Inflammation In Alzheimer's Disease Research Articles

Multimodal Blood-Based Biomarker Panel Reveals Altered Lysosomal Ionic Content in Alzheimer's Disease.

Lysosomal storage disorders (LSDs) and adult neurodegenerative disorders like Alzheimer's disease (AD) share various clinical and pathophysiological features. LSDs are characterized by impaired lysosomal activity caused by mutations in key proteins and enzymes. While lysosomal dysfunction is also linked to AD pathogenesis, its precise role in disease onset or progression remains unclear. Lysosomal ionic homeostasis is recognized as a key feature of many LSDs, but it has not been clinically linked with AD pathology. Thus, investigating whether this regulation is disrupted in AD is important, as it could lead to new therapeutic targets and biomarkers for this multifactorial disease. Here, using two-ion mapping (2-IM) technology, we quantitatively profiled lysosomal pH and Ca2+ in blood-derived monocytes from AD patients and age-matched controls and correlated lysosome ionicity with age and key markers of AD pathology, namely, amyloid deposits, tauopathy, neurodegeneration, and inflammation. Together, the data show that the ionic milieu of lysosomes is dysregulated in monocytes of AD patients and correlates with key plasma biomarkers of AD. Using a machine learning model based on the above parameters, we describe a proof-of-concept combinatorial biomarker platform that accurately distinguishes between patients with AD and control participants with an area under the curve of >96%. Our study introduces a convenient, noninvasive platform with the potential to diagnose Alzheimer's disease based on fluid, cellular, and molecular biomarkers. Further, these findings highlight the potential for investigating therapeutic mechanisms capable of restoring lysosome ionic homeostasis to ameliorate AD.

Repurposing FDA-Approved Drugs Against Potential Drug Targets Involved in Brain Inflammation Contributing to Alzheimer’s Disease

Alzheimer’s disease is a neurodegenerative disease that continues to have a rising number of cases. While extensive research has been conducted on Alzheimer’s disease in the last few decades, only a few drugs have been approved by the FDA for its treatment, and even fewer aim to be curative rather than manage symptoms. There remains an urgent need to understand disease pathogenesis, as well as identify new targets for further drug discovery. Alzheimer’s disease (AD) is known to stem from the build-up of amyloid beta (Aβ) plaques, as well as tangles of tau proteins. Furthermore, inflammation in the brain is known to arise from the degeneration of tissue and the build-up of insoluble material. Therefore, there is a potential link between the pathology of AD and inflammation in the brain, especially as the disease progresses to later stages, where neuronal death and degeneration levels are higher. Proteins that are relevant to both brain inflammation and AD, thus, make ideal potential targets for therapeutics; however, the proteins need to be evaluated to determine which targets would be ideal for potential drug therapeutic treatments, or ‘druggable’ targets. Druggability analysis was conducted using two structure-based methods (i.e., drug-like density analysis and SiteMap), as well as a sequence-based approach, SPIDER. The most druggable targets were then evaluated using single-nucleus sequencing data for their clinical relevance to inflammation in AD. For each of the top five targets, small molecule docking was used to evaluate which FDA approved drugs were able to bind with the chosen proteins. The top targets included DRD2 (inhibits adenylyl cyclase activity), C9 (binds with C5B8 to form the membrane attack complex), C4b (binds with C2a to form C3 convertase), C5AR1 (a GPCR that binds C5a), and GABA-A-R (the GPCR involved in inhibiting neurotransmission). Each target had multiple potential inhibitors from the FDA-approved drug list with decent binding infinities. Among these inhibitors, two drugs were found to be top inhibitors for more than one protein target. They were C15H14N2O2 and v316 (paracetamol), originally used to treat pain/inflammation for cataracts and relieve headaches/fever, respectively. These results provide the groundwork for further experimental investigations or clinical trials.

The neuroinflammatory role of microRNAs in Alzheimer's disease: pathological insights to therapeutic potential.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia, contributing to around 60-80% of cases. The main pathophysiology of AD is characterized by an abnormal accumulation of protein aggregates extracellularly (beta-amyloid plaques) and intracellularly (neurofibrillary tangles of hyperphosphorylated tau). However, an increasing number of studies have also suggested neuroinflammation may have a crucial role in precipitating the cascade reactions that result in the development of AD neuropathology. In particular, several studies indicate microRNAs (miRNAs) can act as regulatory factors for neuroinflammation in AD, with potential to affect the occurrence and/or progression of AD inflammation by targeting the expression of multiple genes. Therefore, miRNAs may have potential as therapeutic targets for AD, which requires more research. This article will review the existing studies on miRNAs that have been identified to regulate neuroinflammation, aiming to gain further insights into the specific regulatory processes of miRNAs, highlight the diagnostic and therapeutic potential of miRNAs as biomarkers in AD, as well as current challenges, and suggest the further work to bridge the gap in knowledge to utilize miRNAs as therapeutic targets for AD.

Combined administration of catalpol, puerarin, gastrodin, and borneol modulates the Tlr4/Myd88/NF-κB signaling pathway and alleviates microglia inflammation in Alzheimer's disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder affecting millions of people worldwide, with no effective treatment currently available. In recent decades, various traditional Chinese medicines (TCMs) and their active ingredients have shown the potential to attenuate the pathogenesis of AD in cellular and animal models. However, the effects of TCM formulas, which are typically administered in practice, have been less studied. This study aims to investigate the therapeutic effects of several formulas consisting of 4 components herbal components: catalpol, puerarin, gastrodin, and borneol, on streptozotocin (STZ)-induced AD models in cells and rats. The new object recognition (NOR), elevated plus maze (EMP), and Morris water maze (MWM) tests were used to evaluate the cognitive functions of rats. Golgi staining, Haematoxylin and Eosin (HE) staining, and Nissl staining analyses were employed assess the physiology of hippocampal tissues. Gene expression profiles were analyzed used transcriptomics and reverse transcription quantitative polymerase chain reaction analysis, while protein expression levels were determined using immunoblotting, immunohistochemical, and immunofluorescence. The production of cytokines was evaluated with enzyme-linked immunosorbent assay. The results demonstrated that the combined administration of these 4 components (CPGB) had superior mitigating effects on AD cell model, as evidenced by the reduced pro-inflammatory cytokine production and decreased deposition of Aβ protein. Further in vivo and in vitro experiments confirmed that varying doses of CPGB formula effectively ameliorated STZ-induced cognitive deficits, as shown by NOR, MWM, and EMP tests, as well as pathological changes in hippocampal tissues and a 3-dimensional brain neurovascular unit (3D-NVU) model, including decreased deposition of Aβ protein and formation of plaques. Transcriptome sequencing and analysis identified 35 genes with significantly altered expression levels due to STZ and CPGB treatment in hippocampal tissues, which were enriched in the Tlr4/Myd88/NF-κB signaling pathway. Interference with this pathway significantly influenced the therapeutic effects of CPGB in the 3D-NVU model. Collectively, these findings suggest that the combined administration of catalpol, puerarin, gastrodin, and borneol offers superior therapeutic effects on AD by modulating the Tlr4/Myd88/NF-κB signaling pathway. This study strengthens the theoretical foundation for using TCMs to treat AD, proving new insights and references for alleviating and treating AD.

Molecular Mechanisms Underlying Amyloid Beta Peptide Mediated Upregulation of Vascular Cell Adhesion Molecule-1 in Alzheimer Disease.

Amyloid β(Aβ) deposition and neurofibrillary tangles are widely considered the primary pathological hallmarks of familial and sporadic forms of Alzheimer disease (AD). However, cerebrovascular inflammation, which is prevalent in 70% of AD patients, is emerging as another core feature of AD pathology. In our current work, we investigated the hypothesis that Aβ42 exposure drives an increase in vascular cell adhesion molecule-1 (VCAM-1) expression, a cerebrovascular inflammatory marker expressed on the blood-brain barrier (BBB) endothelium in humans and murine models. We have demonstrated that the inflammation signaling pathway is upregulated in AD patient brains, and VCAM-1 expression is increased in AD patients compared with healthy controls. Furthermore, dynamic SPEC/CT imaging in APP,PS1 transgenic mice (a mouse model that overexpresses Aβ42) demonstrated VCAM-1 upregulation at the BBB. Although there is a strong association between Aβ42 exposure and an increase in VCAM-1 expression, the underlying mechanisms remain partially understood. Molecular mechanisms driving VCAM-1 expression at the BBB were investigated in polarized human cerebral microvascular endothelial cell monolayers. Moreover, by employing reverse-phase protein array assays and immunocytochemistry we demonstrated that Aβ42 increases VCAM-1 expression via the Src/p38/MEK signaling pathway. Therefore, targeting the Src/p38/MEK pathway may help modulate VCAM-1 expression at the BBB and help mitigate cerebrovascular inflammation in Alzheimer disease. SIGNIFICANCE STATEMENT: Although considered a core pathological feature of Alzheimer disease, molecular pathways leading to cerebrovascular inflammation remain only partially understood. Moreover, clinical diagnostic methods for detecting cerebrovascular inflammation are underdeveloped. This study demonstrated the detection of VCAM-1 using radio-iodinated VCAM-1 antibody and single-photon emission computed tomography/computed tomography imaging. Additionally, exposure to Aβ42 increases VCAM-1 expression on the blood-brain barrier endothelium via the Src/p38/MEK pathway. These findings are expected to aid in the development of diagnostic and therapeutic approaches for addressing cerebrovascular inflammation in AD.

Noradrenaline Protects Human Microglial Cells (HMC3) Against Apoptosis and DNA Damage Induced by LPS and Aβ1-42 Aggregates In Vitro.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) plaques and neuroinflammation. This study investigates the protective effects of noradrenaline (NA) on human microglial cells exposed to lipopolysaccharides (LPS) and Aβ aggregates-major contributors to inflammation and cellular damage in AD. The reduced Aβ aggregation in the HMC3 human microglial cells co-treated with Aβ and NA was confirmed by thioflavin T (ThT) assay, fluorescent ThT staining, and immunocytochemistry (ICC). The significantly increased viability of HMC3 cells after 48 h of incubation with NA at 50 µM, 25 µM, and 10 µM, exposed to IC50 LPS and IC50 Aβ, was confirmed by XTT and LDH assays. Moreover, we found that NA treatment at 25 μM and 50 μM concentrations in HMC3 cells exposed to IC50 LPS or IC50 Aβ results in an increased proliferation of HMC3 cells, their return to normal morphology, decreased levels of DNA damage, reduced caspase-3 activity, decreased expression of pro-apoptotic DDIT3 and BAX, and increased expression of anti-apoptotic BCL-2 genes and proteins, leading to enhanced cell survival, when compared to that of the HMC3 cells treated only with IC50 LPS or IC50 Aβ. Furthermore, we showed that NA induces the degradation of both extracellular and intracellular Aβ deposits and downregulates hypoxia-inducible factor 1α (HIF-1α), which is linked to impaired Aβ clearance and AD progression. These findings indicate that NA holds promise as a therapeutic target to address microglial dysfunction and potentially slow the progression of AD. Its neuroprotective effects, particularly in reducing inflammation and regulating microglial activity, warrant further investigation into its broader role in mitigating neuroinflammation and preserving microglial function in AD.

Myeloid gasdermin D drives early-stage T cell immunity and peripheral inflammation in a mouse model of Alzheimer's disease.

It is now realized that peripheral inflammation and abnormal immune responses, especially T cells, contribute to the development of Alzheimer's disease (AD). Gasdermin D (GSDMD) -mediated pyroptosis has been associated with several neuroinflammatory diseases, but whether GSDMD is involved in the peripheral inflammation and T cell immunity during AD remains unclear. We dynamically investigated GSDMD activation in the peripheral and central nervous system of 5×FAD mouse model and dissected the role of myeloid GSDMD using genetic knockout mice, especially its influence on peripheral T cell responses and AD inflammation. RNA sequencing and in vitro coculture were used to elucidate the underlying immune mechanisms involved. Targeted inhibitor experiments and clinical correlation analysis were used to further verify the function of GSDMD in AD. In the present study, caspase activated GSDMD in the spleen of 5×FAD mice earlier than in the brain during disease progression. Loss of myeloid cell GSDMD was shown to impair early-stage effector T cell activation in the periphery and prevent T cell infiltration into the brain, with an overall reduction in neuroinflammation. Furthermore, myeloid cell GSDMD induced T cell PD-1 expression through the IL-1β/NF-κB pathway, restricting regulatory T cells. The administration of a GSDMD inhibitor combined with an anti-PD-1 antibody was found to mitigate the development of AD-associated inflammation. In some AD patients, plasma sPD-1 is positively correlated with IL-Iβ and clinical features. Our study systematically identified a role for GSDMD in the AD-related peripheral inflammation and early-stage T cell immunity. These findings also suggest the therapeutic potential of targeting GSDMD for the early intervention in AD.

Drug Delivery Targeting Neuroinflammation to Treat Brain Diseases.

Inflammation within the brain is a hallmark of a wide range of brain diseases. The complex role of inflammatory processes in these conditions suggests that neuroinflammation could be a valuable therapeutic target. While several promising anti-inflammatory agents have been identified, their clinical application in brain diseases is often hampered by the inability to cross the blood-brain barrier (BBB) and reach therapeutically effective concentrations at the pathological sites. This limitation highlights the urgent need for effective BBB-penetrating drug delivery systems designed to target brain inflammation. This review critically examines the recent advances over the past five years in drug delivery strategies aimed at mitigating brain inflammation in Alzheimer's disease and ischemic stroke─two of the leading causes of death and disability worldwide. Additionally, we address the key challenges in this field, offering insights into future directions for targeting neuroinflammation in the treatment of brain diseases.

Oxidative stress-mediated neuroinflammation in Alzheimer's disease.

Reactive oxygen species (ROS) are metabolic by-products that constitute an indispensable component of physiological processes, albeit their heightened presence may proffer substantial perils to biological entities. Such a proliferation gives rise to a gradual escalation of oxidative stress within the organism, thereby compromising mitochondrial functionality and inflicting harm upon various bodily systems, with a particular predilection for the central nervous system. In its nascent stages, it is plausible that inflammation has been a facilitator in the progression of the malady. The precise role of inflammation in Alzheimer's disease (AD) remains somewhat enigmatic, although it is conceivable that activated microglia and astrocytes might be implicated in the removal of amyloid-β (Aβ) deposits. Nonetheless, prolonged microglial activation is associated with Tau phosphorylation and Aβ aggregation. Research studies have indicated that AD brains upregulate complementary molecules, inflammatory cytokines, acute phase reacting agents, and other inflammatory mediators that may cause neurodegeneration. In this review, oxidative damage products will be discussed as potential peripheral biomarkers for AD and its early stages. The disordered excretion of pro-inflammatory cytokines, chemokines, oxygen, and nitrogen-reactive species, along with the stimulation of the complement system by glial cells, has the potential to disrupt the functionality of neuronal termini. This perturbation, in turn, culminates in compromised synaptic function, a phenomenon empirically linked to the manifestation of cognitive impairments. The management of neurodegenerative conditions in the context of dementia necessitates therapeutic interventions that specifically target the excessive production of inflammatory and oxidative agents. Furthermore, we shall deliberate upon the function of microglia and oxidative injury in the etiology of AD and the ensuing neurodegenerative processes.

Roles of Cytokines in Alzheimer's Disease.

The neuroimmune system is a collection of immune cells, cytokines, and the glymphatic system that plays a pivotal role in the pathogenesis and progression of Alzheimer's disease (AD). Of particular focus are cytokines, a group of immune signaling molecules that facilitate communication among immune cells and contribute to inflammation in AD. Extensive research has shown that the dysregulated secretion of certain cytokines (IL-1β, IL-17, IL-12, IL-23, IL-6, and TNF-α) promotes neuroinflammation and exacerbates neuronal damage in AD. However, anti-inflammatory cytokines (IL-2, IL-3, IL-33, and IL-35) are also secreted during AD onset and progression, thereby preventing neuroinflammation. This review summarizes the involvement of pro- and anti-inflammatory cytokines in AD pathology and discusses their therapeutic potential.

Nutrition, Immunity and Aging: Current Scenario and Future Perspectives in Neurodegenerative Diseases.

Aging is a gradual decline of physiological function and tissue homeostasis and, in many instances, is related to increased (neuro)-degeneration, together with inflammation, becoming one of the most important risks for developing neurodegenerative diseases. Certain individual nutrients or foods in combination may counteract aging and associated neurodegenerative diseases by promoting a balance between the pro- and anti-inflammatory responses. Thus, nutrition could represent a powerful modulator of this fine balance, other than a modifiable risk factor to contrast inflammaging. This narrative review explores from a broad perspective the impact of nutrition on the hallmarks of aging and inflammation in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis Syndrome (ALS), starting from nutrients up to single foods and complex dietary patterns.

Transcriptome and Animal Model Integration Reveals Inhibition of Calcium Homeostasis-Associated Gene ITPKB Alleviates Amyloid Plaque Deposition.

Alzheimer's disease (AD) is a severe neurological illness that causes memory loss and is a global problem. The calcium hypothesis recently steadily evolved in AD. The prospective targets for calcium homeostasis therapy, however, are limited, and gene expression-level research connected to calcium homeostasis in AD remains hazy. In this study, we analyzed the microarray dataset (GSE132903) taken from the Gene Expression Omnibus (GEO) database to investigate calcium homeostasis-related genes for AD. Using immunoblot analysis, we examined the association of ITPKB with inflammation in AD. Additionally, the immunofluorescence technique was employed to assess the impact of pharmacological inhibition of ITPKB on the amyloid-β (Aβ) plaque deposition in APP/PS1 mice. This article's further exploration of calcium homeostasis-related genes has propelled the validation of the calcium homeostasis theory in AD.

The Influence of Myeloid-Derived Suppressor Cell Expansion in Neuroinflammation and Neurodegenerative Diseases.

The neuro-immune axis has a crucial function both during physiological and pathological conditions. Among the immune cells, myeloid-derived suppressor cells (MDSCs) exert a pivotal role in regulating the immune response in many pathological conditions, influencing neuroinflammation and neurodegenerative disease progression. In chronic neuroinflammation, MDSCs could lead to exacerbation of the inflammatory state and eventually participate in the impairment of cognitive functions. To have a complete overview of the role of MDSCs in neurodegenerative diseases, research on PubMed for articles using a combination of terms made with Boolean operators was performed. According to the search strategy, 80 papers were retrieved. Among these, 44 papers met the eligibility criteria. The two subtypes of MDSCs, monocytic and polymorphonuclear MDSCs, behave differently in these diseases. The initial MDSC proliferation is fundamental for attenuating inflammation in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), but not in amyotrophic lateral sclerosis (ALS), where MDSC expansion leads to exacerbation of the disease. Moreover, the accumulation of MDSC subtypes in distinct organs changes during the disease. The proliferation of MDSC subtypes occurs at different disease stages and can influence the progression of each neurodegenerative disorder differently.

Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment

Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD.

DNA hypomethylation promotes the expression of CASPASE-4 which exacerbates inflammation and amyloid-β deposition in Alzheimer’s disease

Alzheimer’s disease (AD) is the sixth leading cause of death in the USA. It is established that neuroinflammation contributes to the synaptic loss, neuronal death, and symptomatic decline of AD patients. Accumulating evidence suggests a critical role for microglia, innate immune phagocytes of the brain. For instance, microglia release pro-inflammatory products such as IL-1β which is highly implicated in AD pathobiology. The mechanisms underlying the transition of microglia to proinflammatory promoters of AD remain largely unknown. To address this gap, we performed reduced representation bisulfite sequencing (RRBS) to profile global DNA methylation changes in human AD brains compared to no disease controls. We identified differential DNA methylation of CASPASE-4 (CASP4), which when expressed promotes the generation of IL-1β and is predominantly expressed in immune cells. DNA upstream of the CASP4 transcription start site was hypomethylated in human AD brains, which was correlated with increased expression of CASP4. Furthermore, microglia from a mouse model of AD (5xFAD) express increased levels of CASP4 compared to wild-type (WT) mice. To study the role of CASP4 in AD, we developed a novel mouse model of AD lacking the mouse ortholog of CASP4 and CASP11, which is encoded by mouse Caspase-4 (5xFAD/Casp4−/−). The expression of CASP11 was associated with increased accumulation of pathologic protein aggregate amyloid-β (Aβ) and increased microglial production of IL-1β in 5xFAD mice. Utilizing RNA-sequencing, we determined that CASP11 promotes unique transcriptomic phenotypes in 5xFAD mouse brains, including alterations of neuroinflammatory and chemokine signaling pathways. Notably, in vitro, CASP11 promoted generation of IL-1β from macrophages in response to cytosolic Aβ through cleavage of downstream effector Gasdermin D (GSDMD). Therefore, here we unravel the role for CASP11 and GSDMD in the generation of IL-1β in response to Aβ and the progression of pathologic inflammation in AD. Overall, our results demonstrate that overexpression of CASP4 due to differential DNA methylation in AD microglia contributes to the progression of AD pathobiology. Thus, we identify CASP4 as a potential target for immunotherapies for the treatment and prevention of AD.

In Silico Identification of a Potential TNF-Alpha Binder Using a Structural Similarity: A Potential Drug Repurposing Approach to the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with no conclusive remedy. Yohimbine, found in Rauwolfia vomitoria, may reduce brain inflammation by targeting tumour necrosis factor-alpha (TNFα), implicated in AD pathogenesis. Metoserpate, a synthetic compound, may inhibit TNFα. The study is aimed at assessing the potential utility of repurposing metoserpate for TNFα inhibition to reduce neuronal damage and inflammation in AD. The development of safe and effective treatments for AD is crucial to address the growing burden of the disease, which is projected to double over the next two decades. Our study repurposed an FDA-approved drug as TNFα inhibitor for AD management using structural similarity studies, molecular docking, and molecular dynamics simulations. Yohimbine was used as a reference compound. Molecular docking used SeeSAR, and molecular dynamics simulation used GROMACS. Metoserpate was selected from 10 compounds similar to yohimbine based on pharmacokinetic properties and FDA approval status. Molecular docking and simulation studies showed a stable interaction between metoserpate and TNFα over 100 ns (100000 ps). This suggests a reliable and robust interaction between the protein and ligand, supporting the potential utility of repurposing metoserpate for TNFα inhibition in AD treatment. Our study has identified metoserpate, a previously FDA-approved antihypertensive agent, as a promising candidate for inhibiting TNFα in the management of AD.

MiRNA let-7d-5p Alleviates Inflammatory Responses by Targeting Map3k1 and Inactivating ERK/p38 MAPK Signaling in Microglia.

Alzheimer's disease (AD) is the most common form of dementia. Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of AD. In a large case-control study recruiting 208 patients with AD and 205 elderly control subjects, miRNA-let-7d-5p attracted our attention for its downregulated level in patients with AD. However, the biological functions of let-7d-5p in AD pathogenesis have not been investigated. This study emphasized the functions and mechanisms of let-7d-5p in the pathogenesis of AD. Mouse microglial BV2 cells treated with amyloid-β (Aβ)1-42 were used as in vitro AD inflammation models. We reported that let-7d-5p was downregulated in Aβ1-42-stimulated BV2 cells, and upregulation of let-7d-5p promoted the transversion of microglial cells from Ml phenotype to M2 phenotype. Then, the binding relationship between let-7d-5p and Map3k1 was verified by luciferase reporter assays. Mechanistically, let-7d-5p could target Map3k1 3'UTR to inactivate ERK/p38 MAPK signaling. Therefore, it was suggested that let-7d-5p might be a novel modulator of microglial neuroinflammation and serve as a novel target for diagnosis and treatment of AD.

Evaluation of Early Diagnosis via Some Blood Parameters in Alzheimer Type Dementia and Type 2 Diabetes Mellitus Patients

Aim: Alzheimer's disease is a neurodegenerative disease with cognitive loss, which does not have a curative treatment and a bloodbased
 biomarker to make a definitive diagnosis. There is a strong relationship between Alzheimer's disease and type 2 diabetes mellitus.
 Neutrophil-lymphocyte, platelet-lymphocyte and monocyte-lymphocyte ratios are recommended parameters as inflammation markers.
 It was aimed to compare blood parameters and their ratios to each other in terms of their potential to provide early diagnosis in patients
 with Alzheimer's disease and type 2 diabetes mellitus.
 Material and Methods: 80 healthy controls, 47 type 2 diabetes mellitus and 45 Alzheimer's type dementia patients were included in this
 study. Various blood parameters and their ratios to each other were scanned. One way ANOVA and post hoc Scheffe tests were used for
 statistical analysis.
 Results: Serum iron levels were lower in type 2 diabetes mellitus (53.21±29.28 μg/dL) and Alzheimer’s disease (61.26±21.69 μg/dL)
 groups compared to the control (76.96±30.99 μg/dL) (p=0.001). Lymphocyte numbers were lower in type 2 diabetes mellitus (1.94±0.79
 count.10³) and Alzheimer’s disease (1.84±0.68 count.10³) groups compared to the control (2.25±1.03 count.10³) (p=0.032). Monocytelymphocyte
 ratio were significantly higher in type 2 diabetes mellitus (0.3±0.18) and Alzheimer’s disease (0.28±0.11) groups compared
 to the control (0.24±0.1) (p=0.039).
 Conclusion: The high monocyte-lymphocyte ratio can be considered as an indicator of systemic inflammation in Alzheimer's disease
 and type 2 diabetes mellitus. In conclusion, serum iron levels, lymphocyte numbers and monocyte-lymphocyte ratio as inflammation
 markers can be useful for the early diagnosis of type 2 diabetes mellitus and Alzheimer’s disease

Comparison of Neuroinflammation Induced by Hyperphosphorylated Tau Protein Versus Ab42 in Alzheimer's Disease.

Both neurofibrillary tangles and senile plaques are associated with inflammation in Alzheimer's disease (AD). Their relative degree of induced neuroinflammation, however, is not well established. Mouse models of AD that expressed either human Aβ42 (n = 7) or human hyperphosphorylated tau protein alone (n = 3), wild type (n = 10), and human AD samples (n = 29 with 18 controls) were studied. The benefit of using mouse models that possess only human tau or amyloid-b is that it allows for the individual evaluation of how each protein affects neuroinflammation, something not possible in human tissue. Three indicators of neuroinflammation were examined: TLRs/RIG1 expression, the density of astrocytes and microglial cells, and well-established mediators of neuroinflammation (IL6, TNFα, IL1β, and CXCL10). There was a statistically significant increase in neuroinflammation with all three variables in the mouse models with human tau only as compared to human Aβ42 only or wild-type mice (each at p < 0.0001). Only the Aβ42 5xFAD mice (n = 4) showed statistically higher neuroinflammation versus wild type (p = 0.0030). The human AD tissues were segregated into Aβ42 only or hyperphosphorylated tau protein with Aβ42. The latter areas showed increased neuroinflammation with each of the three variables compared to the areas with only Aβ42. Of the TLRs and RIG-1, TLR8 was significantly elevated in both the mouse model and human AD and only in areas with the abnormal tau protein. It is concluded that although Aβ42 and hyperphosphorylated tau protein can each induce inflammation, the latter protein is associated with a much stronger neuroinflammatory response vis-a-vis a significantly greater activated microglial response.

Contextualizing the Role of Osteopontin in the Inflammatory Responses of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by progressive accumulations of extracellular amyloid-beta (Aβ) aggregates from soluble oligomers to insoluble plaques and hyperphosphorylated intraneuronal tau, also from soluble oligomers to insoluble neurofibrillary tangles (NFTs). Tau and Aβ complexes spread from the entorhinal cortex of the brain to interconnected regions, where they bind pattern recognition receptors on microglia and astroglia to trigger inflammation and neurotoxicity that ultimately lead to neurodegeneration and clinical AD. Systemic inflammation is initiated by Aβ's egress into the circulation, which may be secondary to microglial activation and can confer both destructive and reparative actions. Microglial activation pathways and downstream drivers of Aβ/NFT neurotoxicity, including inflammatory regulators, are primary targets for AD therapy. Osteopontin (OPN), an inflammatory cytokine and biomarker of AD, is implicated in Aβ clearance and toxicity, microglial activation, and inflammation, and is considered to be a potential therapeutic target. Here, using the most relevant works from the literature, we review and contextualize the evidence for a central role of OPN and associated inflammation in AD.