Amyloid Beta Dynamics in Biological Fluids—Therapeutic Impact

Despite the significant impact of Alzheimer’s disease (AD) at individual and socioeconomic levels and the numerous research studies carried out on this topic over the last decades, the treatments available in daily clinical practice remain less than satisfactory. Among the accepted etiopathogenic hypotheses, the amyloidogenic pathway theory, although intensively studied and even sometimes controversial, is still providing relevant theoretical elements for understanding the etiology of AD and for the further development of possible therapeutic tools. In this sense, this review aims to offer new insights related to beta amyloid (Aβ), an essential biomarker in AD. First the structure and function of Aβ in normal and pathological conditions are presented in detail, followed by a discussion on the dynamics of Aβ at the level of different biological compartments. There is focus on Aβ elimination modalities at central nervous system (CNS) level, and clearance via the blood–brain barrier seems to play a crucial/dominant role. Finally, different theoretical and already-applied therapeutic approaches for CNS Aβ elimination are presented, including the recent “peripheral sink therapeutic strategy” and “cerebrospinal fluid sinks therapeutic strategy”. These data outline the need for a multidisciplinary approach designed to deliver a solution to stimulate Aβ clearance in more direct ways, including from the cerebrospinal fluid level.

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Neural Transplantation

Cell Transplantation ◽

10.1177/096368979500400410 ◽

1995 ◽

Vol 4 (4) ◽

pp. 393-400 ◽

Cited By ~ 17

Author(s):

Olle Lindvall

Keyword(s):

Cell Transplantation ◽

Therapeutic Strategy ◽

Symptomatic Relief ◽

Animal Experiments ◽

Research Field ◽

Term Survival ◽

Demyelinating Disorders ◽

And Function ◽

Further Development

Cell transplantation is now being explored as a new therapeutic strategy to restore function in the diseased human central nervous system. Neural grafts show long-term survival and function in patients with Parkinson's disease but the symptomatic relief needs to be increased. Cell transplantation seems justified in patients with Huntington's disease and, at a later stage, possibly also in demyelinating disorders. The further development in this research field will require systematic studies in animal experiments but also well-designed clinical trials in small groups of patients.

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Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice

Alzheimer s Research & Therapy ◽

10.1186/s13195-019-0556-2 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 4

Author(s):

Hayk Davtyan ◽

Armine Hovakimyan ◽

Sepideh Kiani Shabestari ◽

Tatevik Antonyan ◽

Morgan A. Coburn ◽

...

Keyword(s):

Neurofibrillary Tangles ◽

Senile Plaques ◽

Hyperphosphorylated Tau ◽

Therapeutic Approaches ◽

Meso Scale Discovery ◽

Antibody Titers ◽

Amyloid Aβ ◽

And Control ◽

Epitope Vaccines ◽

Further Development

Abstract Background Alzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aβ or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aβ and tau might be needed for effective disease modification. Methods A combinatorial vaccination approach was designed to concurrently target both Aβ and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aβ and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aβ and tau, respectively, and formulated in AdvaxCpG, a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays. Results T5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of bigenic T5x mice. Conclusions AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD.

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Interactions between Gut Microbiota and Immunomodulatory Cells in Rheumatoid Arthritis

Mediators of Inflammation ◽

10.1155/2020/1430605 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Huihui Xu ◽

Hongyan Zhao ◽

Danping Fan ◽

Meijie Liu ◽

Jinfeng Cao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gut Microbiota ◽

Critical Role ◽

Host Immune System ◽

Therapeutic Approaches ◽

Commensal Microbiota ◽

And Function ◽

Further Development ◽

Gut Microbiota Dysbiosis ◽

Normal Immune Function

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases caused by abnormal immune activation and immune tolerance. Immunomodulatory cells (ICs) play a critical role in the maintenance and homeostasis of normal immune function and in the pathogenesis of RA. The human gastrointestinal tract is inhabited by trillions of commensal microbiota on the mucosal surface that play a fundamental role in the induction, maintenance, and function of the host immune system. Gut microbiota dysbiosis can impact both the local and systemic immune systems and further contribute to various diseases, such as RA. The neighbouring intestinal ICs located in distinct intestinal mucosa may be the most likely intermediary by which the gut microbiota can affect the occurrence and development of RA. However, the reciprocal interaction between the components of the gut microbiota and their microbial metabolites with distinct ICs and how this interaction may impact the development of RA are not well studied. Therefore, a better understanding of the gut microbiota, ICs, and their interactions might improve our knowledge of the mechanisms by which the gut microbiota contribute to RA and facilitate the further development of novel therapeutic approaches. In this review, we have summarized the roles of the gut microbiota in the immunopathogenesis of RA, especially the interactions between the gut microbiota and ICs, and further discussed the strategies for treating RA by targeting/regulating the gut microbiota.

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Solid-phase structures of cerebrospinal fluid in diagnosis of early asymptomatic neurosyphilis

Nauchno-prakticheskii zhurnal «Patogenez» ◽

10.25557/gm.2018.4.9750 ◽

2018 ◽

pp. 56-61

Author(s):

С.Н. Шатохина ◽

Н.А. Кузнецова ◽

В.Н. Шабалин

Keyword(s):

Cerebrospinal Fluid ◽

Visual Analysis ◽

Solid Phase ◽

Biological Fluids ◽

Laboratory Methods ◽

Phase Structures ◽

Morphological Picture ◽

Diagnostic Technology

Цель проведённого исследования состояла в оценке эффективности визуального анализа твёрдофазных структур спинномозговой жидкости для диагностики ранних форм нейросифилиса. Методы. Использован метод краевой дегидратации биологических жидкостей, входящий в состав авторской диагностической технологии «Литос-система». Диагностика раннего асимптомного нейросифилиса заключается в выявлении деструктивных образований в форме овалов в морфологической картине твёрдой фазы спинномозговой жидкости. Результаты. Проведён сравнительный анализ результатов исследования спинномозговой жидкости у 19 больных с подтверждённым диагнозом «ранний асимптомный нейросифилис», полученных традиционными лабораторными методами и методом краевой дегидратации. Выявлено, что локализация овалов внутри сферолитов указывает на длительность заболевания нейросифилисом менее трёх лет, а вне сферолитов - от трех до пяти лет. Заключение. Метод краевой дегидратации позволяет диагностировать ранний асимптомный нейросифилис по наличию деструктивных образований в форме овалов в морфологической картине твёрдой фазы спинномозговой жидкости. The aim of this study was to evaluate effectiveness of visual analysis of solid-phase structures in cerebrospinal fluid to diagnose early forms of neurosyphilis. Methods. We used a method of marginal dehydration of biological fluids as a part of the author’s diagnostic technology, Litos-System. Early asymptomatic neurosyphilis is diagnosed based on detection of destructive, oval-shaped formations in the morphological picture of cerebrospinal fluid solid phase. Results. Data from analyses of cerebrospinal fluid performed with traditional laboratory methods and the method of marginal dehydration were compared for 19 patients with documented diagnosis of early asymptomatic neurosyphilis. A localization of ovals within spherulites indicated a less than a three-year duration of neurosyphilis while a localization outside spherulites indicated a duration of three to five years. Conclusion. The method of marginal dehydration allows detecting early asymptomatic neurosyphilis based on the presence of destructive, oval-shaped formations in the morphological picture of cerebrospinal fluid solid phase.

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ctDNA-Based Liquid Biopsy of Cerebrospinal Fluid in Brain Cancer

Cancers ◽

10.3390/cancers13091989 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1989

Author(s):

Laura Escudero ◽

Francisco Martínez-Ricarte ◽

Joan Seoane

Keyword(s):

Cerebrospinal Fluid ◽

Brain Cancer ◽

Liquid Biopsy ◽

Therapeutic Strategy ◽

Residual Disease ◽

Imaging Techniques ◽

Prognostic Information ◽

Tumour Heterogeneity ◽

Diagnosis And Prognosis ◽

Cns Malignancies

The correct characterisation of central nervous system (CNS) malignancies is crucial for accurate diagnosis and prognosis and also the identification of actionable genomic alterations that can guide the therapeutic strategy. Surgical biopsies are performed to characterise the tumour; however, these procedures are invasive and are not always feasible for all patients. Moreover, they only provide a static snapshot and can miss tumour heterogeneity. Currently, monitoring of CNS cancer is performed by conventional imaging techniques and, in some cases, cytology analysis of the cerebrospinal fluid (CSF); however, these techniques have limited sensitivity. To overcome these limitations, a liquid biopsy of the CSF can be used to obtain information about the tumour in a less invasive manner. The CSF is a source of cell-free circulating tumour DNA (ctDNA), and the analysis of this biomarker can characterise and monitor brain cancer. Recent studies have shown that ctDNA is more abundant in the CSF than plasma for CNS malignancies and that it can be sequenced to reveal tumour heterogeneity and provide diagnostic and prognostic information. Furthermore, analysis of longitudinal samples can aid patient monitoring by detecting residual disease or even tracking tumour evolution at relapse and, therefore, tailoring the therapeutic strategy. In this review, we provide an overview of the potential clinical applications of the analysis of CSF ctDNA and the challenges that need to be overcome in order to translate research findings into a tool for clinical practice.

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Sialic Acid—Modified Nanoparticles—New Approaches in the Glioma Management—Perspective Review

International Journal of Molecular Sciences ◽

10.3390/ijms22147494 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7494

Author(s):

Przemyslaw Wielgat ◽

Katarzyna Niemirowicz-Laskowska ◽

Agnieszka Z. Wilczewska ◽

Halina Car

Keyword(s):

Sialic Acid ◽

Clinical Observation ◽

Malignant Cell ◽

Cellular Heterogeneity ◽

Molecular Processes ◽

Management Perspective ◽

Therapeutic Tools ◽

And Function ◽

Worse Prognosis

The cell surface is covered by a dense and complex network of glycans attached to the membrane proteins and lipids. In gliomas, the aberrant sialylation, as the final stage of glycosylation, is an important regulatory mechanism of malignant cell behavior and correlates with worse prognosis. Better understanding of the role of sialylation in cellular and molecular processes opens a new way in the development of therapeutic tools for human brain tumors. According to the recent clinical observation, the cellular heterogeneity, activity of brain cancer stem cells (BCSCs), immune evasion, and function of the blood–brain barrier (BBB) are attractive targets for new therapeutic strategies. In this review, we summarize the importance of sialic acid-modified nanoparticles in brain tumor progression.

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Relationship between the Geotourism Potential and Function in the Polish Part of the Roztocze Transboundary Biosphere Reserve

Geosciences ◽

10.3390/geosciences11030120 ◽

2021 ◽

Vol 11 (3) ◽

pp. 120

Author(s):

Teresa Brzezińska-Wójcik

Keyword(s):

Sustainable Development ◽

Biosphere Reserve ◽

The Other ◽

Partial Indices ◽

Function Index ◽

Intensive Exploitation ◽

Potential Indicator ◽

Current Product ◽

And Function ◽

Further Development

The Polish part of the Roztocze Transboundary Biosphere Reserve area is characterized by diversified geotourism resources with relatively high value. However, their potential seems not to be fully used in the current product offer. The aim of the study was therefore to assess the spatial variability of the geotourism potential and function and to determine their interrelations in view of further development of geotourism in the Roztocze TBR and the perspective of creation of the “Kamienny Las na Roztoczu” geopark. The study was carried out with the use of the taxonomic method of multidimensional comparative analysis consisting of calculation and analysis of general, total, and partial indices of the geotourism potential and function in 22 communes. The results showed the highest total indicator of geotourism potential in two communes, i.e. Józefów and Krasnobród, and the highest value of the total geotourism function index in Krasnobród. The results of the analysis of the relationships between the geotourism potential and function indicate that the geotourism resources and products are fully used in terms of the development of the function only in Krasnobród commune. In turn, the value of the total geotourism function index in the Zwierzyniec commune exceeds the geotourism potential indicator, which implies that this area is overloaded by tourist movement. The total indicators of geotourism potential in the other communes, especially Józefów, Krasnobród, Lubycza Królewska, and Susiec, indicate the possibility of more intensive exploitation of geotourism resources in preparation of interesting products in compliance with the principles of sustainable development and, consequently, the development of the geotourism function.

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Chronic Inflammation and Radiation-Induced Cystitis: Molecular Background and Therapeutic Perspectives

Cells ◽

10.3390/cells10010021 ◽

2020 ◽

Vol 10 (1) ◽

pp. 21

Author(s):

Carole Helissey ◽

Sophie Cavallero ◽

Clément Brossard ◽

Marie Dusaud ◽

Cyrus Chargari ◽

...

Keyword(s):

Stromal Cells ◽

Therapeutic Strategy ◽

Randomized Trials ◽

Clinical Presentation ◽

Therapeutic Approaches ◽

Radiation Cystitis ◽

Fibrotic Process ◽

Radiation Induced ◽

Therapeutic Irradiation ◽

Underlying Pathophysiology

Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers. Its clinical management remains unclear, and few preclinical data are available on its underlying pathophysiology. The therapeutic strategy is difficult to establish because few prospective and randomized trials are available. In this review, we report on the clinical presentation and pathophysiology of radiation cystitis. Then we discuss potential therapeutic approaches, with a focus on the immunopathological processes underlying the onset of radiation cystitis, including the fibrotic process. Potential therapeutic avenues for therapeutic modulation will be highlighted, with a focus on the interaction between mesenchymal stromal cells and macrophages for the prevention and treatment of radiation cystitis.

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Endothelium as a Source and Target of H2S to Improve Its Trophism and Function

Antioxidants ◽

10.3390/antiox10030486 ◽

2021 ◽

Vol 10 (3) ◽

pp. 486

Author(s):

Valerio Ciccone ◽

Shirley Genah ◽

Lucia Morbidelli

Keyword(s):

Endothelial Dysfunction ◽

Vessel Wall ◽

Redox Reactions ◽

Single Layer ◽

Fine Tuning ◽

Therapeutic Approaches ◽

Impaired Wound Healing ◽

Blood Fluidity ◽

And Function ◽

And Control

The vascular endothelium consists of a single layer of squamous endothelial cells (ECs) lining the inner surface of blood vessels. Nowadays, it is no longer considered as a simple barrier between the blood and vessel wall, but a central hub to control blood flow homeostasis and fulfill tissue metabolic demands by furnishing oxygen and nutrients. The endothelium regulates the proper functioning of vessels and microcirculation, in terms of tone control, blood fluidity, and fine tuning of inflammatory and redox reactions within the vessel wall and in surrounding tissues. This multiplicity of effects is due to the ability of ECs to produce, process, and release key modulators. Among these, gasotransmitters such as nitric oxide (NO) and hydrogen sulfide (H2S) are very active molecules constitutively produced by endotheliocytes for the maintenance and control of vascular physiological functions, while their impairment is responsible for endothelial dysfunction and cardiovascular disorders such as hypertension, atherosclerosis, and impaired wound healing and vascularization due to diabetes, infections, and ischemia. Upregulation of H2S producing enzymes and administration of H2S donors can be considered as innovative therapeutic approaches to improve EC biology and function, to revert endothelial dysfunction or to prevent cardiovascular disease progression. This review will focus on the beneficial autocrine/paracrine properties of H2S on ECs and the state of the art on H2S potentiating drugs and tools.

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Flavonoids in Skin Senescence Prevention and Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms22136814 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6814

Author(s):

Anna Domaszewska-Szostek ◽

Monika Puzianowska-Kuźnicka ◽

Alina Kuryłowicz

Keyword(s):

Therapeutic Strategy ◽

Cancer Susceptibility ◽

Skin Aging ◽

Structure And Function ◽

Tissue Structure ◽

Delayed Wound Healing ◽

Secretory Phenotype ◽

Cellular Pathways ◽

And Function ◽

Increased Susceptibility

Skin aging is associated with the accumulation of senescent cells and is related to many pathological changes, including decreased protection against pathogens, increased susceptibility to irritation, delayed wound healing, and increased cancer susceptibility. Senescent cells secrete a specific set of pro-inflammatory mediators, referred to as a senescence-associated secretory phenotype (SASP), which can cause profound changes in tissue structure and function. Thus, drugs that selectively eliminate senescent cells (senolytics) or neutralize SASP (senostatics) represent an attractive therapeutic strategy for age-associated skin deterioration. There is growing evidence that plant-derived compounds (flavonoids) can slow down or even prevent aging-associated deterioration of skin appearance and function by targeting cellular pathways crucial for regulating cellular senescence and SASP. This review summarizes the senostatic and senolytic potential of flavonoids in the context of preventing skin aging.

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