Age-related Neurodegenerative Diseases Research Articles

Development of a brain-targeted nano drug delivery system to enhance the treatment of neurodegenerative effects of resveratrol

As the aging population continues to increase, aging-related inflammation, oxidative stress, and neurodegenerative diseases have become serious global health threats. Resveratrol, a star molecule in natural polyphenols, has been widely reported to have physiological activities such as anti-aging, anti-inflammatory, antioxidant, and neuroprotection. However, its poor water solubility, rapid metabolism, low bioavailability and poor targeting ability, which limits its application. Accordingly, a brain-targeted resveratrol liposome (ANG-RES-LIP) was developed to solve these issues. Experimental results showed that ANG-RES-LIP has a uniform size distribution, good biocompatibility, and a drug encapsulation rate of over 90%. Furthermore, in vitro cell experiments showed that the modification of the targeting ligand ANG significantly increased the capability of RES to cross the BBB and neuronal uptake. Compared with free RES, ANG-RES-LIP demonstrated stronger antioxidant activity and the ability to rescue oxidatively damaged cells from apoptosis. Additionally, ANG-RES-LIP showed the ability to repair damaged neuronal mitochondrial membrane potential. In vivo experiments further demonstrated that ANG-RES-LIP improved cognitive function by reducing oxidative stress and inflammation levels in the brains of aging model mice, repairing damaged neurons and glial cells, and increasing brain-derived neurotrophic factor. In summary, this study not only provides a new method for further development and application of resveratrol but also a promising strategy for preventing and treating age-related neurodegenerative diseases.

Polyvinylpyrrolidone-Capped Copper Oxide Nanoparticles-Anchored Pramipexole Attenuates the Rotenone-Induced Phenotypes in a Drosophila Parkinson's Disease Model.

Parkinson's disease (PD) is a progressive, age-related neurodegenerative disease. The disease is characterized by the loss of dopaminergic neurons in the substantia nigra, pars compacta of the midbrain. Pramipexole (PPX) is a novel drug used for the treatment of PD. It has a high affinity for the dopamine (DA) D2 receptor subfamily and acts as a targeted mitochondrial antioxidant. It is less effective in the treatment of PD due to its short half-life, highly inconvenient dosing schedule, and long-term side effects. In recent years, PPX-loaded nanoformulations have been actively reported to overcome these limitations. In the current study, we focused on increasing the effectiveness of PPX by minimizing the dosing frequency and improving the treatment strategy for PD. Herein, we report the synthesis of biodegradable polyvinylpyrrolidone (PVP)-capped copper oxide nanoparticles (PVP-CuO NPs), followed by PPX anchoring on the surface of the PVP-CuO NPs (PPX-PVP-CuO NC), in a simple and inexpensive method. The newly formulated PPX-PVP-CuO NC complex was analyzed for its chemical and physical properties. The PPX-PVP-CuO NC was tested to protect against rotenone (RT)-induced toxicity in the Drosophila PD model. The in vivo studies using the RT-induced Drosophila PD model showed significant changes in negative geotaxis behavior and the level of DA and acetylcholinesterase. In addition, oxidative stress markers such as glutathione-S-transferase, total glutathione, thiobarbituric acid reactive species, and protein carbonyl content showed significant amelioration. The positive changes of PPX-PVP-CuO NC treatment in behavior, neurotransmitter level, and antioxidant level suggest its potential role in mitigating the PD phenotype. The formulation can be used for treatment or pharmacological intervention against PD.

Mistranslation-associated perturbations of proteostasis do not promote accumulation of amyloid beta and plaque deposition in aged mouse brain

A common perception in age-related neurodegenerative diseases posits that a decline in proteostasis is key to the accumulation of neuropathogenic proteins, such as amyloid beta (Aβ), and the development of sporadic Alzheimer’s disease (AD). To experimentally challenge the role of protein homeostasis in the accumulation of Alzheimer’s associated protein Aβ and levels of associated Tau phosphorylation, we disturbed proteostasis in single APP knock-in mouse models of AD building upon Rps9 D95N, a recently identified mammalian ram mutation which confers heightened levels of error-prone translation together with an increased propensity for random protein aggregation and which is associated with accelerated aging. We crossed the Rps9 D95N mutation into knock-in mice expressing humanized Aβ with different combinations of pathogenic mutations (wild-type, NL, NL-F, NL-G-F) causing a stepwise and quantifiable allele-dependent increase in the development of Aβ accumulation, levels of phosphorylated Tau, and neuropathology. Surprisingly, the misfolding-prone environment of the Rps9 D95N ram mutation did not affect Aβ accumulation and plaque formation, nor the level of phosphorylated Tau in any of the humanized APP knock-in lines. Our findings indicate that a misfolding-prone environment induced by error-prone translation with its inherent perturbations in protein homeostasis has little impact on the accumulation of pathogenic Aβ, plaque formation and associated phosphorylated Tau.

Serum biomarkers associated with aging and neurodegeneration in common marmosets (Callithrix jacchus)

The common marmoset (Callithrix jacchus), a small South American monkey, is an important nonhuman primate model in the study of aging and age-related neurodegenerative disease, including Alzheimer’s disease, Parkinson’s disease, and related dementias. Thorough characterization of the wild type marmoset brain agingmodel, including biomarkers of aging and neural degeneration, will further the marmoset’s utility in translational research. We measured serum concentration of four key biomarkers of neural degeneration [total tau (T-tau), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and ubiquitin C-terminal hydrolase-L1 (UCH-L1)] via single molecule array from 24 marmosets (female n = 13, male n = 11) ranging in age from 1.3 to 18.7 years. Aged marmosets (>7 years) had significantly higher GFAP, NfL, UCH-L1, and T-tau than adult marmosets. Sex differences were not detected for any of these biomarker concentrations. These data provide an important initial range of reference values for GFAP, NfL, T-tau, and UCH-L1 to evaluate aging and neural health in marmosets, as well as evaluation of therapeutics in clinical models of disease.

Analysis of ADORA2A, MTA1, PTGDS, PTGS2, NSF, and HNMT Gene Expression Levels in Peripheral Blood of Patients with Early Stages of Parkinson's Disease.

Parkinson's disease (PD) is a common chronic, age-related neurodegenerative disease. This disease is characterized by a long prodromal period. In this context, it is important to search for the genes and mechanisms that are involved in the development of the pathological process in the earliest stages of the disease. Published data suggest that blood cells, particularly lymphocytes, may be a model for studying the processes that occur in the brain in PD. Thus, in the present work, we performed an analysis of changes in the expression of the genes ADORA2A, MTA1, PTGDS, PTGS2, NSF, and HNMT in the peripheral blood of patients with early stages of PD (stages 1 and 2 of the Hoehn-Yahr scale). We found significant and PD-specific expression changes of four genes, i.e., MTA1, PTGS2, NSF, and HNMT, in the peripheral blood of patients with early stages of PD. These genes may be associated with PD pathogenesis in the early clinical stages and can be considered as potential candidate genes for this disease. Altered expression of the ADORA2A gene in treated PD patients may indicate that this gene is involved in processes affected by antiparkinsonian therapy.

A role for the cystathionine-β-synthase /H2S axis in astrocyte dysfunction in the aging brain

Astrocytic dysfunction is central to age-related neurodegenerative diseases. However, the mechanisms leading to astrocytic dysfunction are not well understood. We identify that among the diverse cellular constituents of the brain, murine and human astrocytes are enriched in the expression of CBS. Depleting CBS in astrocytes causes mitochondrial dysfunction, increases the production of reactive oxygen species (ROS) and decreases cellular bioenergetics that can be partially rescued by exogenous H2S supplementation or by re-expressing CBS. Conversely, the CBS/H2S axis, associated protein persulfidation and proliferation are decreased in astrocytes upon oxidative stress which can be rescued by exogenous H2S supplementation. Here we reveal that in the aging brain, the CBS/H2S axis is downregulated leading to decreased protein persulfidation, together augmenting oxidative stress. Our findings uncover an important protective role of the CBS/H2S axis in astrocytes that may be disrupted in the aged brain.

GLIOCYTES OF THE BRAIN: CYTOLOGICAL AND FUNCTIONAL PECULIARITIES (LECTURE)

The lecture is devoted to modern data on the types and functions of glial cells (gliocytes), which belong to the auxiliary cells of nervous tissue. A detailed description of the following types of gliocytes is given: astrocytes, oligodendrocytes, microglia and ependymal cells. Previously, it was believed that the cause of the emergence and development of diseases of the central and peripheral nervous system is the dysfunction of synapses and neurons. However, the analysis of the scientific literature of recent years allows us to state that a special role in the development of pathological processes of the central nervous system is assigned to the glial system of the brain. The change of this scientific paradigm took place gradually and at this time there is no doubt or active opposition among specialists – neuroscientists of the whole world. It is known that gliocytes are needed not only to support the normal activity of neurons, they provide nutrition and protection of nerve cells against the impact of harmful pathogenic factors. The lecture offers a modern view of the function and role of different types of gliocytes in the nervous system under normal and pathological conditions of the brain. The described research data prove the importance of glial cells in coordinating the functions of neurons and open up opportunities for further research in the field of developing therapeutic (targeted) approaches. Understanding the role of gliocytes in neuropathological processes can help in the development of new treatments for various diseases of the central nervous system. This is important, given the large number of neuroprotective, or rather neuroprotective pharmacological agents and at the same time the absence of specialized pro-astrocytic, pro-oligoglial, pro-ependymar and specific medicinal substances to inhibit the function of microgliocytes. This significantly impedes the practical aspects of the treatment of various neurotraumatic, cerebrovascular and, especially, age-related neurodegenerative diseases of the brain. It should be emphasized the significant contribution of Ukrainian neurocytomorphologists to the development of the foundations of solving this problem, among which are: O.H. Chernyakhivsʹkyy, M.I. Zazybin, A.K. Kolomiytsev, Yu.B. Chaykovsʹkyy, et al. Thus, the research of glial cells and their functions is one of the directions of modern neurobiology and neuroscience, which has great potential for further development of neurology and improvement of treatment of patients with brain diseases.

Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases.

Most mitochondrial proteins are targeted to the organelle by N-terminal mitochondrial targeting sequences (MTSs, or "presequences") that are recognized by the import machinery and subsequently cleaved to yield the mature protein. MTSs do not have conserved amino acid compositions, but share common physicochemical properties, including the ability to form amphipathic α-helical structures enriched with basic and hydrophobic residues on alternating faces. The lack of strict sequence conservation implies that some polypeptides can be mistargeted to mitochondria, especially under cellular stress. The pathogenic accumulation of proteins within mitochondria is implicated in many aging-related neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases. Mechanistically, these diseases may originate in part from mitochondrial interactions with amyloid-β precursor protein (APP) or its cleavage product amyloid-β (Aβ), α-synuclein (α-syn), and mutant forms of huntingtin (mHtt), respectively, that are mediated in part through their associations with the mitochondrial protein import machinery. Emerging evidence suggests that these amyloidogenic proteins may present cryptic targeting signals that act as MTS mimetics and can be recognized by mitochondrial import receptors and transported into different mitochondrial compartments. Accumulation of these mistargeted proteins could overwhelm the import machinery and its associated quality control mechanisms, thereby contributing to neurological disease progression. Alternatively, the uptake of amyloidogenic proteins into mitochondria may be part of a protein quality control mechanism for clearance of cytotoxic proteins. Here we review the pathomechanisms of these diseases as they relate to mitochondrial protein import and effects on mitochondrial function, what features of APP/Aβ, α-syn and mHtt make them suitable substrates for the import machinery, and how this information can be leveraged for the development of therapeutic interventions.

Exercise mitigates age-related metabolic diseases by improving mitochondrial dysfunction.

The benefits of regular physical activity are related to delaying and reversing the onset of ageing and age-related disorders, including cardiomyopathy, neurodegenerative diseases, cancer, obesity, diabetes, and fatty liver diseases. However, the molecular mechanisms of the benefits of exercise or physical activity on ageing and age-related disorders remain poorly understood. Mitochondrial dysfunction is implicated in the pathogenesis of ageing and age-related metabolic diseases. Mitochondrial health is an important mediator of cellular function. Therefore, exercise alleviates metabolic diseases in individuals with advancing ageing and age-related diseases by the remarkable promotion of mitochondrial biogenesis and function. Exerkines are identified as signaling moieties released in response to exercise. Exerkines released by exercise have potential roles in improving mitochondrial dysfunction in response to age-related disorders. This review comprehensive summarizes the benefits of exercise in metabolic diseases, linking mitochondrial dysfunction to the onset of age-related diseases. Using relevant examples utilizing this approach, the possibility of designing therapeutic interventions based on these molecular mechanisms is addressed.

SARS-CoV-2 Spike Protein S1 Domain Accelerates α-Synuclein Phosphorylation and Aggregation in Cellular Models of Synucleinopathy.

The 2019 novel coronavirus disease (COVID-19) is an infectious disease that began to spread globally since 2019. Some COVID-19 patients have neurological complications, such as olfactory disorders and movement disorders, which coincide with the symptoms of Parkinson's disease (PD). Increasing imaging and autopsy evidence supports that the density of dopaminergic neurons in the nigrostriatal pathway is damaged in some COVID-19 patients. However, the underlying mechanism that causes PD-like symptoms remains unclear. PD is an age-related neurodegenerative disease with Lewy bodies (LBs) as its histopathologic feature. The main component of LBs is abnormally aggregated α-synuclein (α-syn). The prion-like propagation of α-syn aggregates plays a key role in the onset and progression of PD. The spike protein (S protein) of SARS-CoV-2 is a heparin-binding protein that mediates the entry of the virus into host cells. Here we found that the S1 domain interacts with α-syn and promotes α-syn aggregation. The S1 domain induces mitochondrial dysfunction, oxidative stress, and cytotoxicity. The S1-seeded α-syn fibrils show enhanced seeding activity and induce synaptic damage and cytotoxicity. Thus, the S1 domain of SARS-CoV-2 promotes the aggregation of α-syn in the cellular model of synucleinopathy and may contribute to the pathogenesis of PD.

Vitamin D Improves Cognitive Impairment and Alleviates Ferroptosis via the Nrf2 Signaling Pathway in Aging Mice.

Ferroptosis is an iron-dependent mode of cell death associated with the occurrence and development of age-related neurodegenerative diseases. Currently, there are no effective drugs available to prevent or treat these aging-related neurodegenerative diseases. Vitamin D (VD) is an antioxidant and immunomodulator, but its relationship with ferroptosis in aging-related neurodegenerative diseases has not been extensively studied. In this study, we aimed to investigate the role of VD in learning and memory in aging mice. To examine whether VD protects aging hippocampal neurons, we used physiologically active 1,25(OH)2D3. We established aging models in vivo (C57BL/6 mice) and in vitro (HT22 cells) using D-galactose (D-gal). The results demonstrated that VD could improve learning and memory in mice aged via the use of D-gal, and it reduced damage to hippocampal neurons. VD could regulate ferroptosis-related proteins (increasing GPX4 expression and decreasing ACSL4 and ALOX15 protein expression levels), increasing GSH levels, reducing MDA and intracellular and mitochondrial ROS levels, as well as total iron and Fe2+ levels, and improving mitochondrial morphology, thereby alleviating ferroptosis in aging hippocampal neurons. Additionally, VD activated the VDR/Nrf2/HO-1 signaling pathway, thereby inhibiting ferroptosis. Notably, when the VDR was knocked down, VD lost its ability to activate Nrf2. Consequently, inhibiting Nrf2 decreased the protective effect of VD against ferroptosis in aged hippocampal neurons. In summary, VD activates the Nrf2/HO-1 signaling pathway through the VDR, effectively preventing ferroptosis induced by aging in hippocampal neurons.

The neuroprotective effects of Liuwei Dihuang medicine in the APP/PS1 mouse model are dependent on the PI3K/Akt signaling pathway.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that progressively impairs cognitive function and memory. The occurrence and development of Alzheimer's disease involves many processes. In response to the complex pathogenesis of AD, the Traditional Chinese medicine formula Liuwei Dihuang Pill (LWD) has been shown to improve the cognitive function of AD animal models. However, the active ingredients and mechanism of action of LWD have not been fully elucidated. In this study, network pharmacological analysis predicted 40 candidate compounds in LWD, acting on 227 potential targets, of which 185 were associated with AD. Through network pharmacological analysis, the mechanism of action of LWD therapy AD is related to the inhibition of inflammatory response, regulation of neuronal state, and autophagy. In this experiment, LWD was detected in the APP/PS1 transgenic mouse model. The objective was to observe the effects of LWD on hippocampal learning and memory ability, Aβ clearance, autophagy and inflammatory response in APP/PS1 mice. The results showed that LWD improved long-term memory and working memory in APP/PS1 mice compared with the WT group. At the same time, LWD can increase the expression of hippocampal autophagy biomarkers, reduce the precipitation of Aβ, and the activation of microglia and astrocytes. Its mechanism may be related to the regulation of the PI3K/Akt signaling pathway. Thus, we demonstrate for the first time that LWD has a neuroprotective effect on APP/PS1 mice and provide theoretical foundation for the development of a new clinical treatment for AD.

Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum

BackgroundLow-grade, chronic inflammation in the central nervous system characterized by glial reactivity is one of the major hallmarks for aging-related neurodegenerative diseases like Alzheimer’s disease (AD). The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex and may be differentially vulnerable in various neurodegenerative diseases. However, the impact of chronic neuroinflammation on the cholinergic function is still unclear.MethodsTo gain further insight into age-related cholinergic decline, we investigated the cumulative effects of aging and chronic neuroinflammation on the structure and function of the septal cholinergic neurons in transgenic mice expressing interleukin-6 under the GFAP promoter (GFAP-IL6), which maintains a constant level of gliosis. Immunohistochemistry combined with unbiased stereology, single cell 3D morphology analysis and in vitro whole cell patch-clamp measurements were used to validate the structural and functional changes of BFCN and their microglial environment in the medial septum.ResultsStereological estimation of MS microglia number displayed significant increase across all three age groups, while a significant decrease in cholinergic cell number in the adult and aged groups in GFAP-IL6 mice compared to control. Moreover, we observed age-dependent alterations in the electrophysiological properties of cholinergic neurons and an increased excitability profile in the adult GFAP-IL6 group due to chronic neuroinflammation. These results complimented the significant decrease in hippocampal pyramidal spine density seen with aging and neuroinflammation.ConclusionsWe provide evidence of the significant impact of both aging and chronic glial activation on the cholinergic and microglial numbers and morphology in the MS, and alterations in the passive and active electrophysiological membrane properties of septal cholinergic neurons, resulting in cholinergic dysfunction, as seen in AD. Our results indicate that aging combined with gliosis is sufficient to cause cholinergic disruptions in the brain, as seen in dementias.

A Review on Contentious Role of HSV1 in Alzheimer’s Disease and Natural Dietary Benefits to Prevent HSV

Herpes simplex virus 1 (HSV1) is a neuro-invasive virus causing lifelong latent infection in humans. It increases the risk of dementia by entering inside the brain. Herpesviruses have been implicated in Alzheimer’s disease (AD) development. More than 50 million people worldwide are affected by Alzheimer’s disease. Alzheimer’s disease is becoming more prevalent with the increase age-related neurodegenerative diseases, dementia, etc. Therefore, there is an urgent need for better understanding of the pathogenesis of AD as well as its early detection. HSV-1 is a risk factor of for the occurrence of neurodegenerative diseases, sporadic Alzheimer’s disease, prior diagnosis of disease cycle of Herpes Simplex Virus Type 1 in brain tissue will help us to prevent AD in elderly patients. Serological assays were the first choice of detection including whole-antigen-based (non-gG-specific) methods and western blotting (WB) assays, but quantitative PCR (qPCR) & genomic sequencing has shown better efficiency. Recently RNAscope, a novel in situ RNA hybridization assay is developed to visualize and detect the multiple phases of HSV-1. In this review, we discussed about early detection of tau and β-amyloid protein which are biomarkers of AD and track the deposition of amyloid plaques reminiscent in brain. We also discussed the current work on HSV detection through RNAscope hybridization technique & summarized the role of dietary habits as a precautionary measure of the infection as well as anthropological diversification of dementia in India and factors influencing it. We also pointed out some knowledge gaps that are further required to be taken after detection of the infection.

Chrysophanol improves memory impairment and cell injury by reducing the level of ferroptosis in Aβ25-35 treated rat and PC12 cells.

Alzheimer's disease (AD) is a common age-related chronic and neurodegenerative disease that has become a global health problem. AD pathogenesis is complex, and the clinical efficacy of commonly used anti-AD drugs is suboptimal. Recent research has revealed a close association between AD-induced damage and the activation of ferroptosis signaling pathways. Chrysophanol (CHR) the principal medicinal component of Rhubarb, has been reported to have anti-AD effects and can reduce ROS levels in AD-damaged models. AD has been linked to the activation of ferroptosis signaling pathways, which has an important feature of higher levels of reactive oxygen species (ROS). Therefore, the present study explored whether CHR had an anti-AD effect by regulating the ferroptosis levels in AD injury models. Morris water maze, novel object recognition test, Y-maze test, Hematoxylin-eosin (H&E) staining, western blotting, ROS measurement, GPx activity measurement, LPO measurement, transmission electron microscopy, live/dead cell staining were used to investigate the changes in spatial memory level and ferroptosis level in AD model, and the intervention effect of CHR. CHR improved the spatial memory level of AD rat models, reduced the level of hippocampal neuron damage, and improved the survival rate of PC12 cells damaged by β-amyloid (Aβ). Meanwhile, CHR increased glutathione peroxidase-4 (GPX4) protein expression, GPx activity, and GSH, decreased ROS and LPO levels in AD rat models and Aβ-damaged PC12 cells, and improved mitochondrial pathological damage. Our findings suggest that CHR may play a protective role in AD injury by lowering ferroptosis levels, which may provide a potential pathway for developing drugs for AD. However, the mechanism of CHR's role requires further investigation.

Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors.

We have recently shown that multiple tRNA synthetase inhibitors can greatly increase lifespan in multiple models by acting through the conserved transcription factor ATF4. Here, we show that these compounds, and several others of the same class, can greatly upregulate mammalian ATF4 in cells in vitro, in a dose dependent manner. Further, RNASeq analysis of these cells pointed toward changes in protein turnover. In subsequent experiments here we show that multiple tRNA synthetase inhibitors can greatly upregulate activity of the ubiquitin proteasome system (UPS) in cells in an ATF4-dependent manner. The UPS plays an important role in the turnover of many damaged or dysfunctional proteins in an organism. Increasing UPS activity has been shown to enhance the survival of Huntington's disease cell models, but there are few known pharmacological enhancers of the UPS. Additionally, we see separate ATF4 dependent upregulation of macroautophagy upon treatment with tRNA synthetase inhibitors. Protein degradation is an essential cellular process linked to many important human diseases of aging such as Alzheimer's disease and Huntington's disease. These drugs' ability to enhance proteostasis more broadly could have wide-ranging implications in the treatment of important age-related neurodegenerative diseases.

Comprehensive Review of Nutraceuticals against Cognitive Decline Associated with Alzheimer's Disease.

Nowadays, nutraceuticals are being incorporated into functional foods or used as supplements with nonpharmacological approaches in the prevention and management of several illnesses, including age-related conditions and chronic neurodegenerative diseases. Nutraceuticals are apt for preventing and treating such disorders because of their nontoxic, non-habit-forming, and efficient bioactivities for promoting neurological well-being due to their ability to influence cellular processes such as neurogenesis, synaptogenesis, synaptic transmission, neuro-inflammation, oxidative stress, cell death modulation, and neuronal survival. The capacity of nutraceuticals to modify all of these processes reveals the potential to develop food-based strategies to aid brain development and enhance brain function, prevent and ameliorate neurodegeneration, and possibly reverse the cognitive impairment observed in Alzheimer's disease, the most predominant form of dementia in the elderly. The current review summarizes the experimental evidence of the neuroprotective capacity of nutraceuticals against Alzheimer's disease, describing their mechanisms of action and the in vitro and in vivo models applied to evaluate their neuroprotective potential.

Senescent Microglia Represent a Subset of Disease-Associated Microglia in P301S Mice.

The existence and contribution of microglia with senescent-like alterations in the pathogenesis of age-related neurodegenerative diseases like Alzheimer's disease (AD) have been suggested in recent years. However, the identification of this distinct microglial population in vivo has proven challenging, largely due to overlaps in the inflammatory phenotype of activated and senescent microglia. Furthermore, attempts at recapitulating senescence in microglia in vitro are limited. To identify and characterize senescent microglia that occur in vivo in an animal model of neurodegeneration driven by pathologic tau. We analyzed the RNA expression patterns of individual microglia from normal mice and the pathogenic tau P301 S PS19 mouse model. We have previously demonstrated that p16-expressing senescent microglia occur in these mice when neurodegeneration has occurred. Here we identify a subset of disease-associated microglia with senescent features, notably characterized by the expression of Ccl4. This signature overlaps with established markers of senescence from other cell types. Our characterization of senescent microglia can be used to better understand the role of senescent microglia in various age-related contexts, including whether clearance of senescent microglia represents a viable therapeutic option.

Ebselen, Iron Uptake Inhibitor, Alleviates Iron Overload-Induced Senescence-Like Neuronal Cells SH-SY5Y via Suppressing the mTORC1 Signaling Pathway.

Increasing evidence highlights that excessive iron accumulation in the brain plays a vital role in neuronal senescence and is implicated in the pathogenesis of age-related neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Therefore, the chemical compounds that eliminate an iron overload may provide better protection against oxidative stress conditions that cause the accumulation of senescent cells during brain aging. Ebselen has been identified as a strongly useful compound in the research on redox biology mechanisms. We hypothesized that ebselen could alleviate an iron overload-induced oxidative stress and consequently reverses the senescence-like phenotypes in the neuronal cells. In the present study, SH-SY5Y cells were treated with ferric ammonium citrate (FAC) before ebselen, and the evaluation of the cellular iron homeostasis, the indicators of oxidative stress, and the onset of senescence phenotypes and mechanisms were carried out accordingly. Our findings showed that ebselen ameliorated the FAC-mediated iron overload by decreasing the expression of divalent metal transporter 1 (DMT1) and ferritin light chain (FT-L) proteins. In contrast, it increased the expression of ferroportin 1 (FPN1) protein and its correlation led to a decrease in the expression of the cytosolic labile iron pool (LIP). Furthermore, ebselen significantly reduced reactive oxygen species (ROS) and rescued the mitochondrial membrane potential (ΔΨm). Notably, ebselen restored the biomarkers of cellular senescence by reducing the number of senescence-associated β-galactosidase (SA-β-gal) positive cells and senescence-associated secretory phenotypes (SASP). This also suppressed the expression of p53 protein targeting DNA damage response (DDR)/p21 cyclin-dependent kinase (CDK) inhibitor through a mTORC1 signaling pathway. Potentially, ebselen could be a therapeutic agent for treating brain aging and AD by mitigating iron accumulation and restoring senescence in SH-SY5Y cells.

Orthosiphon aristatus (Blume) Miq. Extracts attenuate Alzheimer-like pathology through anti-inflammatory, anti-oxidative, and β-amyloid inhibitory activities

Ethnopharmacological relevanceOrthosiphon aristatus (Blume) Miq. (OA) is a traditional folk-herb, which is usually used to treat acute and chronic nephritis, epilepsy, cystitis, and other diseases. Phenols and flavonoids are the main active compound compounds of OA, with proven anti-inflammatory and antioxidant activities. Aims of this studyBased on evidenced therapeutic activities, we aimed to investigate the impact of OA on Alzheimer's disease (AD) which is the most common age-related neurodegenerative disease, and the pathological features include accumulation of beta-amyloid (Aβ) and neurofibrillary tangles (NFT). Materials and methodsOA was extracted with water, methanol, chloroform, and ethyl acetate, and determined its total flavonoid and phenolic contents. Initially, Aβ1-42 based cytotoxicity was induced in BV2 cells and C6 cells to investigate the therapeutic impact of OA therapy by MTT, RT-PCR, Western blot, and ELISA. Further, Aβ1−42 Oligomer (400 pmol)-induced AD mice model was established to evaluate the impact of OA extract on improving learning and memory impairment. ResultsThe results showed that the extract of OA could increase cell survival, inhibit the expression of TNF-α, IL-6, IL-1β, COX-2, and iNOS, and increase BDNF levels. We infer that the OA extract may attenuate Aβ-induced cytotoxicity by retarding the production of inflammatory-related factors. In the animal behavior test, the number of mice entering darkroom and the time of arriving at the platform were significantly reduced, indicating the learning and memory-improving ability of OA extract. ConclusionsThese findings imply that the OA ethanolic extract demonstrated an improving effect on memory and hence could serve as a potential therapeutic target for the treatment of neurodegenerative diseases like AD.