The Role of Medical Acupuncture Therapy in Alzheimer's Disease.

Objective: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory deficits and other cognitive disorders, which can be accompanied by personality changes. Long-term use of medications available to treat AD today have a variety of side-effects. Acupuncture, as a nonpharmacologic therapeutic modality providing stimulation at acupuncture points, using filiform needles, has been widely tested and used to manage of AD and can be a therapeutic option, considering its effectiveness and lack of side-effects. Methods: This literature review examines the role of acupuncture in AD treatment. Results: Acupuncture can ameliorate AD symptoms through decreasing amyloid-ß protein, reducing neuroinflammation, enhancing the antioxidant system, improving neurogenesis, enhancing prosurvival protein, reducing proapoptotic protein, and regulating brain energy metabolism. Conclusions: According to various research findings, acupuncture may be a therapeutic choice for addressing AD that avoids the long-term side-effects caused by medical therapy.

Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors.

The treatment options for a patient diagnosed with Alzheimer's disease (AD) are currently limited. The cerebral accumulation of amyloid-ß (Aß) is a critical molecular event in the pathogenesis of AD. When the amyloidogenic ß-secretase (BACE1) is inhibited, the production of Aß peptide is reduced. Henceforth, the main goal of this study is the discovery of new small bioactive molecules that potentially reach the brain and inhibit BACE1. The work was conducted by a customized molecular modelling protocol, including pharmacophore-based and molecular docking-based virtual screening (VS). Structure-based (SB) and ligand-based (LB) pharmacophore models were designed to accurately screen several drug-like compound databases. The retrieved hits were subjected to molecular docking and in silico filtered to predict their ability to cross the blood-brain barrier (BBB). Additionally, 34 high-scoring compounds structurally distinct from known BACE1 inhibitors were selected for in vitro screening assay, which resulted in 13 novel hit-compounds for this relevant therapeutic target. This study disclosed new BACE1 inhibitors, proving the utility of combining computational and in vitro approaches for effectively predicting anti-BACE1 agents in the early drug discovery process.

Four new cembranoids from the Chinese soft coral Sinularia sp. and their anti-Aß aggregation activities.

Four new cembranoids (1-4) were isolated from the extracts of a soft coral collected from the sea area near Xisha Island, South China Sea. The structures of these compounds were determined mainly by spectroscopic analyses, with the absolute configuration of 1 being established by X-ray diffraction analysis. In bioassay, compounds 1 and 3 displayed moderate inhibitory activity against Aß42 aggregation (20.6% and 37.2% inhibition at 10 µM). The binding mode of 1 with Aß42 monomer was predicted by molecular docking. In addition, compounds 1 and 3 did not show cytotoxicity against human tumor cell lines (SH-SY5Y, MDA-MB-426, A549, Hep3B, and HT-29) at 100 µM. Taken together, these cembranoids as new anti-Aß aggregation agents derived from Sinularia sp. provided a new chemical scaffold for anti-Alzhemer's disease drug discovery.

Multi-target-directed triazole derivatives as promising agents for the treatment of Alzheimer's disease.

A novel series of triazole-based compounds have been designed, synthesised and evaluated as multi-target-directed ligands (MTDLs) against Alzheimer disease (AD). The triazole-based compounds have been designed to target four major AD hallmarks that include Aß aggregation, metal-induced Aß aggregation, metal dys-homeostasis and oxidative stress. Among the synthesised compounds, 6n having o-CF3 group on the phenyl ring displayed most potent inhibitory activity (96.89% inhibition, IC50 = 8.065 ±â€¯0.129 µM) against Aß42 aggregation, compared to the reference compound curcumin (95.14% inhibition, IC50 = 6.385 ±â€¯0.009 µM). Compound 6n disassembled preformed Aß42 aggregates as effectively as curcumin. Furthermore, 6n displayed metal chelating ability and significantly inhibited Cu2+-induced Aß42 aggregation and disassembled preformed Cu2+-induced Aß42 aggregates. 6n successfully controlled the generation of the reactive oxygen species (ROS) by preventing the copper redox cycle. In addition, 6n did not display cytotoxicity and was able to inhibit toxicity induced by Aß42 aggregates in SH-SY5Y cells. The preferred binding regions and key interactions of 6n with Aß42 monomer and Aß42 protofibril structure was evaluated with molecular docking. Compound 6n binds preferably to the C-terminal region of Aß42 that play a critical role in Aß42 aggregation. The results of the present study highlight a novel triazole-based compound, 6n, as a promising MTDL against AD.

Methanolic extract of Tamarix Gallica attenuates hyperhomocysteinemia induced AD-like pathology and cognitive impairments in rats.

Although few drugs are available today for the management of Alzheimer's disease (AD) and many plants and their extracts are extensively employed in animals' studies and AD patients, yet no drug or plant extract is able to reverse AD symptoms adequately. In the present study, Tamarix gallica (TG), a naturally occurring plant known for its strong antioxidative, anti-inflammatory and anti-amyloidogenic properties, was evaluated on homocysteine (Hcy) induced AD-like pathology and cognitive impairments in rats. We found that TG attenuated Hcy-induced oxidative stress and memory deficits. TG also improved neurodegeneration and neuroinflammation by upregulating synaptic proteins such as PSD95 and synapsin 1 and downregulating inflammatory markers including CD68 and GFAP with concomitant decrease in proinflammatory mediators interlukin-1ß (IL1ß) and tumor necrosis factor α (TNFα). TG attenuated tau hyperphosphorylation at multiple AD-related sites through decreasing some kinases and increasing phosphatase activities. Moreover, TG rescued amyloid-ß (Aß) pathology through downregulating BACE1. Our data for the first time provide evidence that TG attenuates Hcy-induced AD-like pathological changes and cognitive impairments, making TG a promising candidate for the treatment of AD-associated pathological changes.

Redox-Activated Near-Infrared-Responsive Polyoxometalates Used for Photothermal Treatment of Alzheimer's Disease.

Adjustable structure, excellent physiochemical properties, and good biocompatibility render polyoxometalates (POMs) as a suitable drug agent for the treatment of Alzheimer's disease (AD). However, previous works using POMs against AD just focus on the inhibition of amyloid-ß (Aß) monomer aggregation. In consideration that both Aß fibrils and reactive oxygen species (ROS) are closely associated with clinical development of AD symptoms, it would be more effective if POMs can disaggregate Aß fibrils and eliminate ROS as well. Herein, a redox-activated near-infrared (NIR) responsive POMs-based nanoplaform (rPOMs@MSNs@copolymer) is developed with high photothermal effect and antioxidant activity. The rPOMs@MSNs@copolymer can generate local hyperthermia to disaggregate Aß fibrils under NIR laser irradiation because of POMs (rPOMs) with strong NIR absorption. Furthermore, Aß-induced ROS can be scavenged by the antioxidant activity of rPOMs. To the authors' knowledge, there is no report of using rPOMs for NIR photothermal treatment of AD. This work may promote the development of multifunctional inorganic agents for biomedical applications.

Efficient clearance of Aß protofibrils in AßPP-transgenic mice treated with a brain-penetrating bifunctional antibody.

BACKGROUND: Amyloid-ß (Aß) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer's disease (AD). Despite recent progress targeting aggregated forms of Aß, low antibody brain penetrance remains a challenge. In the present study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate brain uptake of our previously developed Aß protofibril-selective mAb158, with the aim of increasing the efficacy of immunotherapy directed toward soluble Aß protofibrils. METHODS: Aß protein precursor (AßPP)-transgenic mice (tg-ArcSwe) were given a single dose of mAb158, modified for TfR-mediated transcytosis (RmAb158-scFv8D3), in comparison with an equimolar dose or a tenfold higher dose of unmodified recombinant mAb158 (RmAb158). Soluble Aß protofibrils and total Aß in the brain were measured by enzyme-linked immunosorbent assay (ELISA). Brain distribution of radiolabeled antibodies was visualized by positron emission tomography (PET) and ex vivo autoradiography. RESULTS: ELISA analysis of Tris-buffered saline brain extracts demonstrated a 40% reduction of soluble Aß protofibrils in both RmAb158-scFv8D3- and high-dose RmAb158-treated mice, whereas there was no Aß protofibril reduction in mice treated with a low dose of RmAb158. Further, ex vivo autoradiography and PET imaging revealed different brain distribution patterns of RmAb158-scFv8D3 and RmAb158, suggesting that these antibodies may affect Aß levels by different mechanisms. CONCLUSIONS: With a combination of biochemical and imaging analyses, this study demonstrates that antibodies engineered to be transported across the blood-brain barrier can be used to increase the efficacy of Aß immunotherapy. This strategy may allow for decreased antibody doses and thereby reduced side effects and treatment costs.

Systems Biology Methods for Alzheimer's Disease Research Toward Molecular Signatures, Subtypes, and Stages and Precision Medicine: Application in Cohort Studies and Trials.

Alzheimer's disease (AD) is a complex multifactorial disease, involving a combination of genomic, interactome, and environmental factors, with essential participation of (a) intrinsic genomic susceptibility and (b) a constant dynamic interplay between impaired pathways and central homeostatic networks of nerve cells. The proper investigation of the complexity of AD requires new holistic systems-level approaches, at both the experimental and computational level. Systems biology methods offer the potential to unveil new fundamental insights, basic mechanisms, and networks and their interplay. These may lead to the characterization of mechanism-based molecular signatures, and AD hallmarks at the earliest molecular and cellular levels (and beyond), for characterization of AD subtypes and stages, toward targeted interventions according to the evolving precision medicine paradigm. In this work, an update on advanced systems biology methods and strategies for holistic studies of multifactorial diseases-particularly AD-is presented. This includes next-generation genomics, neuroimaging and multi-omics methods, experimental and computational approaches, relevant disease models, and latest genome editing and single-cell technologies. Their progressive incorporation into basic research, cohort studies, and trials is beginning to provide novel insights into AD essential mechanisms, molecular signatures, and markers toward mechanism-based classification and staging, and tailored interventions. Selected methods which can be applied in cohort studies and trials, with the European Prevention of Alzheimer's Dementia (EPAD) project as a reference example, are presented and discussed.

Semisynthesis and biological evaluation of prenylated resveratrol derivatives as multi-targeted agents for Alzheimer's disease.

A series of prenylated resveratrol derivatives were designed, semisynthesized and biologically evaluated for inhibition of ß-secretase (BACE1) and amyloid-ß (Aß) aggregation as well as free radical scavenging and neuroprotective and neuritogenic activities, as potential novel multifunctional agents against Alzheimer's disease (AD). The results showed that compound 4b exhibited good anti-Aß aggregation (IC50 = 4.78 µM) and antioxidant activity (IC50 = 41.22 µM) and moderate anti-BACE1 inhibitory activity (23.70% at 50 µM), and could be a lead compound. Moreover, this compound showed no neurotoxicity along with a greater ability to inhibit oxidative stress on P19-derived neuronal cells (50.59% cell viability at 1 nM). The neuritogenic activity presented more branching numbers (9.33) and longer neurites (109.74 µm) than the control, and was comparable to the quercetin positive control. Taken together, these results suggest compound 4b had the greatest multifunctional activities and might be a very promising lead compound for the further development of drugs for AD.

Extracts from two ubiquitous Mediterranean plants ameliorate cellular and animal models of neurodegenerative proteinopathies.

A signature feature of age-related neurodegenerative proteinopathies is the misfolding and aggregation of proteins, typically amyloid-ß (Aß) in Alzheimer's disease (AD) and α-synuclein (α-syn) in Parkinson's disease (PD), into soluble oligomeric structures that are highly neurotoxic. Cellular and animal models that faithfully replicate the hallmark features of these disorders are being increasing exploited to identify disease-modifying compounds. Natural compounds have been identified as a useful source of bioactive molecules with promising neuroprotective capabilities. In the present report, we investigated whether extracts derived from two ubiquitous Mediterranean plants namely, the prickly pear Opuntia ficus-indica (EOFI) and the brown alga Padina pavonica (EPP) alleviate neurodegenerative phenotypes in yeast (Saccharomyces cerevisiae) and fly (Drosophila melanogaster) models of AD and PD. Pre-treatment with EPP or EOFI in the culture medium significantly improved the viability of yeast expressing the Arctic Aß42 (E22G) mutant. Supplementing food with EOFI or EPP dramatically ameliorated lifespan and behavioural signs of flies with brain-specific expression of wild-type Aß42 (model of late-onset AD) or the Arctic Aß42 variant (model of early-onset AD). Additionally, we show that either extract prolonged the survival of a PD fly model based on transgenic expression of the human α-syn A53T mutant. Taken together, our findings suggest that the plant-derived extracts interfere with shared mechanisms of neurodegeneration in AD and PD. This notion is strengthened by evidence demonstrating that EOFI and to a greater extent EPP, while strongly inhibiting the fibrillogenesis of both Aß42 and α-syn, accumulate remodelled oligomeric aggregates that are less effective at disrupting lipid membrane integrity. Our work therefore opens new avenues for developing therapeutic applications of these natural plant extracts in the treatment of amyloidogenic neurodegenerative disorders.