Pathways In Alzheimer's Disease Research Articles

Characterization of Metabolites in a Zebrafish Model of Alzheimer's Disease Supplemented with Mussel-Derived Plasmalogens by Ultraperformance Liquid Chromatography Q-Exactive Orbitrap Mass Spectrometry-Based Unbiased Metabolomics.

Plasmalogens (Pls) are bioactive substances enriched in the brain with a regulatory effect on Alzheimer's disease (AD), while their metabolomic influence accompanying AD and the underlying mechanisms remain unclear. Here, we extracted and purified Pls (purity of ≥90%) from mussels and applied unbiased metabolomics using ultraperformance liquid chromatography Q-Exactive Orbitrap mass spectrometry to analyze the variation of metabolites in the major metabolic pathways of AD and revealed the cognitive improvement effect of Pls using an experimental AD zebrafish model. The results showed that 37 differential endogenous metabolites were identified, among which glycerophosphocholine, choline, S-adenosylmethionine (SAM), l-glutamine, linoleic acid, 9(S)-HPODE, methionine, and creatine were the major abnormally regulated metabolites, and the first four metabolites were viewed as potential endogenous markers. This study suggested that systemic metabolic profiling could reveal the potential metabolic networks of AD and illuminated the protective effect of Pls on AD through biochemistry mechanisms and metabolic pathways.

A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's Disease and Type 2 Diabetes.

Alzheimer's Disease (AD) and Type 2 Diabetes (T2D) share a common hallmark of insulin resistance. Reportedly, two non-canonical Receptor Tyrosine Kinases (RTKs), ALK and RYK, both targets of the same micro RNA miR-1271, exhibit significant and consistent functional down-regulation in post-mortem AD and T2D tissues. Incidentally, both have Grb2 as a common downstream adapter and NOX4 as a common ROS producing factor. Here we show that Grb2 and NOX4 play critical roles in reducing the severity of both the diseases. The study demonstrates that the abundance of Grb2 in degenerative conditions, in conjunction with NOX4, reverse cytoskeletal degradation by counterbalancing the network of small GTPases. PAX4, a transcription factor for both Grb2 and NOX4, emerges as the key link between the common pathways of AD and T2D. Down-regulation of both ALK and RYK through miR-1271, elevates the PAX4 level by reducing its suppressor ARX via Wnt/β-Catenin signaling. For the first time, this study brings together RTKs beyond Insulin Receptor (IR) family, transcription factor PAX4 and both AD and T2D pathologies on a common regulatory platform.

Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics.

BackgroundCognitive decline leading to dementia, accompanied by the accumulation of amyloid-beta (Aβ) in neuritic plaques together with the appearance of neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein (tau), are previously noted hallmarks of Alzheimer's disease (AD). We previously discovered hypervascularity in brain specimens from AD patients and consistent with this observation, we demonstrated that overexpression of Aβ drives cerebrovascular neoangiogenesis leading to hypervascularity and coincident tight-junction disruption and blood-brain barrier (BBB) leakiness in animal models of AD. We subsequently demonstrated that amyloid plaque burden and cerebrovascular pathogenesis subside when pro-angiogenic Aβ levels are reduced. Based on these data, we propose a paradigm of AD etiology where, as a compensatory response to impaired cerebral blood flow (CBF), Aβ triggers pathogenic cerebrovascular neoangiogenesis that underlies the conventional hallmarks of AD. Consequently, here we present evidence that repurposing anti-cancer drugs to modulate cerebrovascular neoangiogenesis, rather than directly targeting the amyloid cascade, may provide an effective treatment for AD and related vascular diseases of the brain.MethodsWe explored whether the anti-cancer drug, Axitinib, a small molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) can inhibit aberrant cerebrovascular neoangiogenic changes, reduce Aβ deposits and reverse cognitive decline in an animal model of AD. One month post-treatment with Axitinib, we employed a battery of tests to assess cognition and memory in aged Tg2576 AD mice and used molecular analysis to demonstrate reduction of amyloid plaques, BBB leakage, hypervascularity and associated disease pathology.FindingsTargeting the pro-angiogenic pathway in AD using the cancer drug, Axitinib, dramatically reduced cerebrovascular neoangiogenesis, restored BBB integrity, resolved tight-junction pathogenesis, diminishes Aβ depositions in plaques and effectively restores memory and cognitive performance in a preclinical mouse model of AD.InterpretationModulation of neoangiogenesis, in an analogous approach to those used to treat aberrant vascularization in cancer and also in the wet form of age-related macular degeneration (AMD), provides an alternative therapeutic strategy for intervention in AD that warrants clinical investigation.

Exploring the Genetic Associations Between the Use of Statins and Alzheimer's Disease

ObjectiveAlzheimer's disease (AD) is the most common cause of dementia. The statins have shown beneficial effects on cognitive functions and reduced the risk of dementia development. However, the exact mechanisms of statin effects in AD are not yet fully understood. In this study, we aimed to explore the underlying mechanisms of statin on AD.MethodsWe downloaded AD blood dataset (GSE63060) and statin-related blood gene expression dataset (GSE86216). Then we performed gene expression analysis of each dataset and compared blood gene expressions between AD patients and statin-treated patients. Then, we downloaded mouse embryonic neural stem cell dataset (GSE111945) and performed gene expression analysis.ResultsFrom the human blood dataset, we identified upregulated/downregulated genes in AD patients and statin-treated patients. Some of the upregulated genes (AEN, MBTPS1, ABCG1) in the blood of AD patients are downregulated in statin-treated patients. Several downregulated genes (FGL2, HMGCS1, PSME2, SRSF3, and ATG3) are upregulated in statin-treated patients. Gene set enrichment analysis using mouse stem cell dataset revealed a significant relationship of Kyoto Encyclopedia of Genes and Genomes-defined pathway of AD in statin-treated neural stem cells compared to vehicle-treated neural stem cells (normalized enrichment score: −2.24 in male and −1.6 in female).ConclusionThese gene expression analyses from human blood and mouse neural stem cell demonstrate the important clues on the molecular mechanisms of impacts of statin on AD disease. Further studies are needed to investigate the exact role of candidate genes and pathways suggested in our AD pathogenesis study.

Atomic Level Investigations of Early Aggregation of Tau43 in Water I. Conformational Propensity of Monomeric Tau43

Recent studies in Alzheimer's disease (AD) investigated the precise mechanisms responsible for neurofibrillary tangles (NFT) and senile plaques formation. NFTs, the aggregated Tau protein isoforms, are one of the primary factors behind AD. The corresponding smallest variant Tau43, as paired helical filaments (PHFs), self‐assemble into pathological diseased aggregates. However, the molecular details in rationalizing the aggregation propensity of Tau43 remain elusive. Herein, using molecular dynamics simulations on aqueous Tau43, we identify the molecular factors responsible for early behavior of Tau43 aggregation propensity in water. The variant is intrinsically unstructured yet compact in nature, in agreement with previous studies. The PHF6 (11VQIVYK16) segment is relatively less fluctuating, yet most extended and hydrophobic, thereby shielded from aqueous environment by intermolecular polar interactions between terminal residues. We also compared structural propensities of Tau43 and oppositely charged Aβ42 peptide, providing a comparative understanding of early AD pathway, leading to corresponding drug designing avenues.

Functional co-activation of the default mode network in APOE ε4-carriers: A replication study

Structural and functional alterations of the brain in persons genetically at-risk for Alzheimer's disease (AD) are crucial in unravelling AD development. Filippini et al. found that the default mode network (DMN) is already affected in young APOE ε4-carriers, with increased co-activation of the DMN during rest and increased hippocampal task activation. We aimed to replicate the early findings of Filippini et al, using the APOE gene, still the principal AD risk gene, and extended this with a polygenic risk score (PRS) analysis for AD, using the Human Connectome Project dataset (HCP). We included participants from the HCP S1200 dataset (age range: 22-36 years). We studied morphometric features, functional DMN co-activation and functional task activation of recollection performance. Permutation Analysis of Linear Models (PALM) was used to test for group differences between APOE ε4-carriers and non-carriers, and to test the association with PRS. PALM controls for biases induced by the family structure of the HCP sample. Results were family-wise error rate corrected at p < 0.05. Our primary analysis did not replicate the early findings of Filippini et al. (2009). However, compared with non-carriers, APOE ε4-carriers showed increased functional activation during the encoding of subsequently recollected items in areas related to facial recognition (p<0.05, t>756.11). This increased functional activation was also positively associated with PRS (APOE variants included) (p<0.05, t>647.55). Our results are supportive for none to limited genetic effects on brain structure and function in young adults. Taking the methodological considerations of replication studies into account, the true effect of APOE ε4-carriership is likely smaller than indicated in the Filippini paper. However, it still holds that we may not yet be able to detect already present measurable effects decades before a clinical expression of AD. Since the mechanistic pathway of AD is likely to encompass many different factors, further research should be focused on the interactions of genetic risk, biomarkers, aging and lifestyle factors over the life course. Sensitive functional neuroimaging as used here may help disentangling these complex interactions.

Fluoride exposure and children’s intelligence: Gene-environment interaction based on SNP-set, gene and pathway analysis, using a case-control design based on a cross-sectional study

BackgroundExcessive fluoride exposure has been associated with intelligence loss, but little is known about gene-fluoride interactions on intelligence at SNP-set, gene and pathway level. ObjectivesHere we conducted a population-based study in Chinese school-aged children to estimate the associations of fluoride from internal and external exposures with intelligence as well as to explore the gene-fluoride interactions on intelligence at SNP-set, gene and neurodevelopmental pathway level. MethodsA total of 952 resident children aged 7 to 13 were included in the current study. The fluoride contents in drinking water, urine, hair and nail were measured using the ion-selective electrode method. LASSO Binomial regression was conducted to screen the intelligence-related SNP-set. The gene-fluoride interactions at gene and pathway levels were detected by the Adaptive Rank Truncated Product method. ResultsThe probability of high intelligence was inversely correlated with fluoride contents in water, urine, hair and nail (all P < 0.001). The SNP-set based on rs3788319, rs1879417, rs57377675, rs11556505 and rs7187776 was related to high intelligence (P = 0.001) alone and by interaction with water, urinary and hair fluoride (P = 0.030, 0.040, 0.010), separately. In gene level, CLU and TOMM40 interacted with hair fluoride (both P = 0.017) on intelligence. In pathway level, Alzheimer disease pathway, metabolic pathway, signal transduction pathway, sphingolipid signaling pathway and PI3K-AKT signaling pathway interacted with fluoride on intelligence in men. ConclusionsOur study suggests that fluoride is inversely associated with intelligence. Moreover, the interactions of fluoride with mitochondrial function-related SNP-set, genes and pathways may also be involved in high intelligence loss.

Treadmill Running Improves Spatial Learning Memory Through Inactivation of Nuclear Factor Kappa B/Mitogen-Activated Protein Kinase Signaling Pathway in Amyloid-β-Induced Alzheimer Disease Rats.

PurposeExercise is known to reduce proinflammatory cytokines production and apoptosis. We investigated the effect of treadmill running on spatial learning memory in terms of activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway in Alzheimer disease (AD) rats. We also evaluated the effect of treadmill running on proinflammatory cytokine production and apoptosis.MethodsUsing the stereotaxic frame, amyloid-β (Aβ) was injected into the lateral ventricle of the brain. The rats belong to treadmill running groups were forced to run on a motorized treadmill for 30 minutes per a day during 4 weeks, starting 3 days after Aβ injection. Morris water maze task was done for the determination of spatial learning memory. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry for cleaved caspase-3, and western blot for NF-κB, inhibitory protein of NF-κB (IκB), MAPK signaling pathway, tumor necrosis factor (TNF)-α, interleukin (IL)-1β were done.ResultsInduction of AD increased proinflammatory cytokine secretion by activating the NF-κB/MAPK signaling pathway. These changes induced apoptosis in the hippocampus and reduced spatial learning memory. In contrast, treadmill running inactivated the NF-κB/MAPK signaling pathway and suppressed proinflammatory cytokine production. These changes inhibited apoptosis and improved spatial learning memory.ConclusionsCurrent results showed that treadmill running promoted spatial learning memory through suppressing proinflammatory cytokine production and apoptosis via inactivation of NF-κB/MAPK signaling pathway. Treadmill exercise can be considered an effective intervention for symptom relieve of AD.

Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy.

Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are hallmark features of Alzheimer's disease (AD). Molecular damage to cerebrovessels in AD may result in alterations in vascular clearance mechanisms leading to amyloid deposition around blood vessels and diminished neurovascular-coupling. The sequelae of molecular events leading to these early pathogenic changes remains elusive. To address this, we conducted a comprehensive in-depth molecular characterization of the proteomic changes in enriched cerebrovessel fractions isolated from the inferior frontal gyrus of autopsy AD cases with low (85.5 ± 2.9 yrs) vs. high (81 ± 4.4 yrs) CAA score, aged-matched control (87.4 ± 1.5 yrs) and young healthy control (47 ± 3.3 yrs) cases. We employed a 10-plex tandem isobaric mass tag approach in combination with our ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method. Enriched cerebrovascular fractions showed very high expression levels of proteins specific to endothelial cells, mural cells (pericytes and smooth muscle cells), and astrocytes. We observed 150 significantly regulated proteins in young vs. aged control cerebrovessels. The top pathways significantly modulated with aging included chemokine, reelin, HIF1α and synaptogenesis signaling pathways. There were 213 proteins significantly regulated in aged-matched control vs. high CAA cerebrovessels. The top three pathways significantly altered from this comparison were oxidative phosphorylation, Sirtuin signaling pathway and TCA cycle II. Comparison between low vs. high CAA cerebrovessels identified 84 significantly regulated proteins. Top three pathways significantly altered between low vs. high CAA cerebrovessels included TCA Cycle II, Oxidative phosphorylation and mitochondrial dysfunction. Notably, high CAA cases included more advanced AD pathology thus cerebrovascular effects may be driven by the severity of amyloid and Tangle pathology. These descriptive proteomic changes provide novel insights to explain the age-related and AD-related cerebrovascular changes contributing to AD pathogenesis. Particularly, disturbances in energy bioenergetics and mitochondrial biology rank among the top AD pathways altered in cerebrovessels. Targeting these failed mechanisms in endothelia and mural cells may provide novel disease modifying targets for developing therapeutic strategies against cerebrovascular deterioration and promoting cerebral perfusion in AD. Our future work will focus on interrogating and validating these novel targets and pathways and their functional significance.

Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease

ABSTRACT Mitochondrial dysfunction is behind several neurodegenerative diseases, including Alzheimer disease (AD). Accumulation of damaged mitochondria is already observed at the early stages of AD and has been linked to impaired mitophagy, but the mechanisms underlying this alteration are still not fully known. In our recent study, we show that intracellular cholesterol enrichment can downregulate amyloid beta (Aβ)-induced mitophagy. Mitochondrial glutathione depletion resulting from high cholesterol levels promotes PINK1 (PTEN induced kinase 1)-mediated mitophagosome formation; however, mitophagy flux is ultimately disrupted, most likely due to fusion deficiency of endosomes-lysosomes caused by cholesterol. Meanwhile, in APP-PSEN1-SREBF2 mice, an AD mouse model that overexpresses the cholesterol-related transcription factor SREBF2, cholesterol accumulation prompts an oxidative- and age-dependent cytosolic aggregation of the mitophagy adaptor OPTN (optineurin), which prevents mitophagosome formation despite enhanced PINK1-PRKN/parkin signaling. Hippocampal neurons from postmortem brain of AD individuals reproduce the progressive accumulation of OPTN in aggresome-like structures accompanied by high levels of mitochondrial cholesterol in advanced stages of the disease. Overall, these data provide new insights into the impairment of the PINK1-PRKN mitophagy pathway in AD and suggest the combination of mitophagy inducers with strategies focused on restoring the cholesterol homeostasis and mitochondrial redox balance as a potential disease-modifying therapy for AD.

Amyloid toxicity in a Drosophila Alzheimer's model is ameliorated by autophagy activation

Alzheimer's disease (AD) is the prevailing form of dementia. Protein degradation and antioxidant pathways have a critical role in preventing the accumulation of protein aggregation; thus, failure of proteostasis in neurons along with redox imbalance mark AD. Herein, we exploited an AD Drosophila model expressing human amyloid precursor (hAPP) and beta-secretase 1 (hBACE1) proteins, to better understand the role of proteostatic or antioxidant pathways in AD. Ubiquitous expression of hAPP, hBACE1 in flies caused more severe degenerative phenotypes versus neuronal targeted expression; it also, suppressed proteasome activity, increased oxidative stress and significantly enhanced stress-sensitivity. Overexpression of Prosβ5 proteasomal subunit or Nrf2 transcription factor in AD Drosophila flies partially restored proteasomal activity but did not rescue hAPP, hBACE1 induced neurodegeneration. On the other hand, expression of autophagy-related Atg8a in AD flies decelerated neurodegeneration, increased stress-resistance, and improved flies' health-/lifespan. Overall, our data suggest that the noxious effects of amyloid-beta aggregates can be alleviated by enhanced autophagy, thus dietary or pharmacological interventions that target autophagy should be considered in AD therapeutic approaches.

Reduced synchrony in alpha oscillations during life predicts post mortem neurofibrillary tangle density in early-onset and atypical Alzheimer's disease.

Neurophysiological manifestations selectively associated with amyloid beta and tau depositions in Alzheimer's disease (AD) are useful network biomarkers to identify peptide specific pathological processes. The objective of this study was to validate the associations between reduced neuronal synchrony within alpha oscillations and neurofibrillary tangle (NFT) density in autopsy examination, in patients with AD. In a well-characterized clinicopathological cohort of AD patients (n=13), we quantified neuronal synchrony within alpha (8-12Hz) and delta-theta (2-8Hz) oscillations, using magnetoencephalography during the disease course, within six selected neocortical and hippocampal regions, including angular gyrus, superior temporal gurus, middle frontal gyrus, primary motor cortex, CA1, and subiculum, and correlated these with regional NFT density quantified at histopathological examination. Abnormal synchrony in alpha, but not in delta-theta, significantly predicted the NFT density at post mortem neuropathological examination. Reduced alpha synchrony is a sensitive neurophysiological index associated with pathological tau, and a potential network biomarker for clinical trials, to gauge the extent of network dysfunction and the degree of rescue in treatments targeting tau pathways in AD.

Extracellular signal-regulated kinase regulates microglial immune responses in Alzheimer's disease.

The importance of mitogen-activated protein kinase (MAPK) pathway signaling in regulating microglia-mediated neuroinflammation in Alzheimer's disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains. In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal-regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole-brain tissue from 5xFAD mice. The importance of ERK signaling in primary microglia cultures was next investigated using transcriptomic profiling and functional assays of amyloid-β and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFNγ-mediated pro-inflammatory activation of microglia, although it was also partly important for constitutive microglial functions. Phospho-ERK was an upstream regulator of disease-associated microglial gene expression (Trem2, Tyrobp), as well as several human AD risk genes (Bin1, Cd33, Trem2, Cnn2), indicative of the importance of microglial ERK signaling in AD pathology. Quantitative proteomic analyses of postmortem human brain showed that ERK1 and ERK2 were the only MAPK proteins with increased protein expression and positive associations with neuropathological grade. In a human brain phosphoproteomic study, we found evidence for increased flux through the ERK signaling pathway in AD. Overall, our analyses strongly suggest that ERK phosphorylation, particularly in microglia in mouse models, is a regulator of pro-inflammatory immune responses in AD pathogenesis.

Altered sphingolipid function in Alzheimer's disease; a gene regulatory network approach

Sphingolipids (SLs) are bioactive lipids involved in various important physiological functions. The SL pathway has been shown to be affected in several brain-related disorders, including Alzheimer's disease (AD). Recent evidence suggests that epigenetic dysregulation plays an important role in the pathogenesis of AD as well. Here, we use an integrative approach to better understand the relationship between epigenetic and transcriptomic processes in regulating SL function in the middle temporal gyrus of AD patients. Transcriptomic analysis of 252 SL-related genes, selected based on GO term annotations, from 46 AD patients and 32 healthy age-matched controls, revealed 103 differentially expressed SL-related genes in AD patients. Additionally, methylomic analysis of the same subjects revealed parallel hydroxymethylation changes in PTGIS, GBA, and ITGB2 in AD.Subsequent gene regulatory network-based analysis identified 3 candidate genes, that is, SELPLG, SPHK1 and CAV1 whose alteration holds the potential to revert the gene expression program from a diseased towards a healthy state. Together, this epigenomic and transcriptomic approach highlights the importance of SL-related genes in AD, and may provide novel biomarkers and therapeutic alternatives to traditionally investigated biological pathways in AD.

Network pharmacology-based study of the therapeutic mechanism of resveratrol for Alzheimer's disease

To investigate the therapeutic mechanism of resveratrol (RES) for Alzheimer's disease (AD) in light of network pharmacology. We searched PubChem, BATMAN-TCM, Genecards, AD, TTD, String 11.0, AlzData, SwissTargetPrediction, Metascape and other databases for the therapeutic targets of RES and human AD-related targets. The intersection was determined using Venny 2.1 to obtain the therapeutic targets of RES for AD. The protein-protein interaction (PPI) network was constructed, the gene ontology (GO) was enriched and the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG pathway) were analyzed. Cytoscape 3.7.1 software was used to construct a target-signaling pathway network of RES in the treatment of AD. Molecular docking verification was carried out on SwissDock (http://www.swissdock.ch/docking). We examined a 293Tau cell model of AD for changes in protein levels of pS396, pS199, Tau5, CDK5, glycogen synthase kinase 3β (GSK3β) and p-GSK3β in response to RES treatment using Western blotting. We obtained 182 targets of RES, 525 targets related to AD, and 36 targets of RES for AD treatment, among which 34.6% of the targets were protein-modifying enzymes, 27.7% were metabolite invertase, 13.8% were gene-specific transcriptional regulators, and 10.3% were transporters. The core key targets of RES in the treatment of AD included INS, APP, ESR1, MMP9, IGF1R, CACNA1C, MAPT (microtubule- associated protein Tau), MMP2, TGFB1 and GSK3B. Enrichment analysis of GO biological process suggested that the biological function of RES in AD treatment mainly involved the response to β-amyloid protein, positive regulation of transferase activity, the transmembrane receptor protein tyrosine kinase signaling pathway, regulation of behavior, learning or memory, aging, and transmembrane transport. KEGG pathway enrichment analysis showed that the most significantly enriched signaling pathways were AD pathway, PI3K-AKT signaling pathway, cGMP-PKG signaling pathway, and MAPK signaling pathway. Molecular docking results showed that RES had strong binding with ESR1, GSK3B, MMP9, IGF1R, APP and INS. In the cell model of AD, treatment with 50 μmol/L RES for 12 h significantly reduced the levels of pS396 and pS199 by regulating CDK5 and GSK3β activity (P < 0.001). RES produces therapeutic effects on AD by acting on multiple targets and affecting multiple signaling pathways and improves AD-associated pathologies via a direct action on Aβ and Tau pathological processes.

Association of neurogranin gene expression with Alzheimer's disease pathology in the perirhinal cortex.

IntroductionSynaptic damage is a key pathology of Alzheimer's disease (AD). The mechanism underlying synaptic vulnerability in AD remains elusive.MethodsUsing a large‐scale transcriptomic dataset, we analyzed the neurogranin‐centered integrative gene network and assessed the correlation of neurogranin (NRGN) gene expression with AD pathology in post mortem brains. We studied the association of NRGN expression with Clinical Dementia Rating (CDR) and neuropathological diagnosis of AD.ResultsWe find that the genes positively correlated with NRGN expression in AD are involved in synaptic transmission and cation channel pathways. NRGN expression is correlated with amyloid and tau pathology in the perirhinal cortex of post mortem brains. NRGN expression is associated with the diagnosis of AD and correlated with CDR.DiscussionTranscriptional regulation of the gene encoding for synaptic protein is involved in selective synaptic damage in AD. Identifying the genes associated with synaptic damage pathways in AD may provide targets for intervention.

Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease.

Vascular risk factors such as atherosclerosis, diabetes, and elevated homocysteine levels are strongly correlated with onset of Alzheimer's disease (AD). Emerging evidence indicates that blood coagulation protein thrombin is associated with vascular and non-vascular risk factors of AD. Here, we examined the effect of thrombin and its direct inhibitor dabigatran on key mediators of neuro-inflammation and AD pathology in the retinoic acid (RA)-differentiated human neuroblastoma cell line SH-SY5Y. SH-SY5Y cells exposed to thrombin concentrations (10-100nM) +/- 250nM dabigatran for 24h were analyzed for protein and gene expression. Electrophoretic mobility shift assay (EMSA) was used to determine DNA binding of NFkB. Western blotting, qRT-PCR and ELISA were used to measure the protein, mRNA, and activity levels of known AD hallmarks and signaling molecules. Dabigatran treatment attenuated thrombin-induced increase in DNA binding of NFκB by 175% at 50nM and by 77% at 100nM thrombin concentration. Thrombin also augmented accumulation of Aβ protein expression and phosphorylation of p38 MAPK, a downstream molecule in the signaling cascade, expression of pro-apoptotic mediator caspase 3, APP, tTau and pTau. Additionally, thrombin increased BACE1 activity, GSK3β expression, and APP, BACE1, Tau and GSK3β mRNA levels. Co-incubation with dabigatran attenuated thrombin-induced increases in the protein, mRNA, and activities of the aforesaid molecules to various extents (between -31% and -283%). Our data demonstrates that thrombin promotes AD-related pathological changes in neuronal cultures and suggests that use of direct oral anticoagulants may provide a therapeutic benefit against thrombin-driven neuroinflammation and downstream pathology in AD.

Apolipoprotein J in Alzheimer's Disease: Shedding Light on Its Role with Cell Signaling Pathway Perspective and Possible Therapeutic Approaches.

Apolipoprotein J (ApoJ), or clusterin, is one of the main apolipoproteins in the brain. It is synthesized and released from astrocytes in a healthy brain, and its expression increases in neurodegenerative disorders. Genetic evidence has suggested an association between ApoJ polymorphism and the risk of Alzheimer's disease (AD)-it is now considered the third main genetic risk factor for late-onset AD. However, the role of ApoJ overexpression in the state of disorder, toxicity, or protection is not yet clear. Since ApoJ plays different roles in AD, we review the function of ApoJ using different cell signaling pathways in AD and outline its paradoxical roles in AD. ApoJ helps in amyloid-beta (Aβ) clearance. Vice versa, ApoJ gene knock-out causes fibrillary Aβ reduction and prevents Aβ-induced neuron cell death. Understanding ApoJ, through various cellular signaling pathways, creates a new perspective on AD's cellular principles. The overall message is that ApoJ can be a valuable tool in controlling AD.

Physical exercise prevents amyloid β1-40-induced disturbances in NLRP3 inflammasome pathway in the hippocampus of mice.

Amyloid beta (Aβ), one of the main hallmarks of Alzheimer's Disease (AD), may stimulate pattern recognition receptors (PRR) such as the NLRP3 inflammasome, inducing a pro-inflammatory state in the brain that contributes to disease development. Physical exercise can have multiple beneficial effects on brain function, including anti-inflammatory and neuroprotective roles. The objective of this study was to investigate the prophylactic effect of moderate treadmill exercise for 4 weeks on inflammatory events related to NLRP3 signaling in the hippocampus of mice after intracerebroventricular Aβ1-40 administration. Our results show that Aβ1-40 administration (400pmol/mouse, i.c.v.) significantly increased the immunocontent Iba-1 (a microglial reactivity marker), NLRP3, TXNIP, and caspase-1 in the hippocampus of mice. However, physical exercise prevented the hippocampal increase in Iba-1, TXNIP, and activation of the NLRP3 inflammasome pathway caused by Aβ1-40. Moreover, physical exercise per se reduced the TXNIP and caspase-1 immunocontent in the hippocampus. No alterations were observed on the immunocontent of GFAP, ASC, and IL-1β in the hippocampus after Aβ1-40 and/or physical exercise. These results reinforce the role of NLRP3 inflammasome pathway in AD and point to physical exercise as a possible non-pharmacological strategy to prevent inflammatory events triggered by Aβ1-40 in mice.

Novel benzoic acid derivatives: Synthesis and biological evaluation as multitarget acetylcholinesterase and carbonic anhydrase inhibitors.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia, memory impairment, cognitive dysfunction, and speech impairment. The utility of cholinergic replacement by acetylcholinesterase (AChE) inhibitors in AD treatment has been well documented so far. Recently, studies have also evidenced that human carbonic anhydrases (hCAs) serve as an important target for AD treatment. In this direction, the improvement of new multitarget drugs, which can simultaneously modulate several mechanisms or targets included in the AD pathway, may be a potent strategy to treat AD. In light of these data for understanding and developing AD-related multitarget AChE and hCAs inhibitors, in this study, novel methylene-aminobenzoic acid and tetrahydroisoquinolynyl-benzoic acid derivatives (4a-g and 6a-g) were designed. The synthesized analogs were experimentally validated for their effects by in vitro and direct enzymatic tests. Also, the compounds were subjected to in silico monitoring withSchrödinger Suite software to assign binding affinities of potential derivatives based on Glide XP scoring, molecular mechanics-generalized Born surface area computing, and validation by molecular docking. The results revealed that 6c (1,3-dimethyldihydropyrimidine-2,4-(1H,3H)-dione-substituted, KI value of 33.00 ± 0.29 nM), 6e (cyclohexanone-substituted, KI value of 18.78 ± 0.09 nM), and 6f (2,2-dimethyl-1,3-dioxan-4-one-substituted, KI value of 13.62 ± 0.21 nM) from the benzoic acid derivatives in this series were the most promising derivatives, as they exhibited a good multifunctional inhibition at all experimental levels and in the in silico validation against hCA I, hCA II, and AChE, respectively, for the treatment of AD.