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Clearance of accumulated protein aggregates is one of the functions of autophagy. Recently, a clearer understanding of non-coding RNAs (ncRNAs) functions documented that ncRNAs have important roles in several biological processes associated with the development and progression of neurodegenerative disorders. Subtypes of ncRNA, including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA), are commonly dysregulated in neurodegenerative disorders such as Alzheimer and Parkinson diseases. Dysregulation of these non-coding RNAs has been associated with inhibition or stimulation of autophagy. Decreased miR-124 led to decreased/increased autophagy in experimental model of Alzheimer and Parkinson diseases. Increased BACE1-AS showed enhanced autophagy in Alzheimer disease by targeting miR-214-3p, Beclin-1, LC3-I/LC3-II, p62, and ATG5. A significant increase in NEAT1led to stimulated autophagy in experimental model of PD by targeting PINK1, LC3-I, LC3-II, p62 and miR-374c-5p. In addition, increased BDNF-AS and SNHG1 decreased autophagy in MPTP-induced PD by targeting miR-125b-5p and miR-221/222, respectively. The upregulation of circNF1-419 and circSAMD4A resulted in an increased autophagy by regulating Dynamin-1 and miR-29c 3p, respectively. A detailed discussion of miRNAs, circRNAs, and lncRNAs in relation to their autophagy-related signaling pathways is presented in this study. Show less

Previous studies have confirmed that choline exerts anti-fibrotic effect in the heart by activating the M Proliferation of cardiac fibroblasts was induced by transforming growth factor (TGF)-β1 The expression of miR-29b decreased when treated with TGF-β1 (P=0.0389) and increased after choline stimulated (P=0.0001). Overexpression of miR-29b could reverse the high expression of collagen I (P<0.0001), α-SMA (P=0.0007), and CTGF (P=0.0038) induced by TGF-β1, whereas inhibition of miR-29b had a tendency to even further increase the expression of fibrosis markers. Meanwhile, inhibition of miR-29b could reverse the anti-fibrotic effect of choline, increasing the expression of collagen I (P=0.0040), α-SMA (P=0.0001), and CTGF (P=0.0185), and promoting the fibroblast proliferation and migration. Moreover, BACE1 protein level, increased after TGF-β1 treatment (P=0.0037) and reversed by overexpression of miR-29b (P=0.0493). Choline could reduce the increase of BACE1 induced by TGF-β1 (P=0.0264), and 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP) increased the expression of BACE1 (P=0.0060). Furthermore, overexpression of BACE1 could reverse the protective effect of miR-29b in cardiac fibrosis, increasing the protein level of collagen I (P=0.0404). The results suggested that M Show less

Neurological disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) manifest through gradually deteriorating cognitive functions. An encouraging strategy for addressing these disorders involves the inhibition of precursor-cleaving enzyme 1 (BACE1). In the current research, a virtual screening technique was employed to identify potential BACE1 inhibitors among selected herbal isolates. This study evaluated 79 flavonoids, anthraquinones (AQs), and cinnamic acid derivatives for their potential blood-brain barrier (BBB) permeability. Using the AutoDock 4.0 tool, molecular docking analysis was conducted to determine the binding affinity of BBB permeable compounds to the BACE1 active site. Molecular dynamics (MD) simulations were performed to assess the stability of the docked poses of the most potent inhibitors. The interactions between the most effective plant-based inhibitors and the residues within the BACE1 catalytic site were examined before and after MD simulations. Ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine were among the highest-ranking BACE1 inhibitors, with inhibition constant values calculated in the nanomolar range. Furthermore, during 10 ns simulations, the docked poses of these ligands were observed to be stable. The findings propose that ponciretin, danthron, chrysophanol, and N-p-coumaroyltyramine might serve as potential choices for the treatment of AD and PD, laying the groundwork for the creation of innovative BACE1 inhibitors. Show less

Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-β-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-β-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-β-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid β (Aβ) production through β-catenin-β-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αβ production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD. Show less

Physical activity has been considered an important non-medication intervention in preserving mnemonic processes during aging. However, how aerobic exercise promotes such benefits for human health remains unclear. In this study, we aimed to explore the neuroprotective and anti-inflammatory effects of aerobic exercise against lipopolysaccharide (LPS)-induced amnesic C57BL/6J mice and BV-2 microglial cell models. In the in vivo experiment, the aerobic exercise training groups were allowed to run on a motorized treadmill 5 days/week for 4 weeks at a speed of 10 rpm/min, with LPS (0.1 mg/kg) intraperitoneally injected once a week for 4 weeks. We found that aerobic exercise ameliorated memory impairment and cognitive deficits among the amnesic mice. Correspondingly, aerobic exercise significantly increased the protein expressions of FNDC5, which activates target neuroprotective markers BDNF and CREB, and antioxidant markers Nrf2/HO-1, leading to inhibiting microglial-mediated neuroinflammation and reduced the expression of BACE-1 in the hippocampus and cerebral cortex of amnesic mice. We estimated that aerobic exercise inhibited neuroinflammation in part through the action of FNDC5/irisin on microglial cells. Therefore, we explored the anti-inflammatory effects of irisin on LPS-stimulated BV-2 microglial cells. In the in vitro experiment, irisin treatment blocked NF-κB/MAPK/IRF3 signaling activation concomitantly with the significantly lowered levels of the LPS-induced iNOS and COX-2 elevations and promotes the Nrf2/HO-1 expression in the LPS-stimulated BV-2 microglial cells. Together, our findings suggest that aerobic exercise can improve the spatial learning ability and cognitive functions of LPS-treated mice by inhibiting microglia-mediated neuroinflammation through its effect on the expression of BDNF/FNDC5/irisin. Show less

Traumatic brain injury (TBI) is one of the important risk factors for the development of Alzheimer's disease (AD). However, the molecular mechanism by which TBI promotes the progression of AD is not elucidated. In this study, we showed that the abnormal production of E2F1 is a major factor in promoting the neuropathological and cognitive deterioration of AD post-TBI. We found that repeated mild TBI can aggravate the neuropathology of AD in APP/PS1 mice. At the same time, the co-expression of E2F1 and beta-site APP cleaving enzyme 1 (BACE1) was upregulated when the mouse hippocampus was dissected. BACE1 is recognized as a rate-limiting enzyme for the production of Aβ. Here, we speculate that E2F1 may play a role in promoting BACE1 expression in AD. Therefore, we collected peripheral blood from patients with AD. Interestingly, there is a positive correlation between E2F1 and brain-derived neurotrophic factor-antisense (BDNF-AS), whereas BDNF-AS in AD can promote the expression of BACE1 and exhibit a neurotoxic effect. We established a cell model and found a regulatory relationship between E2F1 and BDNF-AS. Therefore, based on our results, we concluded that E2F1 regulates BDNF-AS, promotes the expression of BACE1, and affects the progression of AD. Furthermore, E2F1 mediates the TBI-induced neurotoxicity of AD. Show less

Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Aβ, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub-lethal ischemic-reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long-term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD. Female wild-type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open-field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro-vasculature was examined using micro-CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood-brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Aβ levels in the rat frontal cortex were measured using WB, ELISA, or IF staining. RIC enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRβ, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Aβ toxicity, as demonstrated by the enhancement of α-secretase and attenuation of β-secretase (BACE1) and γ- secretase and Aβ1-42 and Aβ1-40 levels as well. Chronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development. Show less

We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI). To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of enalapril. Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle, enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study. MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group. Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats. Show less

ConspectusThe enzyme acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh) at cholinergic synapses of the peripheral and central nervous system. Thus, it is a prime therapeutic target for diseases that occur with a cholinergic deficit, prominently Alzheimer's disease (AD). Working at a rate near the diffusion limit, it is considered one of nature's most efficient enzymes. This is particularly meritorious considering that its catalytic site is buried at the bottom of a 20-Å-deep cavity, which is preceded by a bottleneck with a diameter shorter than that of the trimethylammonium group of ACh, which has to transit through it. Not only the particular architecture and amino acid composition of its active site gorge enable AChE to largely overcome this potential drawback, but it also offers plenty of possibilities for the design of novel inhibitor drug candidates.In this Account, we summarize our different approaches to colonize the vast territory of the AChE gorge in the pursuit of increased occupancy and hence of inhibitors with increased affinity. We pioneered the use of molecular hybridization to design inhibitors with extended binding at the CAS, reaching affinities among the highest reported so far. Further application of molecular hybridization to grow CAS extended binders by attaching a PAS-binding moiety through suitable linkers led to multisite inhibitors that span the whole length of the gorge, reaching the PAS and even interacting with midgorge residues. We show that multisite AChE inhibitors can also be successfully designed the other way around, by starting with an optimized PAS binder and then colonizing the gorge and CAS. Molecular hybridization from a multicomponent reaction-derived PAS binder afforded a single-digit picomolar multisite AChE inhibitor with more than 1.5 million-fold increased potency relative to the initial hit. This illustrates the powerful alliance between molecular hybridization and gorge occupancy for designing potent AChE inhibitors.Beyond AChE, we show that the stereoelectronic requirements imposed by the AChE gorge for multisite binding have a templating effect that leads to compounds that are active in other key biological targets in AD and other neurological and non-neurological diseases, such as BACE-1 and the aggregation of amyloidogenic proteins (β-amyloid, tau, α-synuclein, prion protein, transthyretin, and human islet amyloid polypeptide). The use of known pharmacophores for other targets as the PAS-binding motif enables the rational design of multitarget agents with multisite binding within AChE and activity against a variety of targets or pathological events, such as oxidative stress and the neuroinflammation-modulating enzyme soluble epoxide hydrolase, among others.We hope that our results can contribute to the development of drug candidates that can modify the course of neurodegeneration and may inspire future works that exploit the power of molecular hybridization in other proteins featuring large cavities. Show less

An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives ( Show less

The coronavirus disease 2019 (COVID-19) pandemic has caused extensive disruption of public health worldwide. There were reports of COVID-19 patients having multiple complications. This study investigated COVID-19 from a genetic perspective. We conducted RNA sequencing (RNA-Seq) analysis of respiratory tract samples from 24 patients with COVID-19. Eight patients receiving mechanical ventilation or extracorporeal membrane oxygenation were regarded as severe cases; the remaining 16 patients were regarded as non-severe cases. After quality control, statistical analyses were performed by logistic regression and the Kolmogorov-Smirnov test to identify genes associated with disease severity. Six genes were associated with COVID-19 severity in both statistical tests, namely RNA sequencing analysis showed that severe acute respiratory syndrome coronavirus 2 infection is associated with the overexpression of genes involved in nervous system disorders. Show less

Amyloid precursor protein (APP) is a brain-rich, single pass transmembrane protein that is proteolytically processed into multiple products, including amyloid-beta (Aβ), a major driver of Alzheimer disease (AD). Although both overexpression of APP and exogenously delivered Aβ lead to changes in sleep, whether APP processing plays an endogenous role in regulating sleep is unknown. Here, we demonstrate that APP processing into Aβ40 and Aβ42 is conserved in zebrafish and then describe sleep/wake phenotypes in loss-of-function Show less

The primary aim of this study was to examine the correlation between the formation of Aβ plaques and autophagy, which is regulated by β-asarone and the lncRNA BACE1-AS. Additionally, the study sought to explore potential targets of the drug in inhibiting the deposition of toxic AD-related proteins and restoring impaired mitochondrial and autophagic functions. SHY5Y cells were utilized to construct a stable Alzheimer's disease (AD) model, followed by the utilization of interference and overexpression lentiviruses targeting BACE1-AS to establish a cell model. The cells were categorized into five groups, including a normal group, siRNA/BACE1 group, and β-asarone group. The fluorescence quantitative PCR technique was employed to assess the disparity in BACE1 mRNA expression, while changes in immunofluorescence (IF) were observed to determine the stable interference titre and action time of the lentiviruses. Additionally, western blotting (WB) and fluorescence quantitative PCR were employed to evaluate the expression of proteins and mRNAs associated with AD and autophagy. The findings demonstrated a significant elevation in BACE1 expression levels in brain tissue among individuals with AD compared to those without the condition. Moreover, the results indicated that the introduction of β-asarone led to an increase in the expression of the BACE1-AS gene in the cell group transfected with plasmid H12732. Furthermore, it was observed that β-asarone enhanced the expression levels of shRNA and BACE1 after 72 h. In contrast, β-asarone suppressed the expression of PS1, Aβ, BACE1, APP, and p62, while promoting the expression of syn, LC3 I/II, and Beclin-1. Based on these findings, it can be concluded that β-Asarone exerts a comprehensive influence on the expression of proteins associated with AD and synaptic function. β-Asarone exhibits the potential to mitigate Aβ deposition by impeding the expression of lncBACE1, thereby facilitating autophagy through the suppression of BACE1's inhibitory impact on autophagy. This complements the self-enhancing effect of autophagy. Show less

The study aimed to investigate the change of amyloid precursor protein (APP) processing and amyloid β (Aβ) metabolites in linking periodontitis to Alzheimer's disease (AD). Aβ is one of the main pathological features of AD, and few studies have discussed changes in its expression in peripheral tissues or analyzed the relationship between the peripheral imbalance of Aβ production and clearance. A murine model of periodontitis was established by oral infection with Porphyromonas gingivalis (P. gingivalis). Micro-computed tomography (Micro-CT) was used to observe the destruction of the alveolar bone. Nested quantitative polymerase chain reaction (qPCR) was used to measure small quantities of P.gingivalis DNA in different tissues. Behavioral experiments were performed to measure cognitive function in the mice. The mRNA levels of TNF-α, IL-6, IL-8, RANKL, OPG, APP695, APP751, APP770, and BACE1 in the gingival tissues or cortex were detected by RT-PCR. The levels of Aβ1-40 and Aβ1-42 in gingival crevicular fluid (GCF) and plasma were tested by ELISA. P. gingivalis oral infection was found to cause alveolar bone resorption and impaired learning and memory. P.gingivalis DNA was detected in the gingiva, blood and cortex of the P.gingivalis group by nested qPCR (p < .05). The mRNA expression of TNF-α, IL-6, IL-8, RANKL/OPG, and BACE1 in the gingival tissue was significantly higher than that in the control group (p < .05). Similarly, upregulated mRNA levels of APP695 and APP770 were observed in the gingival tissuses and cortex of the P. gingivalis group (p < .05). The levels of Aβ1-40 and Aβ1-42 in the GCF and plasma of the P. gingivalis group were significantly higher than those in the control group (p < .05). P. gingivalis can directly invade the brain via hematogenous infection. The invasion of P. gingivalis could trigger an immune response and lead to an imbalance between Aβ production and clearance in peripheral tissues, which may trigger an abnormal Aβ metabolite in the brain, resulting in the occurrence and development of AD. Show less

Alzheimer's disease (AD) poses an increasing global health challenge and is marked by gradual cognitive deterioration, memory impairment, and neuroinflammation. Innovative therapeutic approaches as non-pharmacological protocol are urgently needed with side effect risk of drugs. Microcurrent therapy, a non-invasive modality involving low-level electrical currents, has emerged as a potential solution to address AD's complex pathogenesis. This study investigates the optimal application of microcurrent therapy as a clinical protocol for AD, utilizing a comprehensive approach that integrates behavioral assessments and neuroinflammation evaluation in a mouse model of dementia. The results reveal that microcurrent therapy holds promise in ameliorating memory impairment and reducing neuroinflammation in AD. Behavioral assessments, including the Novel Object Recognition Test (NOR) and Radial Arm Maze Test (RAM), demonstrated improved cognitive function following microcurrent therapy. Furthermore, microcurrent therapy inhibited expression of neuroinflammatory proteins, including ionized calcium binding adaptor molecule 1 (Iba1), and glial fibrillary acidic protein (GFAP) in current-treated group. Mechanistic insights suggest that microcurrent therapy may modulate neuroinflammation through the regulation of MAPK signaling pathways. This study emphasizes the prospect of microcurrent therapy as a safe and efficacious non-pharmacological strategy for Alzheimer's disease (AD), providing optimism to the countless individuals impacted by this debilitating ailment. These results contribute to the developments of an innovative clinical protocol for AD and recovery from neurological injury, underscoring the significance of investigating unconventional therapeutic approaches for addressing this complex condition. Show less

Liver hepatocellular carcinoma (LIHC) is the third largest cause of cancer mortality. Exosomes are vital regulators in the development of cancer. However, the mechanisms regarding the association of exosome-related long non-coding RNAs (lncRNAs) in LIHC are not clear. LIHC RNA sequences and exosome-associated genes were collected according to The Cancer Genome Atlas (TCGA), Hepatocellular Carcinoma Cell DataBase (HCCDB) and ExoBCD databases, and exosome-related lncRNAs with prognostic differential expression were screened as candidate lncRNAs using Spearman's method and univariate Cox regression analysis. Candidate lncRNAs were then used to construct a prognostic model and mRNA-lncRNA co-expression network. Differentially expressed genes (DEGs) in low- and high-risk groups were identified and enrichment analysis was performed for up- and down-regulated DEGs, respectively. The expression of immune checkpoint-related genes, immune escape potential and microsatellite instability among different risk groups were further analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) and transwell assay were applied for detecting gene expression levels and invasion and migration ability. Based on 17 prognostical exosome-associated lncRNAs, four hub lncRNAs ( The Risk model constructed by exosome-associated lncRNAs could well predict immunotherapy response and prognostic outcomes for LIHC patients. We comprehensively reveal the clinical features of prognostical exosome-related lncRNAs and their potential ability to predict immunotherapeutic response of patients with LIHC and their prognosis. Show less

Due to the large size and high flexibility of the catalytic active site of BACE1 enzyme, the development of nonpeptide inhibitors with optimal pharmacological properties is still highly demanding. In this work, we have discovered 2-aminobenzimidazole-containg ether scaffolds having potent and selective inhibitory potentials against BACE1 enzyme. We have synthesized novel 29 compounds and optimization of aryl linker region resulted in highly potent BACE1 inhibitory activities with EC Show less

Alzheimer's disease is a neurodegenerative disorder accounting for 60-80% of dementia cases and is accompanied by a high mortality rate in patients above 70 years of age. The formation of senile plaques composed of amyloid-β protein is a hallmark of Alzheimer's disease. Beta-site APP cleaving enzyme 1 (BACE1) is a proteolytic enzyme involved in the degradation of amyloid precursor protein, which further degrades to form toxic amyloid-β fragments. Hence, inhibition of BACE1 was stated to be an effective strategy for Alzheimer's therapeutics. Keeping in mind the structures of different BACE1 inhibitors that had reached the clinical trials, we designed a library of compounds (total 164) based on a substituted 5-amino tetrazole scaffold which was an isosteric replacement of the cyclic amidine moiety, a common component of the BACE1 inhibitors which reached the clinical trials. The scaffold was linked to different structural moieties with the aid of an amide or sulfonamide bond to design some novel molecules. Molecular docking was initially performed and the top 5 molecules were selected based on docking scores and protein-ligand interactions. Furthermore, molecular dynamic simulations were performed for these molecules (3g, 7k, 8n, 9d, 9g) for 100 ns and MM-GBSA calculations were performed for each of these complexes. After critical evaluation of the obtained results, three potential molecules (9d, 8n, and 7k) were forwarded for prolonged stability studies by performing molecular dynamic simulations for 250 ns and simultaneous MM-GBSA calculations. It was observed that the compounds (9d, 8n, and 7k) were forming good interactions with the amino acid residues of the catalytic site of the enzyme with multiple non-covalent interactions. In MD simulations, the compounds have shown better stability and better binding energy throughout the runtime. Show less

Amyloid-β (Aβ) accumulation is the main pathological change in Alzheimer's disease (AD), which results from the imbalance of production and clearance of Aβ in the brain. Our previous study found that chronic sleep deprivation (CSD) led to the deposition of Aβ in the brain by disrupting the balance of Aβ production and clearance, but the specific mechanism was not clear. In the present study, we investigated the effects of oxidative stress on Aβ accumulation in CSD rats. We found that the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) significantly increased after CSD, while superoxide dismutase (SOD) decreased in the brain. Furthermore, the serum ROS was elevated and SOD declined after CSD. The levels of oxidative stress in the brain were significantly correlated with β-site APP-cleaving enzyme 1 (BACE1), low-density lipoprotein receptor-related protein-1 (LRP1), and receptor of advanced glycation end products (RAGE) levels in hippocampus and prefrontal lobe, and the concentration of serum oxidative mediators were strongly correlated with plasma levels of soluble LRP1 (sLRP1) and soluble RAGE (sRAGE). These results suggested that the oxidative stress in the brain and serum may involved in the CSD-induced Aβ accumulation. The underlying mechanism may be associated with disrupting the balance of Aβ production and clearance. Show less

Developing strategies for the radiosensitization of cancer cells by the inhibition of genes, which harbor low toxicity to normal cells, will be useful for improving cancer radiotherapy. Here, we focused on a β-site of amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; β-secretase, memapsin-2). By functional inhibition of this peptidase by siRNA, it has also recently been shown that the DNA strand break marker, γH2AX foci, increased, suggesting its involvement in DNA damage response. To investigate this possibility, we knocked down Show less

Alzheimer's disease (AD) is a degenerative neurological disorder. Recent studies have indicated that histone deacetylases (HDACs) are among the most prominent epigenetic therapy targets and that HDAC inhibitors have therapeutic effects on AD. Here, we identified sodium valproate (VPA), a pan-HDAC inhibitor, and WT161, a novel HDAC6 selective inhibitor, as potential therapeutic agents for AD. Underlying molecular mechanisms were investigated. A cellular model, N2a-APPswe, was established via lentiviral infection, and the APPswe/PSEN1dE9 transgenic mouse model was employed in the study. LC-MS/MS was applied to quantify the concentration of WT161 in the mouse brain. Western blotting, immunohistochemical staining, thioflavin-S staining and ELISA were applied to detect protein expression in cells, tissues, or serum. RNA interference was utilized to knockdown the expression of specific genes in cells. The cognitive function of mice was assessed via the nest-building test, novel object recognition test and Morris water maze test. Previous studies have focused mainly on the impact of HDAC inhibitors on histone deacetylase activity. Our study discovered that VPA and WT161 can downregulate the expression of multiple HDACs, such as HDAC1 and HDAC6, in both AD cell and mouse models. Moreover, they also affect the expression of APP and APP secretases (BACE1, PSEN1, ADAM10). RNA interference and subsequent vitamin C induction further confirmed that the expression of APP and APP secretases is indeed regulated by HDAC1 and HDAC6, with the JNK pathway being the intermediate link in this regulatory process. Through the above pathways, VPA and WT161 effectively reduced Aβ deposition in both AD cell and mouse models and significantly improved cognitive function in AD mice. In general, we have discovered that the HDAC6-JNK-APP secretases cascade is an important pathway for VPA and WT161 to exert their therapeutic effects on AD. Investigations into the safety and efficacy of VPA and WT161 were also conducted, providing essential preclinical evidence for assessing these two epigenetic drugs for the treatment of AD. Show less

Plasmalogens are a family of glycerophospholipids containing one vinyl-ether bond at the sn-1 position in the glycerol backbone, and play important roles in cellular homeostasis including neural transmission. Therefore, reductions of plasmalogens have been associated with neurodegenerative disorders, such as Alzheimer's disease (AD). To evaluate the potential protective effects of plasmalogens against the pathology of AD, protein expression levels of key factors in amyloid precursor protein (APP) metabolic processes were examined using human neuroblastoma SH-SY5Y cells. Here, phosphatidylcholine-plasmalogen-oleic acid (PC-PLS-18) was shown to reduce protein expression levels of β-site APP cleaving enzyme 1 (BACE1), clusterin, and Tau, factors involved in the amyloid β-associated pathogenesis of AD. Thus, PC-PLS-18 may have preventive effects against AD by delaying the onset risk for a certain period. Show less

Identifying individuals before the onset of overt symptoms is key in the prevention of Alzheimer's disease (AD). Investigate the use of miRNA as early blood-biomarker of cognitive decline in older adults. Cross-sectional. Two observational cohorts (CHARIOT-PRO, Alzheimer's Disease Neuroimaging Initiative (ADNI)). 830 individuals without overt clinical symptoms from CHARIOT-PRO and 812 individuals from ADNI. qPCR analysis of a prioritised set of 38 miRNAs in the blood of individuals from CHARIOT-PRO, followed by a brain-specific functional enrichment analysis for the significant miRNAs. In ADNI, genetic association analysis for polymorphisms within the significant miRNAs' genes and CSF levels of phosphorylated-tau, total-tau, amyloid-β42, soluble-TREM2 and BACE1 activity using whole genome sequencing data. Post-hoc analysis using multi-omics datasets. Six miRNAs (hsa-miR-128-3p, hsa-miR-144-5p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-29c-3p and hsa-miR-363-3p) were downregulated in the blood of individuals with low cognitive performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The pathway enrichment analysis indicated involvement of apoptosis and inflammation, relevant in early AD stages. Polymorphisms within genes encoding for hsa-miR-29c-3p and hsa-miR-146a-5p were associated with CSF levels of amyloid-β42, soluble-TREM2 and BACE1 activity, and 21 variants were eQTL for hippocampal MIR29C expression. six miRNAs may serve as potential blood biomarker of subclinical cognitive deficits in AD. Polymorphisms within these miRNAs suggest a possible interplay between the amyloid cascade and microglial activation at preclinical stages of AD. Show less

Heterocyclic compounds play a crucial role in the discovery of therapeutics. Alzheimer's disease (AD) is an unfathomable sporadic neurodegenerative disorder that involves multiple pathological pathways. The failure of current single-target small molecules to address AD's underlying causes has prompted interest in discovering multi-target directed ligands (MTDLs) to slow down the disease's progression. Herein we report the synthesis and biological evaluation of indole-piperidine amides as MTDLs for AD. The 5,6-dimethoxy-indole N-(2-(1-benzylpiperidine) carboxamide (23a) inhibits hAChE and hBACE-1 with IC Show less

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), β-secretase-1 (BACE-1), and inhibition of amyloid β (Aβ) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics. Show less

The β-secretase BACE1 initiates amyloid-β (Aβ) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aβ reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose. We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range. The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aβ deposition. Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12 months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the β-amyloidogenic processing of amyloid precursor protein or Aβ levels in 5XFAD mouse brains. A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy. Show less

The long-term effects of exposure to blast overpressure are an important health concern in military personnel. Increase in amyloid beta (Aβ) has been documented after non-blast traumatic brain injury (TBI) and may contribute to neuropathology and an increased risk for Alzheimer's disease. We have shown that Aβ levels decrease following exposure to a low-intensity blast overpressure event. To further explore this observation, we examined the effects of a single 37 kPa (5.4 psi) blast exposure on brain Aβ levels, production, and clearance mechanisms in the acute (24 h) and delayed (28 days) phases post-blast exposure in an experimental rat model. Aβ and, notably, the highly neurotoxic detergent soluble Aβ42 form, was reduced at 24 h but not 28 days after blast exposure. This reduction was not associated with changes in the levels of Aβ oligomers, expression levels of amyloid precursor protein (APP), or increase in enzymes involved in the amyloidogenic cleavage of APP, the β- and ϒ-secretases BACE1 and presenilin-1, respectively. The levels of ADAM17 α-secretase (also known as tumor necrosis factor α-converting enzyme) decreased, concomitant with the reduction in brain Aβ. Additionally, significant increases in brain levels of the endothelial transporter, low-density related protein 1 (LRP1), and enhancement in co-localization of aquaporin-4 (AQP4) to perivascular astrocytic end-feet were observed 24 h after blast exposure. These findings suggest that exposure to low-intensity blast may enhance endothelial clearance of Aβ by LRP1-mediated transcytosis and alter AQP4-aided glymphatic clearance. Collectively, the data demonstrate that low-intensity blast alters enzymatic, transvascular, and perivascular clearance of Aβ. Show less

Thyroid hormones, which produce critical changes in our bodies even when their physiological levels alter slightly, are crucial hormones that influence gene transcription. Neuronal plasticity, on the other hand, requires both the activation of local proteins as well as protein translation and transcription in response to external signals. So far, no study has examined metaplastic long-term potentiation (LTP) and related gene expression levels in a hyperthyroid experimental model. The Wistar male rats were administered 0.2 mg/kg/day of l-thyroxine for 21 days to induce hyperthyroidism. Perforant path was primed with 1-Hz low-frequency stimuli (LFS) for 900 s to investigate metaplasticity responses. The LFS was followed by high-frequency stimuli (HFS, 100 Hz) after 5 min. Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude were recorded from the granule cell layer of the dentate gyrus. The mRNA levels of genes related to neurodegeneration (Gsk-3β, Cdk5, Akt1, Mapt, p35, Capn1, Bace1, and Psen2) were measured using the RT-PCR method for the stimulated hippocampus. Similar to euthyroid rats, hyperthyroid animals had a lower EPSP slope and PS after LFS. Depression of EPSP prevented subsequently induced EPSP-LTP, although HFS was able to elicit PS-LTP despite depression of PS amplitude in both groups. Despite similarities in metaplastic LTP responses, these electrophysiological findings were accompanied by increased Akt, Bace1, Cdk5, and p35-mRNA expressions and decreased Gsk-3β mRNA expression in hyperthyroid rats' hippocampus. These data support the view that in thyroid hormone excess, the mechanism that keeps synaptic efficacy within a dynamic range occurs concurrently with increased mRNA expression of neurodegeneration-related genes. Our study encourages further examination of the increased risk of neurodegenerative disease in hyperthyroidism. Show less