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Staging β-Amyloid Pathology With Amyloid Positron Emission Tomography.

IMPORTANCE: Different brain regions appear to be involved during β-amyloid (Aβ) accumulation in Alzheimer disease (AD), but a longitudinally valid system to track Aβ stages in vivo using positron emission tomography (PET) is lacking. OBJECTIVE: To construct a longitudinally valid in vivo staging system for AD using amyloid PET. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal multicenter cohort study using data accessed on August 20, 2018, from the Alzheimer's Disease Neuroimaging Initiative database of scans performed from June 9, 2010, to July 12, 2018, from 741 persons: 304 without cogniti

Harpagoside attenuates MPTP/MPP⁺ induced dopaminergic neurodegeneration and movement disorder via elevating glial cell line-derived neurotrophic factor.

Parkinson's disease is a chronic neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. New therapeutic approaches aiming at delaying or reversing the neurodegenerative process are under active investigations. In this work, we found that harpagoside, an iridoid purified from the Chinese medicinal herb Scrophularia ningpoensis, could not only prevent but also rescue the dopaminergic neurodegeneration in MPTP/MPP(+) intoxication with promising efficacy. Firstly, in cultured mesencephalic neurons, harpagoside significantly atte

Toll-Like Receptor 2, Toll-Like Receptor 4, Myeloid Differentiation Response Gene 88, and Toll-IL-1 Receptor Domain-Containing Adaptor-Inducing Interferon-γ (TRIF) Selectively Regulate Susceptibility of P0106-125-Induced Murine Experimental Autoimmune Neuritis.

The functional relevance of the innate immune system has not yet been dissected in P0106-125-induced murine experimental autoimmune neuritis. Therefore, the role of Toll-like receptor (TLR) 2, TLR4, myeloid differentiation response gene 88, and Toll-IL-1 receptor domain-containing adaptor-inducing interferon-γ (TRIF), factors critically involved in the TLR signaling pathway, was studied in experimental autoimmune neuritis. In the absence of TLR2, TLR4, myeloid differentiation response gene 88, or TRIF, the clinical course was significantly attenuated compared to wild-type mice. This could be a

Mobilization of calcium from intracellular stores facilitates somatodendritic dopamine release.

Somatodendritic dopamine (DA) release in the substantia nigra pars compacta (SNc) shows a limited dependence on extracellular calcium concentration ([Ca(2+)](o)), suggesting the involvement of intracellular Ca(2+) stores. Here, using immunocytochemistry we demonstrate the presence of the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) that sequesters cytosolic Ca(2+) into the endoplasmic reticulum (ER), as well as inositol 1,4,5-triphosphate receptors (IP(3)Rs) and ryanodine receptors (RyRs) in DAergic neurons. Notably, RyRs were clustered at the plasma membrane, poised for activat

Tropical spastic paraparesis and HTLV-1 associated myelopathy: clinical, epidemiological, virological and therapeutic aspects.

In 1980, Human T cell leukemia/lymphoma virus type 1 (HTLV-1) was the first oncogenic human retrovirus to be discovered. HTLV-1 belongs to the Retroviridae family, the Orthoretrovirinae subfamily and to the deltaretrovirus genus. HTLV-1 preferentially infects CD4(+) lymphoid cells in vivo. Three molecules have been identified for binding and/or entry of HTLV-1: heparan sulfate proteoglycans, neuropilin-1, and glucose transporter 1. An efficient transfer of the virus from an infected cell to a target cell can occur through the formation of a viral synapse and/or by virofilm structure. As for al

[New insights into the pathogenesis of glaucomatous optic neuropathy and refinement of the objective assessment of its functional damage].

Glaucomatous optic neuropathy is a primary pathological condition responsible for visual dysfunction due to glaucoma. However, how intraocular pressure and other risk factors lead to glaucomatous optic neuropathy is not fully understood. Given that static or kinetic visual field tests for evaluating visual dysfunction in glaucomatous optic neuropathy are a subjective assessments based on a psychophysical principle, the development of a tool for objective assessment of the visual field is needed. In this study, we attempt to elucidate the pathophysiology of glaucomatous optic neuropathy and to

Paclitaxel causes degeneration of both central and peripheral axon branches of dorsal root ganglia in mice.

BackgroundPeripheral neuropathy is a common and dose-limiting side effect of many cancer chemotherapies. The taxane agents, including paclitaxel (Taxol(®)), are effective chemotherapeutic drugs but cause degeneration of predominantly large myelinated afferent sensory fibers of the peripheral nervous system in humans and animal models. Dorsal root ganglia (DRG) neurons are sensory neurons that have unipolar axons each with two branches: peripheral and central. While taxane agents induce degeneration of peripheral axons, whether they also cause degeneration of central nervous system axons is not

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… Paclitaxel binds to microtubules and stabilizes them, which interferes with normal cellular function including cell division and microtubule-dependent intra-cellular and axonal transport [ 4 , 6 ]. … Microtubule-dependent transport is critical for axonal function and health, both in the central and peripheral nervous systems; as such, disruption of axonal transport is implicated in various central nervous system disorders and peripheral neuropathies [ 21 ]. …

Техническое обслуживание дисмиелинических небольших диаметровых аксонов 14-3-3s в центральной нервной системе.

В центральной нервной системе миелин, образующийся вокруг нервных аксонов олигодендроцитом, позволяет эффективно проводить потенциалы действий и поддерживает аксонный гомеостаз. Таким образом, в случае демиелинизирующих заболеваний, таких, как множественный склероз (MS), наблюдается аксональное дегенерация и потеря, особенно в аксонах малых диаметров. Teneurin-4 Недостатки (недостатки)Ten-4 -) Мыши демонстрируют сильное дисмиэлирование микродиаметровых аксонов, но выживают больше года. Здесь мы хотели прояснить механизм выживания аксонов малого диаметра без миелина с помощью Ten-4 - Мыши. Имму

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… APP forms a complex with kinesin‐I, a MT motor protein, and the deletion of the kinesin light chain, which possesses the binding domain to APP, decreased the axonal transport of APP (Kamal et al. 2000 ). … This likely induces an impairment of axonal transport of APP; thereby, disruption of the axonal transport leads to the accumulation of APP, which is detectable by immunohistochemistry, in the demyelination model with cuprizone (Rühling et al. 2019 ). …

Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy.

Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxid

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… Polymerization of Microtubules and Impairment of Axonal Transport Although bortezomib is known as a proteasome inhibitor, increased tubulin polymerization has been observed in both in vivo and in vitro models of BIPN [ 11 , 36 , 37 ]. … These alterations of intracellular tubulin dynamics may result in impairments of axonal transport. Indeed, bortezomib exposure decreased axonal transport of mitochondria and neurofilaments in culture models of DRG neurons [ 37 , 41 ]. …

Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN).

The mitochondrial dysfunction has a critical role in several disorders including chemotherapy-induced peripheral neuropathies (CIPN). This is due to a related dysregulation of pathways involving calcium signalling, reactive oxygen species and apoptosis. Vincristine is able to affect calcium movement through the Dorsal Root Ganglia (DRG) neuronal mitochondrial membrane, altering its homeostasis and leading to abnormal neuronal excitability. Paclitaxel induces the opening of the mitochondrial permeability transition pore in axons followed by mitochondrial membrane potential loss, increased react

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… Moreover, the authors showed that, as a consequence, axonal transport was impaired as happened with antitubulinic chemotherapy [ 128 ]. … Reversible blockade of retrograde axonal transport in the rat sciatic nerve by vincristine J. Pharm. Pharmacol. 1997 49 97 101 10.1111/j.2042-7158.1997.tb06759.x 9120778 5. Theiss C. Meller K. …

Иммуноэксциотоксичность как возможная основная патофизиология, лежащая в основе множественного склероза и других аутоиммунных расстройств.

Аутоиммунные расстройства представляют собой разрушительные процессы, которые считаются атакой на «само» антигены иммунной системы CD+4 T-клеток, которые направлены на антигены, в случае множественного склероза (MS), особенно миелиновых антигенов. Тем не менее все больше фактов свидетельствует о том, что основные разрушительные явления в MS, а также другие аутоиммунные расстройства нецентральной нервной системы (КНС) представляют собой гораздо больше, чем иммунную атаку на CNS, вызванную неправильно управляемой иммунной системой, которая нападает на « само » антиген или антигены в результате п

Chemotherapy-induced peripheral neuropathy in adults: a comprehensive update of the literature.

Commonly used chemotherapeutic agents in oncology/hematology practice, causing toxic peripheral neuropathy, include taxanes, platinum compounds, vinca alkaloids, proteasome inhibitors, and antiangiogenic/immunomodulatory agents. This review paper intends to put together and discuss the spectrum of chemotherapy-induced peripheral neuropathy (CIPN) characteristics so as to highlight areas of future research to pursue on the topic. Current knowledge shows that the pathogenesis of CIPN still remains elusive, mostly because there are several sites of involvement in the peripheral nervous system. In

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… and neuronal bodies, or disturbed axonal transport changes in the affected neurons. 19 , 20 Recent evidence shows that the activation of spinal astrocytes and the inhibition of microtubule-based fast axonal transport may al so be significant contributors to TIPN. 21 The structure of internodal myelin … Morphological evidence of the inhibitory effect of taxol on the fast axonal transport. Neurosci Res. 1999;35(2):113–122. doi: 10.1016/s0168-0102(99)00074-7. 46. Theiss C, Meller K. …

An Overview of Bortezomib-Induced Neurotoxicity.

The boronic acid dipeptide bortezomib, able to induce tumor cell death by degradation of key proteins, is the first proteasome inhibitor drug to enter clinical practice. It is employed as first-line treatment in relapsed or resistant multiple myeloma (MM) patients. However, bortezomib often induces a dose-limiting toxicity in the form of painful sensory neuropathy, which can mainly be reduced by subcutaneous administration or dose modification. In this review we focus on the current understanding of the pathophysiological mechanisms of bortezomib-induced neuropathy to allow further studies in

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… Several preclinical studies suggest that the disruption of axonal transport processes by microtubule dynamics alteration is another possible neurotoxicity mechanism. … transport [ 45 ]. …

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating t

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… Impaired axonal transport of essential cellular components [ 151 , 153 ] and mRNA [ 154 ] to distal neuronal parts due to microtubule disruption may have a significant impact on this process. … Moreover, the inhibition of polymerization into microtubules inhibits axonal transport, which leads to distal axonopathy. …

Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN).

Chemotherapy induced peripheral neuropathy (CIPN) is a type of neuropathic pain that is a major dose-limiting side-effect of potentially curative cancer chemotherapy treatment regimens that develops in a "stocking and glove" distribution. When pain is severe, a change to less effective chemotherapy agents may be required, or patients may choose to discontinue treatment. Medications used to alleviate CIPN often lack efficacy and/or have unacceptable side-effects. Hence the unmet medical need for novel analgesics for relief of this painful condition has driven establishment of rodent models of C

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… Antitubulins (paclitaxel, docetaxel and vincristine) bind to microtubules, interrupt axonal transport, target the soma of sensory neurons as well as nerve axons, to induce neuronal death (Bennett, 2010 ; Cavaletti and Marmiroli, 2010 ; Velasco and Bruna, 2010 ). …

Bortezomib-induced peripheral neuropathy: from molecular mechanisms to clinical management.

Bortezomib (BTZ) is a first-generation proteasome inhibitor that has shown significant efficacy in the treatment of multiple myeloma (MM), providing significant therapeutic benefits without severely compromising overall patient health. However, one of the most common and debilitating side effects associated with BTZ therapy is bortezomib-induced peripheral neuropathy (BIPN). This condition is the leading complication observed in patients undergoing BTZ treatment and has a profound impact on treatment regimens, often necessitating dose reductions or alterations in the dosing schedule. Despite t

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… BTZ-treated animals have been shown to exhibit mitochondrial dysfunction, including respiratory chain damage, reduced adenosine triphosphate (ATP) production, and decreased manganese superoxide dismutase (MnSOD) activity, which leads to ATP depletion and impairs energy-dependent axonal transport. …

Exploring Human Brain Metabolism via Genome-Scale Metabolic Modeling with Highlights on Multiple Sclerosis.

Cerebral dysfunctions give rise to a wide range of neurological diseases due to the structural and functional complexity of the human brain stemming from the interactive cellular metabolism of its specific cells, including neurons and glial cells. In parallel with advances in isolation and measurement technologies, genome-scale metabolic models (GEMs) have become a powerful tool in the studies of systems biology to provide critical insights into the understanding of sophisticated eukaryotic systems. In this study, brain cell-specific GEMs were reconstructed for neurons, astrocytes, microglia,

Связь между окисляющим стрессом, митохондриальной дисфункцией, железным метаболизмом и микроглией в множестве склерозов: обзор нарации.

В последние годы в патогенезе множественного склероза особое внимание уделяется митохондриальным процессам, влияющим на начало заболевания. Окисляющий стресс будет одним из последствий митохондриальной дисфункции, и его воздействие на ткани мозга хорошо описано. Микроглия, как макрофаж мозга, имеет важную функцию в удалении нежелательных метаболитов, а также железа, который является усилителем окислительного стресса. Существуют новшества с точки зрения связи между этими процессами, которые в большей степени перенаправляют исследования на сам процесс нейродегенерации, с тем чтобы больше не дела

Cellular Pathogenesis of Chemotherapy-Induced Peripheral Neuropathy: Insights From Drosophila and Human-Engineered Skin Models.

Chemotherapy-induced peripheral neuropathy (CIPN) is a highly prevalent and complex condition arising from chemotherapy cancer treatments. Currently, there are no treatment or prevention options in the clinic. CIPN accompanies pain-related sensory functions starting from the hands and feet. Studies focusing on neurons in vitro and in vivo models significantly advanced our understanding of CIPN pathological mechanisms. However, given the direct toxicity shown in both neurons and non-neuronal cells, effective in vivo or in vitro models that allow the investigation of neurons in their local envir

Эпигенетика и метаболическая метаболическая дисфункция при многоразовом склерозе: обзор подходов к травяным лекарствам и текущих клинических испытаний.

Множественный склероз (MS) — сложная аутоиммунная болезнь, характеризующаяся воспалением, обезвоживанием и нейродегенерацией в центральной нервной системе (КНС). Хотя точные причины остаются неясными, недавние исследования подчеркивают важную роль эпигенетических изменений и митохондриальной дисфункции в начале и развитии болезни. Эпигенетические изменения, такие, как метилация ДНК, модификация гистона и регулирование микроРНК, влияют на генное выражение, не изменяя последовательности ДНК, что приводит к иммунной дисрегуляции и воспалению. Аналогичным образом, митохондриальная дисфункция, отме

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… Energy failure and oxidative stress within the damaged brain tissue are made worse by the existence of defective mitochondria, which are characterised by reduced axonal transport, susceptibility to oxidative damage, and mutations in mitochondrial DNA [ 31 ]. …