Treatment Of Abstract Alzheimer's Disease Research Articles

Yeni Tiyazolil-Hidrazin Türevlerinin Sentezi ve Asetilkolinesteraz (AChE) ve Bütirilkolinesteraz (BuChE) Aktivite Çalışmaları

Alzheimer hastalığı (AH), zamanla beyin hücrelerinin ölümüne bağlı olarak bilişsel işlevlerde azalma, hafıza kaybı ve bunama ile ilişkilendirilmiştir. Alzheimer hastalığının tedavisinde sınırlayıcı uygulamaların mevcut oluşu, hastalığın sağlık harcamalarında kanser ve kalp hastalıklardan sonra dünyada üçüncü sırada oluşu araştırmacıları AH üzerinde erken evrede tanıma ve yeni tedavi yöntemlerine yönlendirmektedir. Günümüzde kolinerjik anomalikler ile AH arasında doğrudan bir ilişki olduğu düşünülmektedir. Çalışmalar, asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BuChE) inhibisyonunun asetilkolin (ACh) seviyesinde meydana gelen artışların Alzheimer hastalığının başlangıç evrelerindeki bilişsel yetmezliği iyileştirebileceğini kanıtlamıştır. Dolayısıyla ACh düzeylerini arttırmak için uygulanacak en iyi metot ise, ACh’yi yıkan AChE veya BuChE enzimlerinin baskılanmasıdır. Dolayısıyla yapılan bu çalışmada, sübstitüe edilmiş tiyazolilhidrazin türevleri tasarlanmış, sentezlenmiş ve AH’ ye karşı asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BuChE) kolinesteraz enzimlerinin inhibisyon potansiyelleri araştırılmıştır. Hedef bileşiklerin yapıları 1H NMR/13C NMR analiz yöntemleri ile aydınlatılmıştır. Hedef bileşiklerin AChE ve BuChE enzimleri üzerindeki inhibisyon etkileri Ellman yöntemiile değerlendirilmiş ve hedef bileşiklerin enzim inhibisyon çalışmaları sonucunda 3d bileşiğinin orta düzeyde bütirilkolinesteraz enzimini inhibe ettiği tespit edilmiştir.

Tau Acts in Concert With Kinase/Phosphatase Underlying Synaptic Dysfunction.

Alzheimer's disease (AD) is characterized by two pathological features: neurofibrillary tangles (NFTs), formed by microtubule-associated protein tau, and abnormal accumulation of amyloid-β (Aβ). Multiple evidence placed synaptic tau as the vital fact of AD pathology, especially at the very early stage of AD. In the present review, we discuss tau phosphorylation, which is critical for the dendritic localization of tau and synaptic plasticity. We review the related kinases and phosphatases implicated in the synaptic function of tau. We also review the synergistic effects of these kinases and phosphatases on tau-associated synaptic deficits. We aim to open a new perspective on the treatment of AD.

Aduhelm, the Newly Approved Medication for Alzheimer Disease: What Epidemiologists Can Learn and What Epidemiology Can Offer.

Alzheimer disease (AD) is a progressive disorder common among older adults and culminating in profound cognitive impairments and high mortality risk. The US Food and Drug Administration (FDA) recently provided accelerated approval for Aduhelm, a medication for AD treatment. Aduhelm (Biogen Inc., Cambridge, Massachusetts) has been described as the first disease-modifying treatment for AD but has not been demonstrated to improve patients' cognitive or functional outcomes. In this commentary, we describe why Aduhelm approval was controversial and aspects of the current evidence of special pertinence to epidemiologists. The FDA decision was based primarily on 2 randomized controlled trials (RCTs), both terminated early, with conflicting findings about the cognitive benefits of Aduhelm. Both RCTs showed important adverse effects of the medication. The FDA cited the documented reduction in brain amyloid, an AD biomarker hypothesized as a surrogate outcome, to justify accelerated approval. Despite lack of racial/ethnic diversity in the RCT participants, concerns about health disparities have been invoked to argue for public funding of this expensive medication. The Centers for Medicare and Medicaid Services recently made a "Coverage with Evidence Development" determination for Aduhelm and similar medications. We end by describing how innovative study designs could accelerate postapproval research and evaluate the proposed surrogate outcomes.

Microglial activation in Alzheimer's disease: The role of flavonoids and microRNAs

Alzheimer's disease (AD) is the most common form of senile dementia and is characterized by progressive cognitive impairment and neuronal degeneration. Microglial activation is an important pathologic hallmark of AD. During disease progression, microglial cells switch from an alternative or anti-inflammatory and neuroprotective profile (M2) to a classic or proinflammatory and neurotoxic profile (M1). Phenotypically, M1 microglia is characterized by the activation of inflammatory signaling pathways that cause increased expression of proinflammatory genes, including those coding for cytokines and chemokines. This microglia-mediated neuroinflammation contributes to neuronal cell death. Recent studies in microglial cells have shown that a group of plant-derived compounds, known as flavonoids, possess anti-inflammatory properties and therefore exert a neuroprotective effect through regulating microglia activation. Here, we discuss how flavonoids can promote the switch from an inflammatory M1 phenotype to an anti-inflammatory M2 phenotype in microglia and how this represents a valuable opportunity for the development of novel therapeutic strategies to blunt neuroinflammation and boost neuronal recovery in AD. We also review how certain flavonoids can inhibit neuroinflammation through their action on the expression of microglia-specific microRNAs (miRNAs), which also constitute a key therapeutic approach in different neuropathologies involving an inflammatory component, including AD. Finally, we propose novel targets of microglia-specific miRNAs that may be considered for AD treatment.

Technological prospecting of music therapy in Alzheimer's disease

Alzheimer's disease (AD) is characterized by cognitive impairment and progressive memory loss and drug treatments have limited efficacy. Thus, non-pharmacological interventions, such as music therapy, have shown to be promising as supporting pharmacological treatment and, therefore, may arouse commercial interest regarding the development of this type of product. Thus, this study aims to carry out a patentometric survey on patent registrations with music therapy in the treatment of AD. A systematic search was carried out from 2000 to 2020 on the Orbti-Questel website, searching for documents referring to music therapies in AD. The terms “Alzheimer music methodology active therapy” and “Alzheimer music methodology passive therapy” were used. After searching, reading, and excluding duplicate results, we found four patent families referring to music therapy in AD and all were selected as a result, which was considered little compared to the number of studies published on the subject.

Hypermethylation of Mest promoter causes aberrant Wnt signaling in patients with Alzheimer\u2019s disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and behavioral changes. Extracellular deposition of amyloid plaques (Aβ) and intracellular deposition of neurofibrillary tangles in neurons are the major pathogenicities of AD. However, drugs targeting these therapeutic targets are not effective. Therefore, novel targets for the treatment of AD urgently need to be identified. Expression of the mesoderm-specific transcript (Mest) is regulated by genomic imprinting, where only the paternal allele is active for transcription. We identified hypermethylation on the Mest promoter, which led to a reduction in Mest mRNA levels and activation of Wnt signaling in brain tissues of AD patients. Mest knockout (KO) using the CRIPSR/Cas9 system in mouse embryonic stem cells and P19 embryonic carcinoma cells leads to neuronal differentiation arrest. Depletion of Mest in primary hippocampal neurons via lentivirus expressing shMest or inducible KO system causes neurodegeneration. Notably, depletion of Mest in primary cortical neurons of rats leads to tau phosphorylation at the S199 and T231 sites. Overall, our data suggest that hypermethylation of the Mest promoter may cause or facilitate the progression of AD.

Targeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates.

Alzheimer's disease (AD), the most prevalent form of dementia, remains incurable mainly due to our failings in the search for effective pharmacological strategies. Here, we describe the development of targeted multimodal polypeptide-based nanoconjugates as potential AD treatments. Treatment with polypeptide nanoconjugates bearing propargylamine moieties and bisdemethoxycurcumin or genistein afforded neuroprotection and displayed neurotrophic effects, as evidenced by an increase in dendritic density of pyramidal neurons in organotypic hippocampal culture. The additional conjugation of the Angiopep-2 targeting moiety enhanced nanoconjugate passage through the blood-brain barrier and modulated brain distribution with nanoconjugate accumulation in neurogenic areas, including the olfactory bulb. Nanoconjugate treatment effectively reduced neurotoxic β amyloid aggregate levels and rescued impairments to olfactory memory and object recognition in APP/PS1 transgenic AD model mice. Overall, this study provides a description of a targeted multimodal polyglutamate-based nanoconjugate with neuroprotective and neurotrophic potential for AD treatment.

An update on the pathophysiology and pharmacology of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Plaques and tangles are described as the characteristic features of AD, which are neurotoxic entites, deposited in the diseased patients. There are very few drugs available for the treatment of AD. Those available options are primarily the approaches to overcome cholinergic hypofunction, through the inhibition of acetylcholinestrase enzyme. Other disease modifiying candidates are strongly needed to overcome the progressive dementia in AD. These new drugs will serve as a great hope for the AD patients and families of the AD patients.

Cornel Iridoid Glycoside Regulates Modification of Tau and Alleviates Synaptic Abnormalities in Aged P301S Mice

Alzheimer's disease (AD), also defined as a tauopathology, is a common neurodegenerative disease. Hyper-phosphorylation, cleavage or truncation, and aggregation of tau contribute to AD. Thus, targeting the post-translational modifications on tau may be a therapeutic strategy to treat AD. This study understood how cornel iridoid glycoside (CIG) affects tau post-translational modifications and synaptic abnormalities. The 10-month old P301S tau transgenic mice were given CIG at 100 and 200 mg/kg every day orally for 1 month. Hyperphosphorylated and truncated tau, synapse-associated proteins and glutamatergic receptors were all detected using Western blotting. The interactions between Morroniside (MOR) or Loganin (LOG) and tau were detected using Autodock and Surface Plasmon Resonance (SPR). The effects of CIG on the aggregation of tau were investigated using a cell-free system. CIG attenuated tau hyperphosphorylation at Thr205, Ser212, Ser262, Thr231 and Ser235 (AT180), but had no effect on tau truncation in the brains of 10-month old P301S mice. Binding free energies and interactions revealed that MOR and LOG bound with tau. We also found that CIG upregulated synapse-associated proteins such as PSD-95, syntaxin1A and synaptotagmin. In addition, CIG restored N-methyl-D-aspartic acid receptor and glutamate receptor levels. CIG improves post-translational modification of tau as well as synaptic abnormalities. The data presented here reveal that CIG may be used in the treatment of AD.

Neuromodulation for Cognitive Disorders: In Search of Lazarus?

Alzheimer's disease (AD) and other forms of dementia can have a large impact on patients, their families, and for the society as a whole. Current medical treatments have not shown enough potential in treating or altering the course of the disease. Deep brain stimulation (DBS) has shown great neuromodulatory potential in Parkinson's disease, and there is a growing body of evidence for justifying its use in cognitive disorders. At the same time there is mounting interest at less invasive and alternative modes of neuromodulation for the treatment of AD. This manuscript is a brief review of the infrastructure of memory, the current understanding of the pathophysiology of AD, and the body of preclinical and clinical evidence for noninvasive and invasive neuromodulation modalities for the treatment of cognitive disorders and AD in particular.

Targeting Aβ protein in Alzheimer's Disease

Alzheimer's disease (AD) is one of the most common causes of dementia in the society. Recent reports suggest that > 4.7 million people of ≧ 65 years of age are living with AD in the USA. AD is predicted to affect one in 85 people globally by 2050. The malfunctioning and gradual death of neurons in the disease results in loss of memory and cognitive functions. The disease is characterized by accelerated accumulation of amyloid β (Aβ) plaque around neurons and hyperphosphorylated microtubule associated tau protein in the form of neurofibrillary tangles within the cells. In this review, we have described and discussed the recent focus on therapeutic interventions targeting at various Aβ-associated pathological mechanisms of AD and experimental strategies focusing on Aβ which aim to decrease the production of the protein, prevent its aggregation or increase the removal of it from the brain. The β secretase is (the enzyme that initiates the generation of Aβ) an attractive drug target for lowering cerebral levels of APP for the treatment of AD. It was noted that that Aβ represents a potent molecular target for pharmacological manipulation to perhaps prevent the onset and progression of Alzheimer's disease.

Caterpillar Medicinal Mushroom, Cordyceps militaris (Ascomycetes), Protects Aβ1-42-Induced Neurologic Damage in C6 Glial Cells.

Alzheimer's disease (AD) shows neurological symptoms common to cognitive disorders and memory loss. Several hypotheses have suggested that the accumulation of amyloid-beta peptide (Aβ) and reduction of acetylcholine synthesis cause AD. Natural ingredients, such as Cordyceps militaris, have been widely used for AD treatment. Herein, we investigated the protective role of C. militaris against neural dysfunction. First, Aβ1-42 peptide solution was incubated at 37°C for 3 days for aggregation. Next, C6 glial cells were treated with 25 μM of Aβ1-42 solution, followed by the addition of C. militaris ethanol extract (0.5, 1, 1.25, and 2.5 μg/mL); the cell viability, reactive oxygen species (ROS) production, and protein expressions were then evaluated. Reduction of viability of, and ROS generation in, Aβ1-42-treated cells were observed and compared with those in the control group. The expression levels of inducible nitric oxide synthase and cyclooxygenase-2, as well as those of phospho-p38 mitogen-activated protein kinase and phospho-c-Jun N-terminal kinase, were reduced in C. militaris-treated glial cells. Moreover, the expression of brain-derived neurotrophic factor in the C. militaris-treated cells was significantly higher than that in the control group. Thus, our findings indicate that C. militaris has the potential to protect Aβ-induced neurological damage.

Does the Choice of Treatment of Diabetes Mellitus Change Natural Course of Alzheimer Disease?

Alzheimer disease (AD) is common worldwide and almost every case has comorbidities. One of the most common comorbidities of AD is Diabetes mellitus (DM), with or without metabolic syndrome. Both diseases effect nerve tissue and successful treatment would improve the status of the patient. In patients with Alzheimer disease treatment of DM, the treatment could be harmful to the AD, because of that high insulin intake. This may lead to progression of AD. Insulin is considered the best treatment for DM, but insulin therapy could increase comorbidity with AD. No specific therapy for AD is known up to date, so because of that DM is one of the most important risk for AD, concomitant therapy for DM should be planned very carefully. All options of DM therapy should be considered, and different mechanisms of anti-diabetic drugs are preferable. Treatment of AD is more complex metabolic syndrome is present. Any inflammation causes local tissue damage, including brain tissue during AD. Release of interleukins, primarily TNF-α, IL-6, IL-1β in the presence of adipokine leptin, maintains chronic inflammatory status in local brain tissue. Thus, low doses of immunosuppressant therapy should be considered for treatment of AD in future. To delay apoptosis of nerve tissue cells, brain and nerve tissue defend against free oxygen radicals and improve metabolic status.

TREM2 and the Progression of Alzheimer’s Disease

Alzheimer's disease (AD) is the most common form of dementia, which has been currently considered as a genetically complex disorder caused by a combination of environmental and genetic risk factors. Previous studies have reported that triggering receptor expressed on myeloid cells 2 (TREM2) gene represents a promising candidate gene for AD susceptibility and progression. Interestingly, recent findings further suggested that the association between TREM2 variants and AD risk was quite diverse among different ethnicities and populations. As a member of immunoglobulin superfamily, TREM2 protein suppresses inflammatory responses, mediates phagocytic pathways, and contributes to the homeostasis of neuroimmunity in the central nervous system. Emerging evidence has indicated that TREM2 was involved in AD-related neuropathology including amyloid-β deposition, tau hyperphosphorylation, neuroinflammation, and neuronal and synaptic losses in AD animal models, but the precise underlying mechanisms have not been fully characterized yet. Here, we reviewed the new epidemiological findings regarding the association of TREM2 with AD. Meanwhile, we summarized the recent updates about the biological functions of TREM2 and its role in AD pathogenesis. In addition, we also explored the potential TREM2- targeting therapies for AD treatment.

Paradigm shift from diagnosing patients based on common symptoms to categorizing patients into subtypes with different pathogenic mechanisms to guide treatment for Alzheimer's disease.

Alzheimer's disease (AD) is a major cause of dementia in the elderly, and the number of AD patients is rapidly growing as life expectancy increases. However, disease-modifying drugs are not yet available. According to the amyloid hypothesis, disease onset is triggered by aggregation and accumulation of amyloid-β peptide, followed by the formation of neurofibrillary tangles composed of hyperphosphorylated tau, and synaptic loss/neuronal cell death leading to dementia. Based on this hypothesis, various clinical trials for treatment of AD have been conducted, but most were discontinued due to failure to achieve cognitive improvement or appearance of adverse effects. Here we discuss the reasons for the failure of these trials. We suggest that biomarkers of specific, distinct molecular mechanisms of amyloidogenesis should be developed concomitantly with disease-modifying drugs (the so-called companion diagnosis) to aid the proper design of clinical trials, as well as to enable personalized treatment of individual AD patients.

FLZ attenuates learning and memory deficits via suppressing neuroinflammation induced by LPS in mice

Alzheimer's disease (AD) is the most common neurodegenerative disorder in which neuroinflammation plays an important role. FLZ is a novel synthetic derivative of natural squamosamide. Previous studies demonstrated that FLZ had neuroprotective effects on AD models and showed strong anti-inflammatory property in Parkinson's disease models. However, whether the neuroprotective effects of FLZ on AD are associated with its anti-inflammatory property is still not fully elucidated. In this study, we aimed to investigate the ability of FLZ in modulating inflammation. The results showed that FLZ significantly improved memory deficits and alleviated neuronal damage as well as neuronal loss in the hippocampus of mice intracerebroventricular injected with lipopolysaccharide (LPS). Mechanistic studies revealed that the neuroprotective effects of FLZ were due to the suppression of neuroinflammation induced by LPS, as indicated by inactivation of astrocytes and microglia, reduced production of tumor necrosis factor-α, interleukin-1β, and nitric oxide, as well as decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase. The beneficial effects of FLZ on AD were further supported by the finding that FLZ attenuated β-amyloid production through inhibiting β-amyloid precursor protein cleaving enzyme 1 expression. These results suggested that anti-inflammatory agent could be useful for the treatment of AD.

Preclinical and clinical issues in Alzheimer's disease drug research and development.

Preclinical and clinical issues in Alzheimer's disease drug research and development.

Aβ regulation-based multitarget strategy for drug discovery against Alzheimer's disease.

Alzheimer's disease (AD) is a progressively neurodegenerative disease that eventually leads to the irreversible loss of neurons and intellectual abilities, including cognition and memory. AD has become the most common cause of dementia in aged people, and the ill-defined pathogenesis of AD is seriously impeding the current drug discovery against this disease. To date, there is still a lack of etiologically therapeutic drugs for AD, although some symptomatic treatments have been successfully developed. The β-amyloid (Aβ)-induced neurodegeneration is determined as the main pathogenesis of AD, and by targeting the regulation of Aβ in production inhibition or clearance promotion, many active agents have been designed potentially for AD treatment, but no drug has yet been approved in clinical use. Actually, AD has a complex pathogenic mechanism that involves multiple aberrant signaling genes and pathways, and the idea of 'single target' for anti-AD drug research is thus full of challenges. Recently, with a deep understanding of AD pathogeneses and the development of advanced pharmacological techniques, 'multiple target'-based strategy has been widely applied for the drug discovery against this disease, and many promising results have been achieved. Here, we review the recent multitarget strategies for the drug discovery in the treatment of AD by focusing on the involvement of Aβ regulation.

L-3-n-Butylphthalide attenuates β-amyloid-induced toxicity in neuroblastoma SH-SY5Y cells through regulating mitochondrion-mediated apoptosis and MAPK signaling

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid-β protein (Aβ), the hallmark of AD, invokes a cascade of mitochondrial dysfunction and eventually leads to neuronal death. l-3-n-Butylphthalide (l-NBP) has shown the potent neuroprotective effects in stroke and AD animal models. The present study is to evaluate the neuroprotective effect of l-NBP on Aβ25–35-induced neuronal injury and the possible mechanism in the human neuroblastoma SH-SY5Y cells. Our results showed that l-NBP significantly attenuated Aβ25–35-induced cell death and reduced neuronal apoptosis. l-NBP significantly inhibited Aβ25–35-induced mitochondrial dysfunction, including mitochondrial membrane potential reduction, and reactive oxygen species production. Furthermore, l-NBP could partially reverse the elevations of Aβ25–35-induced active caspase-3, caspase-9, and cytochrome c expressions, and the downregulation of anti-apoptosis protein Bcl-2. Moreover, l-NBP markedly inhibited the activations of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase/stress-activated protein kinase signaling pathway. These results demonstrated that l-NBP was capable of protecting neuronal cells from Aβ25–35-induced toxicity through a mitochondrial-dependent apoptotic pathway. Thus, l-NBP shows promising candidate of multi-target neuronal protective agent for the treatment of AD.

Molecular Targeting and Translational Research for New Therapeutic Strategies on Alzheimer's Disease

Alzheimer's disease (AD) is the most common cause of dementia. AD treatments currently approved are commonly regarded as purely symptomatic. Therefore, development of effective disease modifying treatments is eagerly required. Pathological hallmarks of AD brain include amyloid-β (Aβ) accumulation, neurofibrillary tangle (NFT), synaptic loss, and neurodegeneration. Understanding of AD pathogenesis provides deep insight into the therapeutic approach for AD. In this review, we introduce our current translational researches for new therapeutic strategies against AD. We recently revealed that a key molecule for actin assembly, Wiscott-Aldrich syndrome protein family verprolin-homologous protein (WAVE), is accumulated into NFT in an Aβ pathology-dependent manner. Because synaptic function is maintained by precise regulation of actin assembly, abnormal accumulation of WAVE induced by Aβ pathology may expand the NFT pathology to synaptic dysfunction. These results imply that lowering of brain Aβ at the early stage of AD pathogenesis is a promising therapeutic approach. As the approach for the elimination of brain Aβ, we have studied microglial Aβ phagocytosis and proposed its therapeutic application for AD treatment. We demonstrated that anti-Aβ antibody and galantamine promote microglial Aβ phagocytosis by binding to Fc receptors and nicotinic acetylcholine receptors on microglia, respectively. On the other hand, we demonstrated that the transplantation with microglia effectively eliminate brain Aβ and microglia-like Aβ phagocytic cells were successfully prepared from bone marrow derived cells by the stimulation with macrophage colony-stimulating factor. Thus, we have studied cell therapeutic strategy aim at its clinical application for AD treatment by the activation of endogenous microglia and transplantation of exogenous microglia-like Aβ phagocytic cells.