Role In Alzheimer's Disease Research Articles

The Role of Physical Activity in Inflammation and Neurogenesis in 5xFAD Mice

Objective/Hypothesis: The apoliprotein E epsilon 4 (APOE4) variant is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) and is associated with accelerated clinical disease. Increasing evidence suggests that the immune system plays a direct role in AD pathogenesis, and several studies show that APOE genotype alter inflammatory pathways. However, the mechanism by which APOE4 influences the immune system is unknown. Physical activity (PA) is thought to play a neuroprotective role in late-onset AD and represents a possible strategy to attenuate cognitive decline and amyloid beta deposition in APOE4 carriers. We hypothesize that PA counteracts the negative inflammatory effects mediated by APOE4 by promoting a protective microglial response.
 Methods: Mice with humanized APOE3 and APOE4 were crossed to 5xFAD transgenic mice, which carry mutant human APP and presenilin genes to drive amyloid pathology and neurodegeneration. The resultant transgenic mice (5xFAD;APOE4/4 and 5xFAD;APOE3/3) were subjected to a voluntary wheel running paradigm or stationary wheels for 4 months. We used immunohistochemical and ELISA-based techniques to evaluate microglia and neurons. The microglia disease-associated phenotype was assessed by Clec7a staining while homeostatic microglia markers were evaluated by P2ry12 staining. Neuronal numbers in cortical lamina V were evaluated by NeuN staining. Neurogenesis was evaluated by doublecortin staining.
 Results: We expect to see an increase in Clec7a and a decrease in P2ry12 staining on microglia surrounding beta amyloid plaques in 5xFAD;APOE4/4 mice subjected to running compared to mice housed with stationary wheels. In addition, we anticipate PA will ameliorate neuronal loss and promote neurogenesis in the subgranular zone of the dentate gyrus in the hippocampus.
 Conclusion/Potential Impact: The study will support the benefit of PA in attenuating the progression of late-onset AD in individuals with the APOE4 risk allele. The study will also elucidate the relationship between microglial responses, APOE genotype, and PA in AD.

NMDA Receptor GluN2B Subunit Is Involved in Excitotoxicity Mediated by Death-Associated Protein Kinase 1 in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia among the elderly. Excitotoxicity has been implicated as playing a dominant role in AD, especially related to the hyperactivation of excitatory neurons. Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin-dependent kinase and involved in the pathogenesis of AD, but the roles and mechanisms of DAPK1 in excitotoxicity in AD are still uncertain. We mainly explored the underlying mechanisms of DAPK1 involved in the excitotoxicity of AD and its clinical relevance. Differentiated SH-SY5Y human neuroblastoma cells, PS1 V97 L transgenic mice, and human plasma samples were used. Protein expression was assayed by immunoblotting, and intracellular calcium and neuronal damage were analyzed by flow cytometry. Plasma DAPK1 was measured by ELISA. We found that DAPK1 was activated after amyloid-β oligomers (AβOs) exposure in differentiated SH-SY5Y cells. Besides, we found the phosphorylation of GluN2B subunit at Ser1303 was increased, which contributing to excitotoxicity and Ca2+ overload in SH-SY5Y cells. Inhibiting DAPK1 activity, knockdown of DAPK1 expression, and antagonizing GluN2B subunits could effectively prevent AβOs-induced activation of GluN2B subunit, Ca2+ overload, and neuronal apoptosis. Additionally, we found that DAPK1 was elevated in the brain of AD transgenic mouse and in the plasma of AD patients. Our finding will help to understand the mechanism of DAPK1 in the excitotoxicity in AD and provide a reference for the diagnosis and therapy of AD.

Miracle fruit seed as a potential supplement for the treatment of learning and memory disorders in Alzheimer's disease.

Currently, the treatment of Alzheimer's disease (AD) is still at the stage of symptomatic treatment due to lack of effective drugs. The research on miracle fruit seeds (MFSs) has focused on lipid-lowering and antidiabetic effects, but no therapeutic effects have been reported in AD. The purpose of this study was to provide data resources and a potential drug for treatment of AD. An AD mouse model was established and treated with MFSs for 1month. The Morris water maze test was used to assess learning memory function in mice. Nissl staining was used to demonstrate histopathological changes. MFSs were found to have therapeutic implications in the AD mouse model, as evidenced by improved learning memory function and an increase in surviving neurons. To explore the mechanism of MFSs in treating AD, network pharmacological approaches, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking studies were carried out. Based on the network pharmacology strategy, 74 components from MFS corresponded to 293 targets related to the AD pathology. Among these targets, AKT1, MAPK3, ESR1, PPARG, PTGS2, EGFR, PPARA, CNR1, ABCB1, and MAPT were identified as the core targets. According to the relevant number of core targets, cis-8-octadecenoic acid, cis-10-octadecenoic acid, 2-dodecenal, and tetradecane are likely to be highly correlated with MFS for AD. Enrichment analysis indicated the common targets mainly enriched in AD and the neurodegeneration-multiple disease signaling pathway. The molecular docking predictions showed that MFSs were stably bound to core targets, specifically AKT1, EGFR, ESR1, PPARA, and PPARG. MFSs may play a therapeutic role in AD by affecting the insulin signaling pathway and the Wnt pathway. The findings of this study provide potential possibilities and drug candidates for the treatment of AD.

Novel heterozygous mutation in alpha-2-macroglobulin (A2M) suppressing the binding of amyloid-β (Aβ).

Many studies have suggested that the alpha-2-macroglobulin (A2M) gene may be involved in the pathogenesis of Alzheimer's disease (AD). A2M encoded by the A2M gene can specifically bind to the β-amyloid peptide and prevent fiber formation. The patient in this study had progressive memory loss at the age of 60 years and underwent a series of neuropsychological tests, cranial magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarker analysis, and whole-exome sequencing (WES) to evaluate possible mutations. We used in silico tools and three-dimensional (3D) protein structure prediction to analyze the pathogenicity of the mutation and used a co-immunoprecipitation experiment to study the effect of mutations on amyloid-β (Aβ) binding. Based on neuropsychological tests, cranial MRI, and CSF biomarker analysis, the patient was diagnosed with AD. WES showed that there was a missense mutation in A2M (c.1229A>C, p.N410T). Bioinformatics analysis showed that this mutation was pathogenic. Moreover, 3D protein structure analysis showed that the A2M Asn410 residue was an N-glycosylation site, which was necessary for A2M activation to bind to Aβ. Missense mutations led to the loss of glycosylation at this site, which suppressed the binding of Aβ. The functional experiment also confirmed the prediction: the interaction between A2M and Aβ from the patient's plasma was weakened. Our results demonstrate that this novel A2M p.N410T mutation may have a pathogenic role in AD, by altering the binding interactions between A2M and Aβ.

Aquaporin 5 in Alzheimer's disease: a link between oral and brain pathology?

Aquaporin 5 in Alzheimer's disease: a link between oral and brain pathology?

Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease.

Decades of research have demonstrated an incontrovertible role of amyloid-β (Aβ) in the etiology of Alzheimer's disease (AD). However, the overemphasis on the pathological impacts of Aβ may obscure the role of its metabolic precursor, amyloid precursor protein (APP), as a significant hub in the occurrence and progression of AD. The complicated enzymatic processing, ubiquitous receptor-like properties, and abundant expression of APP in the brain, as well as its close links with systemic metabolism, mitochondrial function and neuroinflammation, imply that APP plays multifaceted roles in AD. In this review, we briefly describe the evolutionarily conserved biological characteristics of APP, including its structure, functions and enzymatic processing. We also discuss the possible involvement of APP and its enzymatic metabolites in AD, both detrimental and beneficial. Finally, we describe pharmacological agents or genetic approaches with the capability to reduce APP expression or inhibit its cellular internalization, which can ameliorate multiple aspects of AD pathologies and halt disease progression. These approaches provide a basis for further drug development to combat this terrible disease.

Alzheimer's Disease and Aging Association: Identification and Validation of Related Genes.

Aging is considered a key risk factor for Alzheimer's disease (AD). This study aimed to identify and validate potential aging-related genes associated with AD using bioinformatics analysis. Datasets GSE36980 and GSE5281 were selected to screen differentially expressed genes (DEGs), and the immune cell correlation analysis and GSEA analysis of DEGs were performed. The intersection with senescence genes was taken as differentially expressed senescence-related genes (DESRGs), and the GSE44770 dataset was used for further validation. The potential biological functions and signaling pathways were determined by GO and KEGG, and the hub genes were identified by 12 algorithms in Cytohubba. The expression of 10 hub genes in different brain regions was determined and single-cell sequencing analysis was performed, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. Finally, a miRNA-gene network of diagnostic genes was constructed and targeted drug prediction was performed. A total of 2137 DEGs were screened from the GSE36980 and GSE5281 datasets, and 278 SRGs were identified from the CellAge database. The overlapping DEGs and SRGs constituted 29 DESRGs, including 14 senescence suppressor genes and 15 senescence inducible genes. The top 10 hub genes, including MDH1, CKB, PSMD14, SMARCA4, PEBP1, DDB2, ITPKB, ATF7IP, YAP1, and EWSR1 were screened. Furthermore, four diagnostic genes were identified: PMSD14, PEBP1, ITPKB, and ATF7IP. The ROC analysis showed that the respective area under the curves (AUCs) of PMSD14, PEBP1, ITPKB, and ATF7IP were 0.732, 0.701, 0.747, and 0.703 in the GSE36980 dataset and 0.870, 0.817, 0.902, and 0.834 in the GSE5281 dataset. In the GSE44770 dataset, PMSD14 (AUC, 0.838) and ITPKB (AUC, 0.952) had very high diagnostic values in the early stage of AD. Finally, based on these diagnostic genes, we found that the drug Abemaciclib is a targeted drug for the treatment of age-related AD. Flutamide can aggravate aging-related AD. The results of this study suggest that cellular SRGs might play an important role in AD. PMSD14, PEBP1, ITPKB, and ATF7IP have the potential as specific biomarkers for the early diagnosis of AD.

Programmed Death of Microglia in Alzheimer's Disease: Autophagy, Ferroptosis, and Pyroptosis.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) plaques and the formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Increasing evidence has demonstrated that the damage of cell plays an important role in AD. Cell death is a critical phenomenon for physiological functions, which promotes AD pathogenesis. Programmed cell death, including necroptosis, pyroptosis, autophagy, and ferroptosis, have been discovered that have unique biological functions and pathophysiological characteristics. Here, we review the available evidence detailing the mechanisms of programmed microglial death, including pyroptosis, autophagy, and ferroptosis. We also highlight the role of programmed death of microglia during the process of AD and focus on the connection between the disease and cell death.

Microglial metabolic reconfiguration provides a new strategy for the treatment of Alzheimer's disease.

Microglial metabolic reconfiguration provides a new strategy for the treatment of Alzheimer's disease.

Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core.

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.

Artificial intelligence-driven meta-analysis of brain gene expression identifies novel gene candidates and a role for mitochondria in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia. There is no treatment and AD models have focused on a small subset of genes identified in familial AD. Microarray studies have identified thousands of dysregulated genes in the brains of patients with AD yet identifying the best gene candidates to both model and treat AD remains a challenge. We performed a meta-analysis of microarray data from the frontal cortex (n = 697) and cerebellum (n = 230) of AD patients and healthy controls. A two-stage artificial intelligence approach, with both unsupervised and supervised machine learning, combined with a functional network analysis was used to identify functionally connected and biologically relevant novel gene candidates in AD. We found that in the frontal cortex, genes involved in mitochondrial energy, ATP, and oxidative phosphorylation, were the most significant dysregulated genes. In the cerebellum, dysregulated genes were involved in mitochondrial cellular biosynthesis (mitochondrial ribosomes). Although there was little overlap between dysregulated genes between the frontal cortex and cerebellum, machine learning models comprised of this overlap. A further functional network analysis of these genes identified that two downregulated genes, ATP5L and ATP5H, which both encode subunits of ATP synthase (mitochondrial complex V) may play a role in AD. Combined, our results suggest that mitochondrial dysfunction, particularly a deficit in energy homeostasis, may play an important role in AD.

Ginsenoside Rd protects transgenic Caenorhabditis elegans from β-amyloid toxicity by activating oxidative resistant.

Alzheimer's disease (AD) is a serious public health issue but few drugs are currently available for the disease, and these only target the symptoms. It is well established that oxidative stress plays a crucial role in AD, and there is compelling evidence linking oxidative stress to β-amyloid (Aβ). An exciting source of potential new AD therapeutic medication possibilities is medicinal plants. Ginsenoside Rd (GS-Rd) is one of the main bioactive substances in ginseng extracts. In our study, we used a network pharmacology analysis to identify overlapping GS-Rd (therapeutic) and AD (disease)-relevant protein targets, gene ontology (GO) and bio-process annotation, and the KEGG pathway analysis data predicted that GS-Rd impacts multiple targets and pathways, such as the MAPK signal pathway and the JAT-STAT3 signaling pathway. We then assessed the role of GS-Rd in C. elegans and found that GS-Rd prolongs lifespan, improves resistance to heat stress, delays physical paralysis and increases oxidative stress responses. Overall, these results suggest that GS-Rd protects against the toxicity of Aβ. The RNA-seq analysis revealed that GS-Rd achieves its effects by regulating gene expressions like daf-16 and skn-1, as well as by participating in many AD-related pathways like the MAPK signaling pathway. In addition, in CL4176 worms, GS-Rd decreased reactive oxygen species (ROS) levels and increased SOD activity. Additional research with transgenic worms showed that GS-Rd aided in the movement of DAF-16 from the cytoplasm to the nucleus. Taken together, the results indicate that GS-Rd significantly reduces Aβ aggregation by targeting the MAPK signal pathway, induces nuclear translocation of DAF-16 to activate downstream signaling pathways and increases resistance to oxidative stress in C. elegans to protect against Aβ-induced toxicity.

GWAS for CSF TREM2 levels identify new variants implicated on TREM2 biology and Alzheimer disease

AbstractBackgroundIt is demonstrated that the soluble TREM2 in the cerebrospinal fluid (CSF) is associated with Alzheimer disease (AD). Recent studies by our group found that it is the MS4A4A and/or MS4A6A locus that plays a role in modulating sTREM2 and is also associated with AD risk. The goal of this study is to validate and extend findings from previous studies using a larger cohort, identify functional genes, and determine the overlap of the genetic architecture of CSF TREM2 levels with other traits.MethodWe used 3,033 individuals from Knight ADRC, ADNI, DIAN, and PPMI, and 8,499,039 variants (MAF >0.01) to identify protein quantitative trait loci (pQTLs) that modify TREM2 levels via a linear regression including age, sex, first 10 genetic principal components and array/cohort as covariates. TREM2 protein measurements were obtained from SomaScan 7k platform. Colocalization analyses were conducted for AD risk as well as functional genes from eQTLGen. LDSC and GNOVA and Mendelian randomization (MR) is being used to determine the overlap of the genetic architecture of sTREM2 levels with those for AD risk, onset and progression, as well as cardiovascular and lipid traits.ResultThe pQTL analysis identified the previously discovered MS4A gene region on chr11 (rs72918674, P = 7.009e‐58) as well as a peak on chr3 (rs73823326, P = 2.227e‐09). The lead variant resides in the intron of MS4A6A gene. Conditional analysis on this variant revealed rs10897026 as an additional independent signal located in the intron of MS4A4A. Chr11 peak colocalized with AD risk (PP‐H4 = 0.97) and MS4AE and MS4A6A expression QTL in blood (PP‐H4 = 0.97 and 0.96, respectively). Four regulatory region variants are in high linkage disequilibrium (LD) with chr3 index variant. RBMS3 and TGFBR2 are two genes flanking the chr3 peak, both expressed in microglia.ConclusionThis is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. The findings validated discoveries from previous studies and identified a novel signal on chr3 at genome‐wide significance. We propose two new genes, RBMS3 and TGFBR2 on chr3, could be involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD.

Intricate connections between aging and Alzheimer’s diseases molecular trajectories revealed by plasma proteomics

AbstractBackgroundAging is the greatest non‐genetic risk factor for many diseases including Alzheimer’s Disease (AD) and its mechanisms are thus increasingly recognized as potential therapeutic targets.Since the molecular relationships between normal aging and AD are still largely unknown, we took advantage of recent methodological developments to measure more than 7k proteins in plasma to identify common but also different molecular mechanisms involved in aging and AD.MethodRecently, we developed new data‐driven bioinformatics approaches that uncovered marked non‐linear alterations in the human plasma proteome with age (Lehallier et al. Nature Medicine 2019). We applied these machine learning approaches to 271 patients at different stages of AD (61 subjects with Subjective Cognitive Decline: SCD, 106 with Mild Cognitive Impairment: MCI and 104 with AD) and compared these changes to those observed in a healthy aging cohort (370 subjects, 18‐69 years).ResultThe analysis of proteomics trajectories confirmed marked non‐linear alterations in the human plasma proteome with aging and uncovered the complex molecular choreography of AD. By analyzing trajectories of groups of proteins, we identified multiple clusters of proteins that are differentially affected during aging and AD. These clusters were enriched for various biological processes relevant for AD progression such as the complement and coagulation cascades, axon guidance and angiogenesis (q<0.05)ConclusionAltogether, our results reveal the intricate connections between aging and AD at the molecular level. The integrated proteomics trajectories analysis performed in this study allows the identification of new targets possibly playing a key role in AD but also pinpoints when these proteins are deviating from their normal trajectories and thus when they should be targeted by new therapies.

The Neuroprotective Potentiality of Flavonoids on Alzheimer’s Disease

Alzheimer's disease (AD), due to its spread, has become a global health priority, and is characterized by senile dementia and progressive disability. The main cause of AD and other neurodegenerations (Huntington, Parkinson, Amyotrophic Lateral Sclerosis) are aggregated protein accumulation and oxidative damage. Recent research on secondary metabolites of plants such as polyphenols demonstrated that they may slow the progression of AD. The flavonoids' mechanism of action in AD involved the inhibition of acetylcholinesterase, butyrylcholinesterase, Tau protein aggregation, β-secretase, oxidative stress, inflammation, and apoptosis through modulation of signaling pathways which are implicated in cognitive and neuroprotective functions, such as ERK, PI3-kinase/Akt, NFKB, MAPKs, and endogenous antioxidant enzymatic systems. This review focuses on flavonoids and their role in AD, in terms of therapeutic potentiality for human health, antioxidant potential, and specific AD molecular targets.

New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common progressive and irreversible neurodegeneration characterized by the impairment of memory and cognition. Despite years of studies, no effective treatment and prevention strategies are available yet. Identifying new AD therapeutic targets is crucial for better elucidating the pathogenesis and establishing a valid treatment of AD. Growing evidence suggests that microglia play a critical role in AD. Microglia are resident macrophages in the central nervous system (CNS), and their core properties supporting main biological functions include surveillance, phagocytosis, and the release of soluble factors. Activated microglia not only directly mediate the central immune response, but also participate in the pathological changes of AD, including amyloid-beta (Aβ) aggregation, tau protein phosphorylation, synaptic dissection, neuron loss, memory function decline, etc. Based on these recent findings, we provide a new framework to summarize the role of microglia in AD memory impairment. This evidence suggests that microglia have the potential to become new targets for AD therapy.

Inhibition of circ_0004381 improves cognitive function via miR-647/PSEN1 axis in an Alzheimer disease mouse model.

Circ_0004381 promotes neuronal damage in Parkinson disease, but its role in Alzheimer disease (AD) is unreported. The goal of this study was to investigate the role and potential mechanisms of circ_0004381 effects in AD models. Primary hippocampal neurons were treated with amyloid-β (Aβ1-42) to construct AD cell models. We found that circ_0004381 was upregulated in Aβ1-42-treated hippocampal neurons. Knockdown of circ_0004381 attenuated Aβ1-42-induced apoptosis, oxidative stress, and mitochondrial dysfunction in hippocampal neurons. Next, we induced microglia activation with lipopolysaccharide (LPS). The results of flow cytometry experiments showed that knockdown of circ_0004381 promoted microglial M2-type polarization and knockdown of circ_0004381 inhibited the production of inflammatory factors by microglia. Furthermore, knockdown of circ_0004381 improved cognitive function of male APPswe/PS1dE9 transgenic mice. Mechanistically, circ_0004381 regulated presenilin-1 (PSEN1) expression by absorbing miR-647. MiR-647 inhibition attenuated the effects of circ_0004381 knockdown. In conclusion, knockdown of circ_0004381 attenuated hippocampal neuronal damage and promoted microglia M2-type polarization through the miR-647/PSEN1 axis, ultimately improving cognitive function in AD model mice.

Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro.

Numerous studies have demonstrated that type 2 diabetes (T2D) is closely linked to the occurrence of Alzheimer's disease (AD). Nevertheless, the underlying mechanisms for this association are still unknown. Insulin resistance (IR) hallmarked by hyperinsulinemia, as the earliest and longest-lasting pathological change in T2D, might play an important role in AD. Since hyperinsulinemia has an independent contribution to related disease progressions by promoting inflammation in the peripheral system, we hypothesized that hyperinsulinemia might have an effect on microglia which plays a crucial role in neuroinflammation of AD. In the present study, we fed 4-week-old male C57BL/6 mice with a high-fat diet (HFD) for 12 weeks to establish IR model, and the mice treated with standard diet (SD) were used as control. HFD led to obesity in mice with obvious glucose and lipid metabolism disorder, the higher insulin levels in both plasma and cerebrospinal fluid, and aberrant insulin signaling pathway in the whole brain. Meanwhile, IR mice appeared impairments of spatial learning and memory accompanied by neuroinflammation which was characterized by activated microglia and upregulated expression of pro-inflammatory factors in different brain regions. To clarify whether insulin contributes to microglial activation, we treated primary cultured microglia and BV2 cell lines with insulin in vitro to mimic hyperinsulinemia. We found that hyperinsulinemia not only increased microglial proliferation and promoted M1 polarization by enhancing the production of pro-inflammatory factors, but also impaired membrane translocation of glucose transporter 4 (GLUT4) serving as the insulin-responding glucose transporter in the processes of glucose up-taking, reduced ATP production and increased mitochondrial fission. Our study provides new perspectives and evidence for the mechanism underlying the association between T2D and AD.

Inflammation-Related microRNAs-146a and -155 Are Upregulated in Mild Cognitive Impairment Subjects Among Older Age Population in Montenegro.

Pathological and clinical features of Alzheimer's disease (AD) are in temporal discrepancy and currently accepted clinical tests provide the diagnosis decades after the initial pathophysiological events. In order to enable a more timely detection of AD, research efforts are directed to identification of biomarkers of the early symptomatic stage. Neuroinflammatory signaling pathways and inflammation-related microRNAs (miRNAs) could possibly have a crucial role in AD, making them promising potential biomarkers. We examined the expression of circulatory miRNAs with a documented role in AD pathophysiology: miR-29a/b, miR-101, miR-125b, miR-146a, and miR-155 in the plasma of AD patients (AD, n = 12), people with mild cognitive impairment (MCI, n = 9), and normocognitive group (CTRL, n = 18). We hypothesized that these miRNA expression levels could correlate with the level of participants' cognitive decline. The study participants completed the standardized interview, neurological examination, neuropsychological assessment, and biochemical analyses. miRNA expression levels were assessed by RT-PCR. Neurological and laboratory findings could not account for MCI, but miR-146a and -155 were upregulated in the MCI group compared to the control. miR-146a, known to mediate early neuroinflammatory AD events, was also upregulated in the MCI compared to AD group. ROC curve analysis for miRNA-146a showed 77.8% sensitivity and 94.4% specificity and 66.7% sensitivity and 88.9% specificity for miR-155. Determination of circulatory inflamma-miRs-146a and -155 expression, together with neuropsychological screening, could become a non-invasive tool for detecting individuals with an increased risk for AD, but research on a larger cohort is warranted.

The role of transforming growth factor β1 /Smad pathway in Alzheimer's disease inflammation pathology.

Alzheimer's disease (AD), a progressive disorder, has become a global health problem and is now the main cause of dementia. The aetiology of AD is complex and remains elusive making effective AD treatment difficult. Current drugs for AD only improve symptoms but do not interfere with pathogenic mechanisms. Three main hypotheses have been brought forward regarding AD aetiology, one of them being the 'inflammation hypothesis'. A number of studies have demonstrated that inflammation plays a critical role in AD. Self-limiting neuroinflammation is considered beneficial to AD, whereas chronic inflammation aggravates brain injury and neuronal death. Transforming growth factor β 1(TGF-β1) is an anti-inflammatory cytokine with neuroprotective properties. Smad proteins are downstream molecules of TGF-β signalling. They are cytoplasmic transcription factors that can regulate targeted gene expression. In AD, impairments of TGF-β1/Smad pathways have been observed. Moreover, microglia, astrocytes, inflammasomes, and insulin resistance also have been implicated in AD pathogenesis. Elucidating the molecular mechanisms underlying AD pathogenesis is a fundamental step toward designing new treatment options. In this review, we detail the changes in TGF-β1/Smad pathways in AD and hope this will facilitate further research on AD treatment.