Strategy For Treatment Of Alzheimer's Disease Research Articles

Tau-aggregation inhibitors derived from Streptomyces tendae MCCC 1A01534 protect HT22 cells against okadaic acid-induced damage

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by tau aggregating into neurofibrillary tangles. Targeting tau aggregation is one of the most critical strategies for AD treatment and prevention. Herein, a high-throughput screening of tau-aggregation inhibitors was performed by thioflavin T (ThT) fluorescence assay and tauR3 peptides. According to bioactivity-guided isolation, homoprejadomycin (1) was obtained from the marine bacterium Streptomyces tendae MCCC 1A01534. Two new stable derivatives, 2 and 3, were yielded in a one-step reaction. By ThT assay, transmission electron microscopy, and circular dichroism, we demonstrated that the angucyclinones 2 and 3 inhibited tau aggregation and disaggregated tau fibrils. In the presence of 2, native tauR3 peptides maintained the disorder conformation, whereas the tauR3 aggregates reduced β-sheet structures. And compound 2 was confirmed to inhibit the aggregation of full-length 2N4R tau protein. Furthermore, 2 with low cytotoxicity protected HT22 cells from okadaic acid-induced damage by suppressing tau aggregates. These results indicated that 2 was a promising lead structure with tau therapeutic potency for AD treatment.

Current emerging novel therapies for Alzheimer's disease and the future prospects of magneto-mechanical force therapy.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly, and the morbidity increases with the aging population aggravation. The clinical symptoms of AD mainly include cognitive impairment and memory loss, which undoubtedly bring a huge burden to families and society. Currently, the drugs in clinical use only improve the symptoms of AD but do not cure or prevent the progression of the disease. Therefore, it is urgent for us to develop novel therapeutic strategies for effective AD treatment. To provide a better theoretical basis for exploring novel therapeutic strategies in future AD treatment, this review introduces the recent AD treatment technologies from three aspects, including nanoparticle (NP) based drug therapy, biological therapy and physical therapy. The nanoparticle-mediated therapeutic approaches at the nanomaterial-neural interface and biological system are described in detail, and in particular the magneto-regulated strategies by magnetic field actuating magnetic nanoparticles are highlighted. Promising application of magneto-mechanical force regulated strategy in future AD treatment is also addressed, which offer possibilities for the remote manipulation in a precise manner. In the future, it may be possible for physicians to realize a remote, precise and effective therapy for AD using magneto-mechanical force regulated technology based on the combination of magnetic nanoparticles and an external magnetic field.

Raw Inonotus obliquus polysaccharide counteracts Alzheimer's disease in a transgenic mouse model by activating the ubiquitin-proteosome system.

Inonotus obliquus has been used as antidiabetic herb around the world, especially in the Russian and Scandinavian countries. Diabetes is widely believed to be a key factor in Alzheimer's disease (AD), which is widely considered to be type III diabetes. To investigate whether I. obliquus can also ameliorate AD, it would be interesting to identify new clues for AD treatment. We tested the anti-AD effects of raw Inonotus obliquus polysaccharide (IOP) in a mouse model of AD (3×Tg-AD transgenic mice). SPF-grade 3×Tg-AD mice were randomly divided into three groups (Control, Metformin, and raw IOP groups, n = 5 per group). β-Amyloid deposition in the brain was analyzed using immunohistochemistry for AD characterization. Gene and protein expression of pertinent factors of the ubiquitin-proteasome system (UPS) was determined using real-time quantitative polymerase chain reaction and Western blotting. Raw IOP significantly reduced the accumulation of amyloid aggregates and facilitated UPS activity, resulting in a significant reduction in AD-related symptoms in an AD mouse model. The presence of raw IOP significantly enhanced the expression of ubiquitin, E1, and Parkin (E3) at both the mRNA and protein levels in the mouse hippocampus. The mRNA level of ubiquitin carboxyl-terminal hydrolase isozyme L1, a key factor involved in UPS activation, also increased by approximately 50%. Raw IOP could contribute to AD amelioration via the UPS pathway, which could be considered as a new potential strategy for AD treatment, although we could not exclude other mechanisms involved in counteracting AD processing.

Multi-target QSAR modeling for the identification of novel inhibitors against Alzheimer's disease

Alzheimer's disease (AD) is an age-related neurodegenerative disorder, which is the most common cause of dementia in elderly individuals. It is characterized by selective neuronal cell death that affects the brain area related to memory and learning. So far, various computational research targeting AD have been reported, but we are still far from finding a precise treatment strategy for AD. It appeared of interest to us to carry out a two-dimensional quantitative structure-activity relationship (2D-QSAR) analysis against multiple targets of AD using large datasets to determine the essential structural features which are responsible for the inhibition of the enzymes/targets. In the present research, we have implemented 2D-QSAR modeling against twelve major targets (AChE, BuChE, BACE1, β-amyloid, 5-HT6, CDK-5, Gamma-secretase, Glutaminyl Cyclase, GSK-3β, MAO-B, NMDA and Phosphodiester (PDE10A) enzymes) of AD for the identifications of novel multitarget inhibitors. The models were used to check the applicability domain of a pool of ∼19 million compounds obtained from the four chemical drug-like databases (ZINC12, Asinex, NCI, and InterBioscreen databases) and provided prioritized compounds for experimental detection of their performance as anti-Alzheimer's drug. Additionally, we have also developed the quantitative structure activity-activity relationship (QSAAR) and selectivity-based models to explore the most important features contributing to the dual inhibition against the respective targets. Furthermore, we have also performed chemical Read-Across predictions using the Read-Across-v3.1 tool (https://dtclab.webs.com/software-tools), the results for the external validation metrics were found to be better than the 2D-QSAR-derived predictions. Furthermore, molecular docking experiments have been performed to understand the molecular interactions between ligands and enzymes at the atomic level, and the observations are compared with the structural features acquired from QSAR models that justified the mechanistic aspect of binding phenomena. The proposed models and read-across hypotheses could be used as potential tools to identify essential molecular features for designing suitable drug(s) for Alzheimer's therapy using rational design of multi-target inhibitors.

Promoting Endogenous Neurogenesis as a Treatment for Alzheimer's Disease.

Alzheimer's disease (AD) is the most universal neurodegenerative disorder characterized by memory loss and cognitive impairment. AD is biologically defined by production and aggregation of misfolded protein including extracellular amyloid β (Aβ) peptide and intracellular microtubule-associated protein tau tangles in neurons, leading to irreversible neuronal loss. At present, regulation of endogenous neurogenesis to supplement lost neurons has been proposed as a promising strategy for treatment of AD. However, the exact underlying mechanisms of impaired neurogenesis in AD have not been fully explained and effective treatments targeting neurogenesis for AD are limited. In this review, we mainly focus on the latest research of impaired neurogenesis in AD. Then we discuss the factors affecting stages of neurogenesis and the interplay between neural stem cells (NSCs) and neurogenic niche under AD pathological conditions. This review aims to explore potential therapeutic strategies that promote endogenous neurogenesis for AD treatments.

Midazolam alleviates cellular senescence in SH-SY5Y neuronal cells in Alzheimer's disease.

Alzheimer's disease (AD) impacts the daily life of aging people. Oligomerized amyloid β (Aβ)-associated neuronal senescence is involved in the pathological mechanism of AD. Blockage of neuronal senescence has been considered an important strategy for the treatment of AD. Midazolam is a hypnotic-sedative drug with pleiotropic properties. However, the effects of Midazolam in oligomerized Aβ1.42 -induced neurotoxicity have not been reported previously. Here, we investigate whether Midazolam possesses a beneficial effect against oligomerized Aβ1.42 in SH-SY5Y neuronal cells. Cellular senescence was assessed using senescence-associated β-galactosidase staining. Telomerase activity was measured using the TeloTAGGG Telomerase PCR ELISA. First, the lactate dehydrogenase release assay demonstrates that 10 and 20 µM are the optimal concentrations of Midazolam used for cell cultures. Senescence-associated β-galactosidase staining results indicate that exposure to oligomerized Aβ1.42 significantly increased cellular senescence of SH-SY5Y cells, but it was significantly alleviated by Midazolam. Additionally, Midazolam restored the oligomerized Aβ1.42 -induced reduction of telomerase activity. Interestingly, we found that oligomerized Aβ1.42 remarkably reduced human telomerase reverse transcriptase (hTERT) gene expression but increased the telomeric repeat-binding factor 2 (TERF2) expression. However, treatment with Midazolam reversed the effects of oligomerized Aβ1.42 on the hTERT and TERF2 gene expressions. Importantly, the presence of Midazolam attenuated Aβ1.42 -induced p53 and p21 expressions. Mechanistically, Midazolam repressed the level of cyclooxygenase-2 (COX-2) and the release of prostaglandin E2. Importantly, overexpression of COX-2 abolished the impact of Midazolam against oligomerized Aβ1.42 in neuronal senescence. We conclude that the usage of Midazolam is a potential treatment strategy for AD.

RETRACTED ARTICLE: Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer’s disease- like alterations through multi-targeting activities in two animal models

BackgroundRecent investigations suggested that anticancer agents may inhibit the progression of Alzheimer's disease (AD) pathology. Conyza dioscoridis (L.) was demonstrated to have anticancer, antioxidant, anti-inflammatory and antidiabetic effects. This study was carried out to investigate the efficacy of polyphenols from Conyza dioscoridis (L.) extract (PCDE) on AD.MethodsImpacts of 3 doses of PCDE and donepezil, a reference drug, on the features of Alzheimer's disease in two animal models were investigated.ResultsPCDE ameliorated the memory and learning impairment shown in rats following a single dose of scopolamine (scopolamine model) or 17 weeks of high-fat/high-fructose(HF/Hfr) diet coupled with a single dose of streptozotocin, (25 mg/kg) (T2D model). They reduced significantly the high hippocampal cholinesterase activity in the two models of rats. Administration of PCDE for 8 weeks in the T2D model showed a significant reduction in hippocampal GSK-3β, caspase-3 activity and increase in the inhibited glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). A significant reduction of HOMA-insulin resistance and serum hypercholesterolemia was observed. The Tau hyperphosphorylation and Aβ 1–42 generation in the hippocampal of T2D rats were significantly decreased by PCDE. Modulation of the oxidative stress markers, (rise in GH and SOD; decrease in MDA levels) and a significant reduction of TNF-α and IL-1β in the hippocampus of T2D rats treated by PCDE extract were important findings in this study. The highest dose tested was 4% of the highest safe dose.ConclusionOur study suggests that PCDE is multi-targeting agent with multiple beneficial activities in combating features of AD. This study may provide a novel therapeutic strategy for AD treatment that warrants clinical studies.

Discovery of novel β-carboline-1,2,3-triazole hybrids as AChE/GSK-3β dual inhibitors for Alzheimer's disease treatment

Alzheimer's disease (AD) is characterized by progressive cognitive impairment and mental behavior. The combination inhibition of two essential AD targets, acetylcholinesterase (AChE) and glycogen synthase kinase-3β (GSK-3β), might be a breakthrough in the discovery of therapeutic success. Herein, 17 β-carboline-1,2,3-triazole hybrids were designed, synthesized, and evaluated for their AChE and GSK-3β inhibitory potential. The results indicated that compound 21 has the most potent inhibition against eeAChE (IC50 = 0.20 ± 0.02 μM), hAChE (IC50 = 0.34 ± 0.01 μM) and GSK-3β (IC50 = 1.14 ± 0.05 μM) among these compounds. In addition, it inhibited hAChE in a mixed type manner and could occupy the binding pocket forming diverse interactions with the target of AChE and GSK-3β. Moreover, compound 21 showed low cytotoxicity against SH-SY5Y and HepG2 cell lines and good BBB permeability. Compound 21 also attenuated the tau hyperphosphorylation in the Tau (P301L) 293T cell model. The ADME projection exhibited that compound 21 has acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and GSK-3β dual inhibition as a promising strategy for AD treatment.

The effect of chronic stress and its preconditioning on spatial memory as well as hippocampal LRP1 and RAGE expression in a streptozotocin-induced rat model of Alzheimer’s disease

According to available evidence, prolonged or chronic exposure to stress is detrimental to various brain structures, including the hippocampus. The current study examined the expression of two critical blood-brain barrier receptors required for amyloid-beta clearance to understand better the mechanism by which chronic stress impairs learning and memory in patients with Alzheimer's disease (AD). Rats were randomly assigned to one of two groups in this study: experiment 1 and experiment 2. Each main group was then divided into four subgroups. Rats were bilaterally injected with streptozotocin (STZ, 3mg/kg, twice) using the intracerebroventricular (ICV) technique to induce the Alzheimer's model. Additionally, they were subjected to foot shock (1mA, 1Hz) for 10s every 60s (1h/day) for ten consecutive days prior to and following STZ injection. The Morris Water Maze (MWM) test was used to assess spatial learning and memory. Real-time PCR was used to determine Low-density lipoprotein receptor-related protein-1 (LRP1) and receptor for advanced glycation end-products (RAGE) mRNA levels in the hippocampus. Moreover, the animals' body weights were determined as physiological parameters in all groups. The results indicated that 10-day chronic electric foot shock stress reduced body weight, impaired spatial learning and memory, decreased hippocampal LRP1 mRNA expression, and increased hippocampal RAGE mRNA expression in a rat AD model. It can be concluded that chronic stress in conjunction with AD alters the expression of LRP1 and RAGE in the hippocampus. The findings pave the way for scientists to develop novel treatment strategies for AD.

Current understanding of AD pathophysiology and impact of amyloid beta-targeted treatments on biomarkers and clinical endpoints.

Alzheimer's disease (AD) is a fatal, neurodegenerative disease whose pathogenesis includes the buildup of amyloid beta (Aß; one of the defining brain changes of AD) years before clinical symptoms appear. Anti-Aß therapeutics that target the complex underlying AD pathophysiology have been the focus of many recent clinical trials, representing a viable option that may ultimately slow cognitive decline in some patients. Evidence has been accumulating within the science community that plaque-removing monoclonal antibodies can impact Aß, tau, and neurodegeneration, the hallmarks of AD. The spring 2022 Alzheimer's Association's Research Roundtable (AARR) convened leaders from industry and academia, as well as patients, clinicians, and government scientists and regulatory agencies, to discuss the topic, “Current Understanding of AD Pathophysiology & Impact of Amyloid Beta–Targeted Treatments on Biomarkers and Clinical Endpoints.” The meeting addressed two fundamental questions: (1) What is the evidence regarding the relationship between Aß and tau? and (2) What does the evidence show about how anti-Aß therapies alter clinical function? The meeting opened with a series of presentations to lay the groundwork on what we know about the biology of AD, including a primer on various species of Aß and how animal models may inform our understanding of disease progression. The meeting continued with representatives from active, observational studies sharing how biomarker and clinical data contribute to our understanding of Aß, tau, and other pathologies, and subject matter experts who presented modeling data to advance AD treatment strategies. Several major pharmaceutical companies that are AARR members also presented current evidence from multiple phase 2 and 3 clinical trials that manipulation (or removal) of Aß has a clear downstream impact on tau, neurodegeneration, and cognitive/functional measures. At the conclusion of the 2-day meeting, presenters, panelists, and the AARR membership in attendance came to several conclusions based on the scientific evidence presented, discussed and debated. The totality of scientific evidence (clinical trials, animal data, modeling, and observational studies) on Aß is helping our understanding of the downstream effects and overall importance of lowering Aß. Based on data from multiple phase 2 and 3 clinical trials of monoclonal antibodies, there is evidence to support that a change in Aß is associated with a change in tau and clinical endpoints. And finally, biomarker changes in Aß are reasonably likely to predict changes in clinical outcome measures, and should be considered meaningful to all patients who may potentially benefit from these treatments. The spring 2022 AARR meeting not only furthered our understanding of the pathophysiology of AD, but also brought to light the strength of the evidence supporting the hypothesis that a change in Aß can produce meaningful change in biomarkers and clinical endpoints. There is much work to be done, and the scientific community needs to stay focused on defining those tools most appropriate to capture these changes, the populations best suited to enroll in clinical trials, and defining our expectations of what changes can be expected over a particular interval of time. A more detailed report of this meeting will appear in a future issue of Alzheimer's & Dementia.

Hippocampal neural circuit connectivity alterations in an Alzheimer's disease mouse model revealed by monosynaptic rabies virus tracing

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts, particularly in countries with aging populations. The examination of neural circuit mechanisms in AD mouse models is a recent focus for identifying new AD treatment strategies. We hypothesize that age-progressive changes of both long-range and local hippocampal neural circuit connectivity occur in AD. Recent advancements in viral-genetic technologies provide new opportunities for semi-quantitative mapping of cell-type-specific neural circuit connections in AD mouse models. We applied a recently developed monosynaptic rabies tracing method to hippocampal neural circuit mapping studies in AD model mice to determine how local and global circuit connectivity to hippocampal CA1 excitatory neurons may be altered in the single APP knock-in (APP-KI) AD mouse model. To determine age-related AD progression, we measured circuit connectivity in age-matched littermate control and AD model mice at two different ages (3–4 vs. 10–11 months old). We quantitatively mapped the connectivity strengths of neural circuit inputs to hippocampal CA1 excitatory neurons from brain regions including hippocampal subregions, medial septum, subiculum and entorhinal cortex, comparing different age groups and genotypes. We focused on hippocampal CA1 because of its clear relationship with learning and memory and that the hippocampal formation shows clear neuropathological changes in human AD. Our results reveal alterations in circuit connectivity of hippocampal CA1 in AD model mice. Overall, we find weaker extrinsic CA1 input connectivity strengths in AD model mice compared with control mice, including sex differences of reduced subiculum to CA1 inputs in aged female AD mice compared with aged male AD mice. Unexpectedly, we find a connectivity pattern shift with an increased proportion of inputs from the CA3 region to CA1 excitatory neurons when comparing young and old AD model mice, as well as old wild-type mice and old AD model mice. These unexpected shifts in CA3-CA1 input proportions in this AD mouse model suggest the possibility that compensatory circuit increases may occur in response to connectivity losses in other parts of the hippocampal circuits. We expect that this work provides new insights into the neural circuit mechanisms of AD pathogenesis.

Aspartic Acid-Modified Phospholipids Regulate Cell Response and Rescue Memory Deficits in APP/PS1 Transgenic Mice.

Misfolding and accumulation of amyloid-β (Aβ) to form senile plaques are the main neuropathological signatures of Alzheimer's disease (AD). Decreasing Aβ production, inhibiting Aβ aggregation, and clearing Aβ plaques are thus considered an important strategy for AD treatment. However, numerous drugs cannot enter the AD clinical trials due to unsatisfactory biocompatibility, poor blood-brain barrier penetration, little biomarker impact, and/or low therapeutic indicators. Here, a pair of chiral aspartic acid-modified 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (l- and d-Asp-DPPE) are prepared to build stabilized chiral liposomes. We find that both l- and d-liposomes are able to rescue Aβ aggregation-induced apoptosis, oxidative stress, and calcium homeostasis, in which the effect of d-liposomes is more obvious than that of l-ones. Furthermore, in AD model mice (APPswe/PS1d9 double-transgenic mice), chiral liposomes not only show biosafety but also strongly improve cognitive deficits and reduce Aβ deposition in the brain. Our results suggest that chiral liposomes, particularly, d-liposomes, could be a potential therapeutic approach for AD treatment. This study opens new horizons by showing that liposomes will be used for drug development in addition to delivery and targeting functions.

Spatio-temporal Tensor Multi-Task Learning for Predicting Alzheimer's Disease in a Longitudinal study.

The utilisation of machine learning techniques to predict Alzheimer's Disease (AD) progression will substantially assist researchers and clinicians in establishing effective AD prevention and treatment strategies. In this research, we present a novel Multi-Task Learning (MTL) model for modelling AD progression based on tensor formation from spatio-temporal similarity measures of brain biomarkers. In this model, each patient sample's prediction in the tensor is assigned to a task, with each task sharing a set of latent factors acquired via tensor decomposition. To further improve the performance of the model, we present a novel regularisation term which utilises the convex combination of disease progression to modify longitudinal stability and ensure that two regression models have a minimal variation at successive time points. The model can be utilised to effectively predict AD progression with magnetic resonance imaging (MRI) data and cognitive scores of AD patients at various stages. We conducted extensive experiments to evaluate the performance for the proposed model and algorithm utilising data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Compared to single-task and state-of-the-art multi-task regression techniques, our proposed method has greater accuracy and stability for predicting AD progress in terms of root mean square error, with an average reduction of 2.60 compared to single-task regression methods and 1.17 compared to multi-task regression methods in the Mini-Mental State Examination (MMSE) questionnaire; with an average reduction of 5.08 compared to single-task regression methods and 2.71 compared to multi-task regression methods in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog).

Functionalized Allopurinols Targeting Amyloid-Binding Alcohol Dehydrogenase Rescue Aβ-Induced Mitochondrial Dysfunction.

Alzheimer's disease (AD) is the most common dementia affecting one in nine people over 65. Only a handful of small-molecule drugs and the anti-β amyloid (Aβ) antibody aducanumab are approved to treat AD. However, they only serve to reduce symptoms of advanced disease. Novel treatments administered early in disease progression before the accumulation of Aβ and tau reaches the threshold where neuroinflammation is triggered and irreversible neuronal damage occurs are more likely to provide effective therapy. There is a growing body of evidence implying that mitochondrial dysfunction occurs at an early stage of AD pathology. The mitochondrial enzyme amyloid-binding alcohol dehydrogenase (ABAD) binds to Aβ potentiating toxicity. Moreover, ABAD has been shown to be overexpressed in the same areas of the brain most affected by AD. Inhibiting the Aβ-ABAD protein-protein interaction without adversely affecting normal enzyme turnover is hypothesized to be a potential treatment strategy for AD. Herein, we conduct structure-activity relationship studies across a series of functionalized allopurinol derivatives to determine their ability to inhibit Aβ-mediated reduction of estradiol production from ABAD. The lead compound resulting from these studies possesses potent activity with no toxicity up to 100 μM, and demonstrates an ability to rescue defective mitochondrial metabolism in human SH-SY5Y cells and rescue both defective mitochondrial metabolism and morphology ex vivo in primary 5XFAD AD mouse model neurons.

Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion.

Hypoxic-ischemic injury has been linked with increased risk for developing Alzheimer's disease (AD). The underlying mechanism of this association is poorly understood. Here, we report distinct roles for hypoxia-inducible factor-1α (Hif-1α) in the regulation of BACE1 and γ-secretase activity, two proteases involved in the production of amyloid-beta (Aβ). We have demonstrated that Hif-1α upregulates both BACE1 and γ-secretase activity for Aβ production in brain hypoxia-induced either by cerebral hypoperfusion or breathing 10% O2. Hif-1α binds to γ-secretase, which elevates the amount of active γ-secretase complex without affecting the level of individual subunits in hypoxic-ischemic mouse brains. Additionally, the expression of full length Hif-1α increases BACE1 and γ-secretase activity in primary neuronal culture, whereas a transcriptionally incompetent Hif-1α variant only activates γ-secretase. These findings indicate that Hif-1α transcriptionally upregulates BACE1 and nontranscriptionally activates γ-secretase for Aβ production in hypoxic-ischemic conditions. Consequently, Hif-1α-mediated Aβ production may be an adaptive response to hypoxic-ischemic injury, subsequently leading to increased risk for AD. Preventing the interaction of Hif-1α with γ-secretase may therefore be a promising therapeutic strategy for AD treatment.

Chrysin-Loaded Chitosan Nanoparticle-Mediated Neuroprotection in Aβ1-42-Induced Neurodegenerative Conditions in Zebrafish.

Amyloid β plaques and neurofibrillary tangles are the characteristic features of Alzheimer's disease (AD). Plaques of amyloid β play a pivotal role in affecting cognitive functions and memory. Alzheimer's disease is a progressive neurodegenerative disease and is one of the leading causes of dementia worldwide. Several treatment strategies focusing on the amyloid cascade have been implemented to treat AD. The blood-brain barrier (BBB) poses the main obstructive barrier by refraining drugs from penetrating the brain. Nanotechnology is a promising research field for brain drug delivery using nanosized particles. Zebrafish is emerging as a model of interest to elaborate on brain targeting and nanotechnology-based therapeutics for neurodegenerative diseases. In the current study, we have synthesized and characterized chrysin-loaded chitosan nanoparticles (Chr-Chi NPs) and evaluated them for neuroprotection against amyloid-β-induced toxicity. We find that treatment with Chr-Chi NPs helps to retain memory, cognition, and synaptic connections, which are otherwise compromised due to Aβ1-42 toxicity. The NPs further help in reducing aggregates of amyloid β, thus decreasing neuronal death and generation of reactive oxygen species (ROS). Taken together, our study brings to light a novel strategy for treating AD by a combined action on the neurons and amyloid aggregates mediated by chrysin and chitosan, respectively. Chr-Chi NPs, therefore, have the potential to provide a beneficial combinatorial treatment strategy for AD.

Sleep-Wake Disorders in Alzheimer's Disease: A Review.

Alzheimer's disease (AD) is a multifactorial disease, and it has become a serious health problem in the world. Senile plaques (SPs) and neurofibrillary tangles (NFTs) are two main pathological characters of AD. SP mainly consists of aggregated β-amyloid (Aβ), and NFT is formed by hyperphosphorylated tau protein. Sleep-wake disorders are prevalent in AD patients; however, the links and mechanisms of sleep-wake disorders on the AD pathogenesis remain to be investigated. Here, we referred to the sleep-wake disorders and reviewed some evidence to demonstrate the relationship between sleep-wake disorders and the pathogenesis of AD. On one hand, the sleep-wake disorders may lead to the increase of Aβ production and the decrease of Aβ clearance, the spreading of tau pathology, as well as oxidative stress and inflammation. On the other hand, the ApoE4 allele, a risk gene for AD, was reported to participate in sleep-wake disorders. Furthermore, some neurotransmitters, such as acetylcholine, glutamate, serotonin, melatonin, and orexins, and their receptors were suggested to be involved in AD development and sleep-wake disorders. We discussed and suggested some possible therapeutic strategies for AD treatment based on the view of sleep regulation. In general, this review explored different views to find novel targets of diagnosis and therapy for AD.

Revisiting Small Molecule Inhibitors of Amyloid‐β Aggregation

Alzheimer’s disease (AD) is associated with amyloid formation and accumulation in the brain contributing to neurodegeneration. To date, there are no suitable mitigation strategies that stop or slow AD progression. Novel therapeutic approaches applicable at different stages of AD amyloid formation are direly needed. The long‐term goal of this research is to establish effective treatment strategy for AD. Our overall objective is to develop and validate a new proprietary class of anti‐amyloidogenic molecules to impede the formation of Aβ toxic oligomers. The specific aims of our research are 1) to provide a relevant library of small molecules, 2) to identify the key chemical moieties driving their effect in interfering with oligomer formation (structure‐activity relationship). The potency of at least three different series of small molecules to reduce the formation of amyloid fibrils and toxic oligomers was assessed in vitrousing biophysical methods such as Thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM). Based on the screening of 30 newly synthesized molecules, we discovered KN‐21‐48 and MO‐19‐49 as amyloid inhibitors of Aβ1‐40. A preliminary structure‐activity relationship study indicates that compounds KN‐21‐48 and MO‐19‐49 can serve as a scaffold for further modifications in the design of more potent novel small molecules targeting amyloidogenesis in AD. This project may lead to a better understanding of AD by providing a model compound that may confirm or deny the role of amyloidosis in disease progression.

Bioengineered microglia-targeted exosomes facilitate Aβ clearance via enhancing activity of microglial lysosome for promoting cognitive recovery in Alzheimer's disease.

Aggregation of amyloid in the form of senile plaques is currently considered to be one of the main mechanisms driving the development of Alzheimer's disease (AD). Therefore, targeting amyloid homeostasis is an important treatment strategy for AD. Microglia, as the main immune cells, contribute to endocytosis and clearance of amyloid beta (Aβ) via lysosome mediated degradation. As abnormal lysosomal function in microglia is associated with inefficient clearance of Aβ in AD, we designed bioengineered microglia-targeting exosomes to promote the targeted delivery of gemfibrozil (Gem) and restore the lysosomal activity of microglia in clearing Aβ aggregation. Our results suggested that mannose-modified exosomes laden with Gem (MExo-Gem) can not only bind with Aβ but also specifically target microglia through the interaction between Exo-delivered mannose and mannose receptors expressed in microglia, thus promoting Aβ entry into microglia. Exosomal Gem activated lysosomal activity and accelerated lysosome-mediated clearance of Aβ in microglia. Finally, MExo-Gem improved the learning and memory ability of AD model mice.

Claudin-5 relieves cognitive decline in Alzheimer's disease mice through suppression of inhibitory GABAergic neurotransmission.

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, which is considered as the most common form of dementia in the elderly. Recently, it is suggested that impaired cerebrovascular function may precede the onset of AD. Claudin-5, which is the most enriched tight junction protein, has been reported to prevent the passage of damaging material at the blood-brain barrier. However, whether claudin-5 impacts AD has no direct evidence. We found a decrease level of claudin-5 in the hippocampus of AD and elder mice. And intravenous injection of claudin-5 improved learning and memory ability in these mice, while knockout of the protein led to impaired learning and memory and long-term potentiation in adult control mice. Furthermore, the effects of claudin-5 are mediated by suppressing inhibitory GABAergic neurotransmission. Our results suggest benefit effects of claudin-5 on learning and memory, which may provide a new treatment strategy for AD.