhibitor of high mobility group box 1 (HMGB1) which has exerted neuroprotective effect against several HMGB1 mediated pathological conditions. Aim of the studyThe study is aimed to evaluate therapeutic effect of GL against PD in zebrafish. Material and methodsPD in zebrafish larvae is induced by administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Apoptosis was assessed with TUNEL assay. Gene expression was performed to assess the modulation in genes related to neuroinflammatory and autophagy. ResultsWe observed that GL co-treatment increased the length of DA neurons, decreased the number of apoptotic cells in zebrafish brain, and inhibited the loss of vasculature and disorganized vasculature induced by MPTP. GL co-treatment relieved the MPTP-induced locomotor impairment in zebrafish. GL co-treatment suppressed MPTP-induced upregulated mRNA expression of inflammatory markers such as hmgb1a, tlr4b, nfκb, il1β, and il6. GL co-treatment suppressed the autophagy related genes α-syn and atg5 whereas increased the mRNA expression level of parkin and pink1. In addition, molecular docking study reveals that GL has binding interaction with HMGB1, TLR4, and RAGE. ConclusionHence, the effect of GL co-treatment on MPTP-induced PD-like condition in zebrafish is to alleviate apoptosis and autophagy, as well as suppress inflammatory responses.

Iron Metabolism in Aging and Age-Related Diseases.

Iron is a trace metal element necessary to maintain life and is also involved in a variety of biological processes. Aging refers to the natural life process in which the physiological functions of the various systems, organs, and tissues decline, affected by genetic and environmental factors. Therefore, it is imperative to investigate the relationship between iron metabolism and aging-related diseases, including neurodegenerative diseases. During aging, the accumulation of nonheme iron destroys the stability of the intracellular environment. The destruction of iron homeostasis can induce cell damage by producing hydroxyl free radicals, leading to mitochondrial dysfunction, brain aging, and even organismal aging. In this review, we have briefly summarized the role of the metabolic process of iron in the body, then discussed recent developments of iron metabolism in aging and age-related neurodegenerative diseases, and finally, explored some iron chelators as treatment strategies for those disorders. Understanding the roles of iron metabolism in aging and neurodegenerative diseases will fill the knowledge gap in the field. This review could provide new insights into the research on iron metabolism and age-related neurodegenerative diseases.

TREM2 and CD163 Ameliorate Microglia-Mediated Inflammatory Environment in the Aging Brain.

Aging decreases cognitive functions, especially learning and memory. Neuroinflammation is mediated by microglia and occurs in age-related neurodegenerative diseases. The expression profiles in a dataset of cognitively normal controls (GSE11882) were obtained from the Gene Expression Omnibus (GEO) database. Microarray data were used to explore the expression of age-related genes in the human hippocampus. A total of 120 differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was constructed. A total of 18 key genes were identified by the plugin cytoHubba in Cytoscape software. Two genes with a positive impact on cognition during aging were teased out: triggering receptor expressed on myeloid cells 2 (TREM2) and a scavenger receptor (CD163). Finally, the results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) verified that the mRNA expression of these two genes was significantly upregulated in aged mice. Moreover, the levels of the inflammatory factors IL-1β and IL-6 were significantly increased. TREM2 and CD163 may be upregulated to alleviate the inflammatory environment resulting from microglial activation in the aging brain, thereby delaying cognitive decline.