Amyloid-beta Precursor Protein Expression Research Articles

Network meta-analysis on alcohol-mediated modulation of Alzheimer’s disease in the diseases of inflammation including COVID-19

Abstract Objectives Cross sectional surveys have reported that alcohol consumption has skyrocketed during the COVID-19 pandemic. Chronic alcohol use triggers systemic inflammation which leads to neuroinflammation and neurodegeneration. In the present study, we hypothesize that alcohol consumption and cytokine elevation during inflammatory conditions synergistically increase amyloid-beta precursor protein (APP) expression and worsens Alzheimer’s disease (AD) pathology. Methods QIAGEN Ingenuity Pathway Analysis (IPA) was employed to conduct network meta-analysis on the molecular mechanisms underlying ethanol (EtOH) influence on APP expression and AD in inflammatory conditions including COVID-19, inflammation of respiratory system, organ, absolute anatomical region, body cavity, joint, respiratory system component, gastrointestinal tract, large intestine, liver, central nerve system, and lung. IPA tools were utilized to identify the molecules associated with EtOH, inflammatory conditions and the common molecules between them. Results Simulation activity of EtOH, mimicking exposure to alcohol, upregulated the APP expression and augmented AD pathology in all inflammatory conditions including COVID-19. Our studies identified six molecules including ADORA2A, Cytokine, IFN-gamma, IL1-beta, Immunoglobulin and TNF, which concurrently contribute to increased APP expression and AD progression upon EtOH simulation in all diseases studied. Conclusions The present study has revealed molecular mechanisms underlying alcohol augmentation of AD in COVID-19 and other diseases of inflammation.

Neuroprotective effect of piracetam-loaded magnetic chitosan nanoparticles against thiacloprid-induced neurotoxicity in albino rats

Thiacloprid (TH) is a neurotoxic agricultural insecticide and potential food contaminant. The purpose of this study was to investigate the relationship between TH exposure and memory dysfunction in rats, as well as the potential protective effect of piracetam and piracetam-loaded magnetic chitosan nanoparticles (PMC NPs). Rats were divided into five equal groups (six rats/group). The control group received saline. Group II was treated with PMC NPs at a dose level of 200 mg/kg body weight (Bwt); Group III was treated with 1/10 LD50 of TH (65 mg/kg Bwt); Group IV was treated with TH (65 mg/kg Bwt) and piracetam (200 mg/kg Bwt); Group V was co-treated with TH (65 mg/kg Bwt) and PMC NPs (200 mg/kg Bwt). All animal groups were dosed daily for 6 weeks by oral gavage. Footprint analysis, hanging wire test, open field test, and Y-maze test were employed to assess behavioral deficits. Animals were euthanized, and brain tissues were analyzed for oxidative stress biomarkers, proinflammatory cytokines, and gene expression levels of glial fibrillary acidic protein (GFAP), amyloid-beta precursor protein (APP), B-cell lymphoma 2 (Bcl-2), and caspase-3. Brain and sciatic nerve tissues were used for the evaluation of histopathological changes and immunohistochemical expression of tau protein and nuclear factor kappa B (NF-κB), respectively. The results revealed that TH-treated rats suffered from oxidative damage and inflammatory effect on the central and peripheral nerves. The administration of PMC NPs considerably protected against TH-induced neuronal damage, increased antioxidant enzyme activity, decreased inflammatory markers, and improved behavioral performance than the group treated with piracetam. The neuroprotective effect of PMC NPs was mediated through the inhibition of GFAP, APP, caspase-3, Tau, and NF-κB gene expression with induction of Bcl-2 expression. In conclusion, TH could induce oxidative stress, inflammatory and neurobehavior impairment in rats. However, PMC NPs administration markedly mitigated TH-induced brain toxicity, possibly via oxidative and inflammatory modulation rather than using piracetam alone.

Meta-Analysis of APP Expression Modulated by SARS-CoV-2 Infection via the ACE2 Receptor.

Alzheimer’s disease (AD) is characterized by the deposition of amyloid-beta (Aβ) plaques from improper amyloid-beta precursor protein (APP) cleavage. Following studies of inflammation caused by coronavirus-2019 (COVID-19) infection, this study investigated the impact of COVID-19 on APP expression. A meta-analysis was conducted utilizing QIAGEN Ingenuity Pathway Analysis (IPA) to examine the link between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and the modulation of APP expression upon virus binding the Angiotensin-converting enzyme-2 (ACE2) receptor. A Core Analysis was run on the infection by severe acute respiratory syndrome (SARS) coronavirus node, which included molecules affected by SARS-CoV-2, revealing its upstream regulators. Intermediary molecules were found between the upstream regulators and ACE2 and between ACE2 and APP. Activation of the upstream regulators downregulated the expression of ACE2 with a Z-score of −1.719 (p-value = 0.086) and upregulated APP with a Z-score of 1.898 (p-value = 0.058), showing a less than 10% chance of the results occurring by chance and pointing to an inverse relationship between ACE2 and APP expression. The neuroinflammation signaling pathway was the fifth top canonical pathway involved in APP upregulation. The study results suggest that ACE2 could be downregulated by SARS-CoV-2, resulting in APP upregulation, and potentially exacerbating the onset and progression of AD.

Meta-Analysis of Methamphetamine Modulation on Amyloid Precursor Protein through HMGB1 in Alzheimer's Disease.

The deposition of amyloid-beta (Aβ) through the cleavage of amyloid-beta precursor protein (APP) is a biomarker of Alzheimer’s disease (AD). This study used QIAGEN Ingenuity Pathway Analysis (IPA) to conduct meta-analysis on the molecular mechanisms by which methamphetamine (METH) impacts AD through modulating the expression of APP. All the molecules affected by METH and APP were collected from the QIAGEN Knowledge Base (QKB); 78 overlapping molecules were identified. Upon simulation of METH exposure using the “Molecule Activity Predictor” feature, eight molecules were found to be affected by METH and exhibited activation relationships on APP expression at a confidence of p = 0.000453 (Z-score = 3.51, two-tailed). Core Analysis of these eight molecules identified High Mobility Group Box protein 1 (HMGB1) signaling pathway among the top 5 canonical pathways with most overlap with the 8-molecule dataset. Simulated METH exposure increased APP expression through HMGB1 at a confidence of p < 0.00001 (Z-score = 7.64, two-tailed). HMGB1 is a pathogenic hallmark in AD progression. It not only increases the production of inflammatory mediators, but also mediates the disruption of the blood-brain barrier. Our analyses suggest the involvement of HMGB1 signaling pathway in METH-induced modulation of APP as a potential casual factor of AD.

Human recombinant erythropoietin improves motor function in rats with spinal cord compression-induced cervical myelopathy.

ObjectiveErythropoietin (EPO) is a clinically available hematopoietic cytokine. EPO has shown beneficial effects in the context of spinal cord injury and other neurological conditions. The aim of this study was to evaluate the effect of EPO on a rat model of spinal cord compression-induced cervical myelopathy and to explore the possibility of its use as a pharmacological treatment.MethodsTo develop the compression-induced cervical myelopathy model, an expandable polymer was implanted under the C5-C6 laminae of rats. EPO administration was started 8 weeks after implantation of a polymer. Motor function of rotarod performance and grip strength was measured after surgery, and motor neurons were evaluated with H-E, NeuN and choline acetyltransferase staining. Apoptotic cell death was assessed with TUNEL and Caspase-3 staining. The 5HT, GAP-43 and synaptophysin were evaluated to investigate the protection and plasticity of axons. Amyloid beta precursor protein (APP) was assessed to evaluate axonal injury.To assess transfer of EPO into spinal cord tissue, the EPO levels in spinal cord tissue were measured with an ELISA for each group after subcutaneous injection of EPO.ResultsHigh-dose EPO maintained motor function in the compression groups. EPO significantly prevented the loss of motor neurons and significantly decreased neuronal apoptotic cells. Expression of 5HT and synaptophysin was significantly preserved in the EPO group. APP expression was partly reduced in the EPO group. The EPO levels in spinal cord tissue were significantly higher in the high-dose EPO group than other groups.ConclusionEPO improved motor function in rats with compression-induced cervical myelopathy. EPO suppressed neuronal cell apoptosis, protected motor neurons, and induced axonal protection and plasticity. The neuroprotective effects were produced following transfer of EPO into the spinal cord tissue. These findings suggest that EPO has high potential as a treatment for degenerative cervical myelopathy.

Neuroprotective effects of clavulanic acid following permanent bilateral common carotid artery occlusion in rats.

We investigated whether clavulanic acid could improve learning and memory, in rats underwent bilateral occlusion of common carotid artery (2VO). Seventy male Wistar rats were subjected to 2VO, with a 1-week interval between right and left artery occlusions. After 2VO, animals received clavulanic acid (10, 20, 40 mg/kg, intraperitoneally), from day 8 to 20. Spatial memory was assessed in the Morris water maze, 1 week after the induction of 2VO (day 15). The mRNA expression levels of bcl-2, bcl2-associated x protein (bax), caspase-3, inducible nitric oxide synthase (iNOS), and amyloid beta precursor protein (APP) were measured in the neocortex and hippocampus. Clavulanic acid significantly decreased the escape latency and swimming time in the training trial days. As well, it increased time and distance percentage in the target quadrant, while it decreased such factors in the opposite quadrant in the final trial day, compared to 2VO + normal saline animals. Real time-PCR data showed a significant higher mRNA expression of bax, caspase 3, and iNOS in the hippocampus and neocortex of 2VO animal compared to nonoccluded rats. APP increased in the neocortex but not hippocampus. Compared with 2VO animals, clavulanic acid significantly down-regulated the expression of iNOS, caspase 3, and APP, accompanied by diminishing the bax/bcl2 ratio. Our results reveal a potential therapeutic use of clavulanic acid for cognitive dysfunction associated with cerebral hypoperfusion in vascular dementia and Alzheimer disease.

Peroxisome Proliferator-Activated Receptor γ Agonist Rosiglitazone Protects Blood-Brain Barrier Integrity Following Diffuse Axonal Injury by Decreasing the Levels of Inflammatory Mediators Through a Caveolin-1-Dependent Pathway.

Our early experiments confirmed that rosiglitazone (RSG), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, had therapeutic potential for the treatment of diffuse axonal injury (DAI) by inhibiting the expression of amyloid-beta precursor protein and reducing the loss and abnormal phosphorylation of tau, but the underlying mechanisms were not fully defined. In this study, we aimed to investigate a possible role for PPARγ in the protection of blood-brain barrier (BBB) integrity in a rat model of DAI, and the underlying mechanisms. PPAR agonists and antagonists were intraperitoneally injected after DAI. Treatment with RSG ameliorated axonal injury, cell apoptosis, glia activation, and the release of inflammatory factors such as TNF-α, IL-1β, and IL-6. It also increased the expression of tight junction-associated proteins like ZO-1, claudin-5, and occludin-1, whereas the PPARγ antagonist GW9662 had the opposite effects. These effects were also studied in a BBB in vitro model, consisting of a monolayer of human microvascular endothelial cells (HBMECs) subjected to oxygen and glucose deprivation (OGD). Treatment with RSG ameliorated the loss of BBB integrity and the increased permeability induced by OGD by reducing the release of inflammatory factors and maintaining the expression of tight junction-associated proteins. Interestingly, caveolin-1 was found located mainly in endothelial cells, and RSG increased the expression of caveolin-1, which decreased following OGD. In contrast, caveolin-1 siRNA abrogated the protective effects of RSG in the in vitro BBB model. In conclusion, we provide evidence that PPARγ plays an important role in a series of processes associated with DAI, and that the PPARγ agonist RSG can protect BBB integrity by decreasing the levels of inflammatory mediators through a caveolin-1-dependent pathway.

Expression of neprilysin in periodontitis-affected gingival tissues

ObjectiveAlthough the pathogeneses of Alzheimer’s disease (AD) and periodontal diseases have overlapping features, including ageing and chronic inflammation, the association between AD and periodontitis remains unclear. To explore the pathogenesis of periodontitis, a comprehensive gene expression/transcriptome analysis in periodontitis-affected gingival tissues found that the AD pathway was significantly up-regulated in periodontitis-affected gingival tissues. AD-related genes, amyloid beta precursor protein (APP), interleukin-1 beta and compliment 1QA, were significantly elevated in periodontitis. In the present study, balance between mRNA expression of APP and a potent amyloid degradation enzyme, neprilysin (NEP), as well as protein localisation of APP and NEP were analysed. DesignEighteen periodontitis-affected and 18 clinically healthy control gingival tissues were taken from patients with severe chronic periodontitis or undergoing tooth extraction. Total RNA was purified and used for quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR). The localisation of APP and NEP was analysed by immunohistochemistry (IHC). ResultsBoth APP and NEP genes were up-regulated in periodontitis-affected gingival tissues. APP-expressing macrophages and NEP-expressing neutrophils and fibroblasts, reflecting inflammatory stages, were detected in inflamed gingival tissues by IHC. ConclusionThe up-regulation of APP and NEP mRNA levels in periodontitis-affected gingival tissues compared with healthy controls was confirmed by qRT-PCR analyses. Since NEP is one of the primary enzymes that degrades amyloid beta, increased NEP mRNA levels in periodontitis may act as an inhibitor of amyloid beta accumulation in gingival tissues, balancing increased APP mRNA expression. However, NEP has several effects including degradation of vasoactive substances; therefore, further sresearch is needed.

Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up-regulating caveolin-1 expression.

Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postulated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser(404)(p-tau (S(404))), and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S(404)) levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury.

Taking TREM to the brain

TREM2 deficiency protects mice from Alzheimer’s disease.

Alternative splicing of VEGFA, APP and NUMB genes in colorectal cancer.

To investigate alternative splicing in vascular endothelial growth factor A (VEGFA), amyloid beta precursor protein (APP), and Numb homolog (NUMB) in colorectal cancer (CRC). Real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and PCR-restriction fragment length polymorphism analyses were performed to detect the expression of VEGFA, APP, and NUMB mRNA in 20 CRC tissues and matched adjacent normal tissues, as well as their alternative splicing variants. qRT-PCR analysis revealed that the expression of APP, NUMB, and VEGFA165b mRNA were significantly downregulated, while VEGFA mRNA was upregulated, in CRC tissues (all P < 0.05). PCR-restriction fragment length polymorphism analysis revealed that the expression of VEGFA165a/b in CRC tissues was significantly higher than in adjacent normal tissues (P < 0.05). Compared with adjacent normal tissues, the expression of NUMB-PRR(S) in CRC tissues was significantly decreased (P < 0.05), and the expression of NUMB-PRR(L) was increased (P < 0.05). Alternative splicing of VEGFA, APP, and NUMB may regulate the development of CRC, and represent new targets for its diagnosis, prognosis, and treatment.

Memantine combined with environmental enrichment improves spatial memory and alleviates Alzheimer's disease-like pathology in senescence-accelerated prone-8 (SAMP8) mice

Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease (AD). Environmental enrichment (EE) has shown significant beneficial effects on functional improvement in AD. In this study, we sought to determine whether combining these two distinct therapies would yield greater benefit than either drug used alone. We investigated the effect of memantine combined with EE on spatial learning and memory and AD-like pathology in a widely used AD model, the senescence-accelerated prone mice (SAMP8). The SAMP8 mice were randomly assigned to enriched housing (EH) or standard housing (SH), where either memantine (20 mg/kg) or saline was given by gastric lavage once daily continuously for eight weeks. Our results showed that, when provided separately, memantine and EE significantly improved spatial learning and memory by shortening escape latencies and increasing the frequency of entrance into the target quadrant. When combined, memantine and EE showed additive effect on learning and memory as evidenced by significant shorter escape latencies and higher frequency of target entrance than either drug alone. Consistent with the behavior results, pathological studies showed that both memantine and EE significantly reduced hippocampal CA1 neurofibrilliary tangles (NFTs) as well as amyloid beta precursor protein (APP) levels. Combining both therapies synergistically lessened NFTs and APP expression compared to either drug alone in SAMP8 mice, indicating that the combination of memantine with EE could offer a novel and efficient therapeutic strategy for the treatment of AD.

Copper Depletion Down-regulates Expression of the Alzheimer's Disease Amyloid-β Precursor Protein Gene

Alzheimer's disease is characterized by the accumulation of amyloid-beta peptide, which is cleaved from the amyloid-beta precursor protein (APP). Reduction in levels of the potentially toxic amyloid-beta has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the regulation of the APP gene. Recent in vivo and in vitro studies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for APP and amyloid-beta in copper homeostasis. We hypothesized that metals and in particular copper might alter APP gene expression. To test the hypothesis, we utilized human fibroblasts overexpressing the Menkes protein (MNK), a major mammalian copper efflux protein. MNK deletion fibroblasts have high intracellular copper, whereas MNK overexpressing fibroblasts have severely depleted intracellular copper. We demonstrate that copper depletion significantly reduced APP protein levels and down-regulated APP gene expression. Furthermore, APP promoter deletion constructs identified the copper-regulatory region between -490 and +104 of the APP gene promoter in both basal MNK overexpressing cells and in copper-chelated MNK deletion cells. Overall these data support the hypothesis that copper can regulate APP expression and further support a role for APP to function in copper homeostasis. Copper-regulated APP expression may also provide a potential therapeutic target in Alzheimer's disease.