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INTRODUCTION Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS Bulk RNA-sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co-expression network analysis (WGCNA) and deconvolution analysis identified AD-associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD-associated genes, gene modules, cell types, and established AD classification models. RESULTS WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell-type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. Highlights We comprehensively analyze the blood transcriptomes of a well-characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune-associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease.

[Background] The polygenic nature of Alzheimer’s disease (AD) suggests that multiple variants jointly contribute to disease susceptibility. As an individual’s genetic variants are constant throughout life, evaluating the combined effects of multiple disease-associated genetic risks enables reliable AD risk prediction. Because of the complexity of genomic data, current statistical analyses cannot comprehensively capture the polygenic risk of AD, resulting in unsatisfactory disease risk prediction. However, deep learning methods, which capture nonlinearity within high-dimensional genomic data, may enable more accurate disease risk prediction and improve our understanding of AD etiology. Accordingly, we developed deep learning neural network models for modeling AD polygenic risk. [Methods] We constructed neural network models to model AD polygenic risk and compared them with the widely used weighted polygenic risk score and lasso models. We conducted robust linear regression analysis to investigate the relationship between the AD polygenic risk derived from deep learning methods and AD endophenotypes (i.e., plasma biomarkers and individual cognitive performance). We stratified individuals by applying unsupervised clustering to the outputs from the hidden layers of the neural network model. [Results] The deep learning models outperform other statistical models for modeling AD risk. Moreover, the polygenic risk derived from the deep learning models enables the identification of disease-associated biological pathways and the stratification of individuals according to distinct pathological mechanisms. [Conclusion] Our results suggest that deep learning methods are effective for modeling the genetic risks of AD and other diseases, classifying disease risks, and uncovering disease mechanisms.

Compounds that are chemical derivatives of Rhy possessing comparable or more potent inhibitory activity against EphA4 signaling, are disclosed which have the structure: (see formula I) wherein each R1 is independently selected from hydrogen and alkyl; each R2 is independently selected from hydrogen and acyl; each Rq is independently selected an electron pair, lower alkyl, allyl, and arylmethyl; L is a linker selected from a bond, an alkylene and an arylalkylene; X is selected from a bond, -O-, -S-, and -N(R4)-, wherein when L is a bond, X is also a bond; R3 is selected from hydrogen, halo, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroarylalkyl, aroylmethyl, acyl, acylalkyl, (R4)2 N-alkylene, and (see formula II) wherein when L is a bond, R3 is selected from hydrogen, aryl, arylalkyl, heteroarylalkyl, acyl, and acylalkyl; wherein when X is -O-, -S-, or -N(R4)-, R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroarylalkyl, aroylmethyl, acyl, acylalkyl, and (R4)2N-alkylene; and each R4 is independently selected from hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroarylalkyl, acyl, and acylmethyl.

Background: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population. However, epidemiological studies on the demographics of AD in Hong Kong population are lacking. Objective: We investigated the demographics, comorbidities, mortality rates, and medication use of patients with AD in Hong Kong to understand how the disease has been managed locally. Methods: This was a collaborative study of The Hong Kong University of Science and Technology and the Hospital Authority Data Collaboration Lab. We analyzed the demographic data, clinical records, diagnoses, and medication records of patients with AD under the care of the Hospital Authority between January 1, 2007 and December 31, 2017. Results: We identified 23,467 patients diagnosed with AD. The median age at diagnosis was 84 years old, and 71% of patients were female. The most common comorbidity was hypertension (52.6%). 39.9% of patients received medications for dementia; of those, 68.4% had taken those medications for > 1 year. Compared to nonusers, long-term AD medication users had a significantly younger age of AD onset and were taking more lipid-regulating medication, diabetes medication, or antidepressants. Surprisingly, the use of antipsychotics in patients with AD was quite common; 50.7% of patients had received any type of antipsychotic during disease progression. Conclusion: This study provides detailed information on the demographics and medication use of patients with AD in Hong Kong. The data from this AD cohort will aid our future research aiming to identify potential AD risk factors and associations between AD and other diseases.

Introduction: Blood proteins are emerging as candidate biomarkers for Alzheimer's disease (AD). We systematically profiled the plasma proteome to identify novel AD blood biomarkers and develop a high-performance, blood-based test for AD. Methods: We quantified 1160 plasma proteins in a Hong Kong Chinese cohort by high-throughput proximity extension assay and validated the results in an independent cohort. In subgroup analyses, plasma biomarkers for amyloid, tau, phosphorylated tau, and neurodegeneration were used as endophenotypes of AD. Results: We identified 429 proteins that were dysregulated in AD plasma. We selected 19 “hub proteins” representative of the AD plasma protein profile, which formed the basis of a scoring system that accurately classified clinical AD (area under the curve = 0.9690–0.9816) and associated endophenotypes. Moreover, specific hub proteins exhibit disease stage-dependent dysregulation, which can delineate AD stages. Discussion: This study comprehensively profiled the AD plasma proteome and serves as a foundation for a high-performance, blood-based test for clinical AD screening and staging. © 2021 the Alzheimer's Association

Cholinergic neurons are ubiquitous and involved in various higher brain functions including learning and memory. Patients with Alzheimer's disease exhibit significant dysfunction and loss of cholinergic neurons. Meanwhile, such cholinergic deficits can be potentially relieved pharmacologically by increasing acetylcholine. Acetylcholinesterase (AChE) inhibitors have been used to improve cholinergic transmission in the brain for two decades and have proven effective for alleviating symptoms in the early stages of Alzheimer's disease. Therefore, the search for AChE inhibitors for drug development is ongoing. The enzymatic pocket of AChE has long been the target of several drug designs over the last two decades. The peripheral and catalytic sites of AChE are simultaneously bound by several dimeric molecules, enabling more-efficient inhibition. Here, we used 6-chlorotacrine and the tetrahydroquinolone moiety of huperzine A to design and synthesize a series of heterodimers that inhibit AChE at nanomolar potency. Specifically, compound 7b inhibits AChE with an IC50 < 1 nM and spares butyrylcholinesterase. Administration of 7b to mouse brain slices restores synaptic activity impaired by pirenzepine, a muscarinic M1-selective antagonist. Moreover, oral administration of 7b to C57BL/6 mice enhances hippocampal long-term potentiation in a dose-dependent manner and is detectable in the brain tissue. All these data supported that 7b is a potential cognitive enhancer and is worth for further exploration. © 2021 Elsevier Masson SAS

Introduction: Blood proteins are emerging as candidate biomarkers for Alzheimer's disease (AD). We systematically profiled the plasma proteome to identify novel AD blood biomarkers and develop a high-performance, blood-based test for AD. Methods: We quantified 1160 plasma proteins in a Hong Kong Chinese cohort by high-throughput proximity extension assay and validated the results in an independent cohort. In subgroup analyses, plasma biomarkers for amyloid, tau, phosphorylated tau, and neurodegeneration were used as endophenotypes of AD. Results: We identified 429 proteins that were dysregulated in AD plasma. We selected 19 “hub proteins” representative of the AD plasma protein profile, which formed the basis of a scoring system that accurately classified clinical AD (area under the curve = 0.9690–0.9816) and associated endophenotypes. Moreover, specific hub proteins exhibit disease stage-dependent dysregulation, which can delineate AD stages. Discussion: This study comprehensively profiled the AD plasma proteome and serves as a foundation for a high-performance, blood-based test for clinical AD screening and staging. © 2021 the Alzheimer's Association

Background Blood proteins are emerging candidate biomarkers for Alzheimer’s disease (AD). A comprehensive investigation of the AD blood proteome will help identify additional biomarkers to delineate the disease’s pathways and define specific AD stages. Method We quantified 1,160 plasma proteins in a Hong Kong Chinese cohort (n = 106 AD patients, n = 74 healthy controls) by high-throughput proximity extension assay to identify AD-associated plasma proteins. Result Plasma proteins involved in diverse biological processes were found to be dysregulated in AD. A subset of plasma proteins was selected to represent the AD plasma protein profile, which formed the basis of a scoring system that can accurately classify AD and associated endophenotypes. In addition, we showed that certain plasma proteins and biological processes exhibit stage-specific dysregulation in AD, thus adding biological annotations to AD stages. Conclusion This study comprehensively profiled the AD plasma proteome and serves as a foundation for a high-performance, blood-based test for clinical AD screening and staging.

Introduction: Dozens of Alzheimer's disease (AD)‐associated loci have been identified in European‐descent populations, but their effects have not been thoroughly investigated in the Hong Kong Chinese population. / Methods: TaqMan array genotyping was performed for known AD‐associated variants in a Hong Kong Chinese cohort. Regression analysis was conducted to study the associations of variants with AD‐associated traits and biomarkers. Lasso regression was applied to establish a polygenic risk score (PRS) model for AD risk prediction. / Results: SORL1 is associated with AD in the Hong Kong Chinese population. Meta‐analysis corroborates the AD‐protective effect of the SORL1 rs11218343 C allele. The PRS is developed and associated with AD risk, cognitive status, and AD‐related endophenotypes. TREM2 H157Y might influence the amyloid beta 42/40 ratio and levels of immune‐associated proteins in plasma. / Discussion: SORL1 is associated with AD in the Hong Kong Chinese population. The PRS model can predict AD risk and cognitive status in this population.

The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer’s disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs—ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin—as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays. We initially screened a database of FDA-approved drugs using molecular docking against the ligand-binding domain of EphA4. Then, we selected 22 candidate drugs and examined their inhibitory activity towards EphA4. Among them, five drugs inhibited EphA4 clustering induced by ephrin-A in cultured primary neurons. Specifically, nilotinib, a kinase inhibitor, inhibited the binding of EphA4 and ephrin-A at micromolar scale in a dosage-dependent manner. Furthermore, nilotinib inhibited the activation of EphA4 and EphA4-dependent growth cone collapse in cultured hippocampal neurons, demonstrating that the drug exhibits EphA4 inhibitory activity in cellular context. As demonstrated in our combined computational and experimental approaches, repurposing of FDA-approved drugs to inhibit EphA4 may provide an alternative fast-track approach for identifying and developing new treatments for AD.

Natural occurring inhibitors of cyclin-dependent protein kinase 5 (Cdk5), isolated from the root of Rhodiola Rosea are structurally different from the known Cdk inhibitors. They show selectivity among different Cdks and efficacy to inhibit Cdk via a mixed-type of inhibition, which should lead to less toxicity and side-effects. They are useful in preventing and treating diseases and disorders associated with aberrant Cdk5 activities, such as acute and/or chronic pain, neuropathic pain, diabetes mellitus, cancer, neurodegenerative diseases and neuropathological disorders.

Background: Historically, traditional Chinese medicine has been widely used to treat stroke. Based on the theory of Chinese medicine and the modern pharmacological knowledge of herbal medicines, we have designed a neuroprotective formula called Post-Stroke Rehabilitation (PSR), comprising seven herbs - Astragalus membranaceus (Fisch.) Bunge, Salvia miltiorrhiza Bunge, Paeonia lactiflora Pall., Cassia obtusifolia L., Ligusticum chuanxiong Hort., Angelica sinensis (Oliv.) Diels, and Glycyrrhiza uralensis Fisch. We aim to examine the neuroprotective activity of PSR in vitro and in vivo, and to explore the underlying molecular mechanisms, to better understand its therapeutic effect and to further optimize its efficacy. Methods: PSR extract or vehicle was applied to primary rat neurons to examine their survival effects against N-methyl-D-aspartate (NMDA)- elicited excitotoxicity. Whole-cell patch-clamp recording was conducted to examine the NMDA-induced current in the presence of PSR. ERK- and CREB-activation were revealed by western blot analysis. Furthermore, PSR was tested for CRE promoter activation in neurons transfected with a luciferase reporter. The protective effect of PSR was then studied in the rat middle cerebral artery occlusion (MCAO) model. MCAO rats were either treated with PSR extract or vehicle, and their neurobehavioral deficit and cerebral infarct were evaluated. Statistical differences were analyzed by ANOVA or t-test. Results: PSR prominently reduced the death of cultured neurons caused by NMDA excitotoxicity in a dose-dependent manner, indicating its neuroprotective property. Furthermore, PSR significantly reduced NMDA-evoked current reversibly and activated phosphorylation of ERK and CREB with distinct time courses, with the latter's kinetics slower. PSR also triggered CRE-promoter activity as revealed by the increased expression of luciferase reporter in transfected neurons. PSR effectively reduced cerebral infarct and deficit in neurological beh

This invention relates to extracts and refined fractions of a traditional Chinese medicinal herb, Alpinia officinarum (AO), components thereof, and the use of such compounds and compositions to treat neurodegenerative or neuropathological conditions or to inhibit aggregation of a-synuclein.

Alzheimer’s disease is a neurodegenerative disease characterized by cognitive dysfunction. We previously demonstrated an unanticipated role of the signaling of EphA4, a receptor tyrosine kinase, in mediating hippocampal synaptic dysfunction in Alzheimer’s disease. Furthermore, we have identified a small molecule rhynchophylline that can effectively block EphA4-dependent signaling in neurons, rescuing the impaired long-term potentiation in the APP/PS1 mouse model of Alzheimer’s disease. Here, we further demonstrated that rhynchophylline ameliorates the Alzheimer’s disease-like pathology in APP/PS1 mice. Soluble Aβ content and the extent of amyloid plaque deposition were significantly reduced in the cortices of APP/PS1 mice orally administrated with rhynchophylline. Intriguingly, rhynchophylline also regulated the microgliosis in APP/PS1 mice, suggesting that the small molecule reduces neuroinflammation. Taken together, rhynchophylline may be developed as a therapeutic intervention for Alzheimer’s disease.

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans-2,6-dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two-step trans arylation of AR products to access 2,6-trans-dihydropyranones. This new trans-arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier-type and Tsuji–Trost-type reactions, was finally enabled by an unprecedented, highly regioselective γ-deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck–Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (−)-musellarins A–C and 12 analogues in 11–12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three-to-six times greater potency than the musellarins as promising new leads.

Alzheimer’s disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a small-molecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.

Cycloastragenol (CAG) is an aglycone of astragaloside IV. It was first identified when screening Astragalus membranaceus extracts for active ingredients with antiaging properties. The present study demonstrates that CAG stimulates telomerase activity and cell proliferation in human neonatal keratinocytes. In particular, CAG promotes scratch wound closure of human neonatal keratinocyte monolayers in vitro. The distinct telomerase-activating property of CAG prompted evaluation of its potential application in the treatment of neurological disorders. Accordingly, CAG induced telomerase activity and cAMP response element binding (CREB) activation in PC12 cells and primary neurons. Blockade of CREB expression in neuronal cells by RNA interference reduced basal telomerase activity, and CAG was no longer efficacious in increasing telomerase activity. CAG treatment not only induced the expression of bcl2, a CREB-regulated gene, but also the expression of telomerase reverse transcriptase in primary cortical neurons. Interestingly, oral administration of CAG for 7 days attenuated depression- like behavior in experimental mice. In conclusion, CAG stimulates telomerase activity in human neonatal keratinocytes and rat neuronal cells, and induces CREB activation followed by tert and bcl2 expression. Furthermore, CAG may have a novel therapeutic role in depression. (C) 2014 S. Karger AG, Basel

Impairment of hippocampal synaptic plasticity is associated with learning and memory deficit in Alzheimer’s disease. It is therefore important to understand the molecular mechanisms underlying synaptic dysfunctions. We found that activity of a receptor tyrosine kinase EphA4 was increased in hippocampal synaptic fractions of APP/PS1 Alzheimer’s disease mouse model at 3 months, an early stage when the deposition of amyloid plaques s is observed. Furthermore, deletion of postsynaptic EphA4 was able to alleviate the suppression of hippocampal long-term potentiation in the Schaffer collateral-CA1 pathway of APP/PS1 mice. Thus, our findings suggest that EphA4 is a potential target for disease-modifying strategies for Alzheimer’s disease. Using docking analysis, we identified various small molecule inhibitors for EphA4, which were able to inhibit the binding between EphA4 and its endogenous ligands in cultured neurons. Further analysis showed that oral administration of an EphA4 inhibitor blocked the EphA4 signaling in APP/PS1 mice, and rescued the impaired synaptic plasticity observed in those mice. Taken together, blockade of the EphA4-ligand interaction is a promising approach to developing effective treatments for Alzheimer’s disease.

Cycloastragenol (CAG) is an aglycone of astragaloside IV. It was first identified when screening Astragalus membranaceus extracts for active ingredients with antiaging properties. The present study demonstrates that CAG stimulates telomerase activity and cell proliferation in human neonatal keratinocytes. In particular, CAG promotes scratch wound closure of human neonatal keratinocyte monolayers in vitro. The distinct telomerase-activating property of CAG prompted evaluation of its potential application in the treatment of neurological disorders. Accordingly, CAG induced telomerase activity and cAMP response element binding (CREB) activation in PC12 cells and primary neurons. Blockade of CREB expression in neuronal cells by RNA interference reduced basal telomerase activity, and CAG was no longer efficacious in increasing telomerase activity. CAG treatment not only induced the expression of bcl2, a CREB-regulated gene, but also the expression of telomerase reverse transcriptase in primary cortical neurons. Interestingly, oral administration of CAG for 7 days attenuated depression- like behavior in experimental mice. In conclusion, CAG stimulates telomerase activity in human neonatal keratinocytes and rat neuronal cells, and induces CREB activation followed by tert and bcl2 expression. Furthermore, CAG may have a novel therapeutic role in depression. (C) 2014 S. Karger AG, Basel

Impairment of hippocampal synaptic plasticity is associated with learning and memory deficit in Alzheimer’s disease. It is therefore important to understand the molecular mechanisms underlying synaptic dysfunctions. We found that activity of a receptor tyrosine kinase EphA4 was increased in hippocampal synaptic fractions of APP/PS1 Alzheimer’s disease mouse model at 3 months, an early stage when the deposition of amyloid plaques s is observed. Furthermore, deletion of postsynaptic EphA4 was able to alleviate the suppression of hippocampal long-term potentiation in the Schaffer collateral-CA1 pathway of APP/PS1 mice. Thus, our findings suggest that EphA4 is a potential target for disease-modifying strategies for Alzheimer’s disease. Using docking analysis, we identified various small molecule inhibitors for EphA4, which were able to inhibit the binding between EphA4 and its endogenous ligands in cultured neurons. Further analysis showed that oral administration of an EphA4 inhibitor blocked the EphA4 signaling in APP/PS1 mice, and rescued the impaired synaptic plasticity observed in those mice. Taken together, blockade of the EphA4-ligand interaction is a promising approach to developing effective treatments for Alzheimer’s disease.

The maintenance of a high density of neurotransmitter receptors at the postsynaptic apparatus is critical for efficient neurotransmission. Acetylcholine receptors (AChRs) are neurotransmitter receptors densely packed on the postsynaptic muscle membrane at the neuromuscular junction (NMJ) via anchoring onto the actin cytoskeletal network. However, how the receptor-associated actin is coordinately regulated is not fully understood. We report here that Coronin 6, a newly identified member of the coronin family, is highly enriched at adult NMJs and regulates AChR clustering through modulating the interaction between receptors and the actin cytoskeletal network. Experiments with cultured myotubes reveal that Coronin 6 is important for both agrin-and laminin-induced AChR clustering. Furthermore, Coronin 6 forms a complex with AChRs and actin in a manner dependent on its C-terminal region and a conserved Arg(29) residue at the N terminus, both of which are critical for the cytoskeletal anchorage of AChRs. Importantly, in vivo knockdown of Coronin 6 in mouse skeletal muscle fibers leads to destabilization of AChR clusters. Together, these findings demonstrate that Coronin 6 is a critical regulator of AChR clustering at the postsynaptic region of the NMJs through modulating the receptor-anchored actin cytoskeleton.

Cycloastragenol (CAG) is an aglycone of astragaloside IV. It was first identified when screening Astragalus membranaceus extracts for active ingredients with antiaging properties. The present study demonstrates that CAG stimulates telomerase activity and cell proliferation in human neonatal keratinocytes. In particular, CAG promotes scratch wound closure of human neonatal keratinocyte monolayers in vitro. The distinct telomerase-activating property of CAG prompted evaluation of its potential application in the treatment of neurological disorders. Accordingly, CAG induced telomerase activity and cAMP response element binding (CREB) activation in PC12 cells and primary neurons. Blockade of CREB expression in neuronal cells by RNA interference reduced basal telomerase activity, and CAG was no longer efficacious in increasing telomerase activity. CAG treatment not only induced the expression of bcl2, a CREB-regulated gene, but also the expression of telomerase reverse transcriptase in primary cortical neurons. Interestingly, oral administration of CAG for 7 days attenuated depression- like behavior in experimental mice. In conclusion, CAG stimulates telomerase activity in human neonatal keratinocytes and rat neuronal cells, and induces CREB activation followed by tert and bcl2 expression. Furthermore, CAG may have a novel therapeutic role in depression. (C) 2014 S. Karger AG, Basel

Oleanolic acid (3 beta-hydroxy-olea-12-en-28-oic acid) is a natural pentacyclic triterpenoic acid found in many fruits, herbs and medicinal plants. In the past decade, increasing evidence has suggested that oleanolic acid exhibits inhibitory activities against different types of cancer including skin cancer and colon cancer, but not leukemia. We report here that a derivative of oleanolic acid, olean-12-eno[2,3-c] [1,2,5]oxadiazol-28-oic acid (designated OEOA) effectively blocks the proliferation of human leukemia cells. OEOA significantly reduces cell proliferation without inducing cell death in three types of leukemia cell lines, including K562, HEL and Jurket. Moreover, exposure of K562 cells to OEOA results in G(1) cell cycle arrest, with a concomitant induction of cyclin-dependent kinase inhibitor p27 and downregulation of cyclins and Cdks that are essential for cell cycle progression. Interestingly, OEOA also enhances erythroid differentiation in K562 cells through suppressing the expression of Bcr-Abl and phosphorylation of Erk1/2. These findings identify a novel chemical entity for further development as therapeutics against leukemia.

The present invention provides therapeutically active oxazolidine derivatives and compositions as NMDA antagonists, which are useful in preventing and treating central nervous system disorders by inhibiting over-activation of NMDA receptors. In one aspect, the present invention provides methods of treating and/or preventing neurodegenerative diseases and neuropathological disorders, methods of providing neuroprotection under stress conditions such as a stroke, and methods of enhancing the brain's cognitive functions in mammals and humans. For example, the compounds can prevent glutamate-induced neuro- toxicity by inhibiting the activities of the NMDA receptor in the presence of toxic doses of NMDA. In addition, the compounds can potentiate the calcium current in the presence of low dose of NMDA.

Novel heterodimers of tetrahydroacridines and tetrahydroquinolinones are disclosed. The heterodimers are capable of acting as both acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. The heterodimers may be used to improve cognitive defects via treatment or prevention in both humans and non-humans.

The present invention provides therapeutically active compounds and compositions as NMDA and MC receptor antagonists, which are useful in preventing and treating central nervous system disorders by inhibiting over-activation of NMDA and/or MC receptors. In one aspect, the present invention provides methods of treating and/or preventing neurodegenerative diseases and neuropathological disorders, methods of providing neuroprotection under stress conditions such as a stroke, methods of enhancing the brain's cognitive functions and methods of treating depression, anxiety and cachexia induced by a chronic disease in mammals and humans.

One of the pathological hallmarks of Alzheimer's disease (AD) is deposition of extracellular amyloid-beta(A beta) peptide, which is generated from the cleavage of amyloid precursor protein (APP). Accumulation of A beta is thought to associate with the progressive neuronal death observed in AD. However, the precise signaling mechanisms underlying the action of A beta in AD pathophysiology are not completely understood. Here, we report the involvement of the transcription factor signal transducer and activator of transcription 3 (STAT3) in mediating A beta -induced neuronal death. We find that tyrosine phosphorylation of STAT3 is elevated in the cortex and hippocampus of APP/PS1 transgenic mice. Treatment of cultured rat neurons with A beta or intrahippocampal injection of mice with A beta both induces tyrosine phosphorylation of STAT3 in neurons. Importantly, reduction of either the expression or activation of STAT3 markedly attenuates A beta-induced neuronal apoptosis, suggesting that STAT3 activation contributes to neuronal death after A beta exposure. We further identify Tyk2 as the tyrosine kinase that acts upstream of STAT3, as A beta-induced activation of STAT3 and caspase-3-dependent neuronal death can be inhibited in tyk2(-/-) neurons. Finally, increased tyrosine phosphorylation of STAT3 is also observed in postmortem brains of AD patients. Our observations collectively reveal a novel role of STAT3 in A beta -induced neuronal death and suggest the potential involvement of Tyk2/STAT3 signaling in AD pathophysiology.

Novel heterodimers of tetrahydroacridines and tetrahydroquinolinones are disclosed. The heterodimers are capable of acting as both acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. The heterodimers may be used to improve cognitive defects via treatment or prevention in both humans and non-humans.