المؤلفون: Alexa DeMaio, Shikhar Mehrotra, Kumar Sambamurti, Shahid Husain

المصدر: Journal of Neuroinflammation, Vol 19, Iss 1, Pp 1-19 (2022)

مصطلحات موضوعية: T cells, Neurodegeneration, Inflammation, Immune system, Lymphocytes, Neurology. Diseases of the nervous system, RC346-429

الوصف: Abstract The adaptive immune system and associated inflammation are vital in surveillance and host protection against internal and external threats, but can secondarily damage host tissues. The central nervous system is immune-privileged and largely protected from the circulating inflammatory pathways. However, T cell involvement and the disruption of the blood–brain barriers have been linked to several neurodegenerative diseases including Parkinson's disease, Alzheimer’s disease, and multiple sclerosis. Under normal physiological conditions, regulatory T cells (Treg cells) dampen the inflammatory response of effector T cells. In the pathological states of many neurodegenerative disorders, the ability of Treg cells to mitigate inflammation is reduced, and a pro-inflammatory environment persists. This perspective review provides current knowledge on the roles of T cell subsets (e.g., effector T cells, Treg cells) in neurodegenerative and ocular diseases, including uveitis, diabetic retinopathy, age-related macular degeneration, and glaucoma. Many neurodegenerative and ocular diseases have been linked to immune dysregulation, but the cellular events and molecular mechanisms involved in such processes remain largely unknown. Moreover, the role of T cells in ocular pathologies remains poorly defined and limited literature is available in this area of research. Adoptive transfer of Treg cells appears to be a vital immunological approach to control ocular pathologies. Similarities in T cell dysfunction seen among non-ocular neurodegenerative diseases suggest that this area of research has a great potential to develop better therapeutic agents for ocular diseases and warrants further studies. Overall, this perspective review article provides significant information on the roles of T cells in numerous ocular and non-ocular neurodegenerative diseases.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1742-2094Test

الوصول الحر: https://doaj.org/article/713435f6059747e6898a5f2d325c1dc0Test

المؤلفون: Burkhard Poeggeler, Sandeep Kumar Singh, Kumar Sambamurti, Miguel A. Pappolla

المصدر: International Journal of Molecular Sciences, Vol 24, Iss 19, p 14533 (2023)

مصطلحات موضوعية: aging, amino acids, antioxidant, arginine, nitric oxide, oxidative stress, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/24/19/14533Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/cb03961ab2544617a0da1ae3fa77dd10Test

المؤلفون: Burkhard Poeggeler, Sandeep Kumar Singh, Kumar Sambamurti, Miguel Angelo Pappolla

المصدر: International Journal of Molecular Sciences, Vol 24, Iss 8, p 7112 (2023)

مصطلحات موضوعية: n/a, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: This editorial summarizes the eight articles that have been collected for the Special Issue entitled “Tryptophan in Nutrition and Health 2 [...]

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/24/8/7112Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/fd414f5828d34bf19a6df9d83d4ce156Test

المؤلفون: Piyush Padhi, Carter Worth, Gary Zenitsky, Huajun Jin, Kumar Sambamurti, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G. Kanthasamy

المصدر: Frontiers in Neuroscience, Vol 16 (2022)

مصطلحات موضوعية: neurodegeneration, microbiome, neuroinflammation, protein aggregation, gut microbiota, gut metabolome, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: The human gut microbiota is a complex, dynamic, and highly diverse community of microorganisms. Beginning as early as in utero fetal development and continuing through birth to late-stage adulthood, the crosstalk between the gut microbiome and brain is essential for modulating various metabolic, neurodevelopmental, and immune-related pathways. Conversely, microbial dysbiosis – defined as alterations in richness and relative abundances – of the gut is implicated in the pathogenesis of several chronic neurological and neurodegenerative disorders. Evidence from large-population cohort studies suggests that individuals with neurodegenerative conditions have an altered gut microbial composition as well as microbial and serum metabolomic profiles distinct from those in the healthy population. Dysbiosis is also linked to psychiatric and gastrointestinal complications – comorbidities often associated with the prodromal phase of Parkinson’s disease (PD) and Alzheimer’s disease (AD). Studies have identified potential mediators that link gut dysbiosis and neurological disorders. Recent findings have also elucidated the potential mechanisms of disease pathology in the enteric nervous system prior to the onset of neurodegeneration. This review highlights the functional pathways and mechanisms, particularly gut microbe-induced chronic inflammation, protein misfolding, propagation of disease-specific pathology, defective protein clearance, and autoimmune dysregulation, linking gut microbial dysbiosis and neurodegeneration. In addition, we also discuss how pathogenic transformation of microbial composition leads to increased endotoxin production and fewer beneficial metabolites, both of which could trigger immune cell activation and enteric neuronal dysfunction. These can further disrupt intestinal barrier permeability, aggravate the systemic pro-inflammatory state, impair blood–brain barrier permeability and recruit immune mediators leading to neuroinflammation and neurodegeneration. Continued biomedical advances in understanding the microbiota-gut-brain axis will extend the frontier of neurodegenerative disorders and enable the utilization of novel diagnostic and therapeutic strategies to mitigate the pathological burden of these diseases.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fnins.2022.836605/fullTest; https://doaj.org/toc/1662-453XTest

الوصول الحر: https://doaj.org/article/7ed39c9ba36d4a898939a236bb3f2a94Test

المؤلفون: Miguel A. Pappolla, George Perry, Xiang Fang, Michael Zagorski, Kumar Sambamurti, Burkhard Poeggeler

المصدر: Neurobiology of Disease, Vol 156, Iss , Pp 105403- (2021)

مصطلحات موضوعية: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Sporadic late-onset Alzheimer's disease (AD) is the most frequent cause of dementia associated with aging. Due to the progressive aging of the population, AD is becoming a healthcare burden of unprecedented proportions. Twenty years ago, it was reported that some indole molecules produced by the gut microbiota possess essential biological activities, including neuroprotection and antioxidant properties. Since then, research has cemented additional characteristics of these substances, including anti-inflammatory, immunoregulatory, and amyloid anti-aggregation features. Herein, we summarize the evidence supporting an integrated hypothesis that some of these substances can influence the age of onset and progression of AD and are central to the symbiotic relationship between intestinal microbes and the brain. Studies have shown that some of these substances' activities result from interactions with biologically conserved pathways and with genetic risk factors for AD. By targeting multiple pathologic mechanisms simultaneously, certain indoles may be excellent candidates to ameliorate neurodegeneration. We propose that management of the microbiota to induce a higher production of neuroprotective indoles (e.g., indole propionic acid) will promote brain health during aging. This area of research represents a new therapeutic paradigm that could add functional years of life to individuals who would otherwise develop dementia.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0969996121001522Test; https://doaj.org/toc/1095-953XTest

الوصول الحر: https://doaj.org/article/93acfc95685c4349a5ce313e397e5963Test

المؤلفون: Balmiki Ray, Bryan Maloney, Kumar Sambamurti, Hanuma K. Karnati, Peter T. Nelson, Nigel H. Greig, Debomoy K. Lahiri

المصدر: Translational Psychiatry, Vol 10, Iss 1, Pp 1-1 (2020)

مصطلحات موضوعية: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2158-3188Test

الوصول الحر: https://doaj.org/article/441050358cc74977bc835c9457b108edTest

المؤلفون: Miguel Pappolla, Kumar Sambamurti, Ruben Vidal, Javier Pacheco-Quinto, Burkhard Poeggeler, Etsuro Matsubara

المصدر: Neurobiology of Disease, Vol 71, Iss , Pp 215-219 (2014)

مصطلحات موضوعية: Lymph node, Amyloid beta protein, Alzheimer's disease, Protein clearance, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Evidence has shown that lymphatic drainage contributes to removal of debris from the brain but its role in the accumulation of amyloid β peptides (Aβ) has not been demonstrated. We examined the levels of various forms of Aβ in the brain, plasma and lymph nodes in a transgenic model of Alzheimer's disease (AD) at different ages. Herein, we report on the novel finding that Aβ is present in the cervical and axillary lymph nodes of AD transgenic mice and that Aβ levels in lymph nodes increase over time, mirroring the increase of Aβ levels observed in the brain. Aβ levels in lymph nodes were significantly higher than in plasma. At age 15.5 months, there was a significant increase of monomeric soluble Aβ40 (p = 0.003) and Aβ42 (p = 0.05) in the lymph nodes over the baseline values measured at 6 months of age. In contrast, plasma levels of Aβ40 showed no significant changes (p = 0.68) and plasma levels Aβ42 significantly dropped (p = 0.02) at the same age. Aβ concentration was low to undetectable in splenic lymphoid tissue and several other control tissues including heart, lung, liver, kidneys and intestine of the same animals, strongly suggesting that Aβ peptides in lymph nodes are derived from the brain.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0969996114002137Test; https://doaj.org/toc/1095-953XTest

الوصول الحر: https://doaj.org/article/0d3786ccd46946028db237d5b4eda318Test

المؤلفون: Javier Pacheco-Quinto, Elena B. Rodriguez de Turco, Steven DeRosa, Altovise Howard, Felix Cruz-Sanchez, Kumar Sambamurti, Lorenzo Refolo, Suzana Petanceska, Miguel A. Pappolla

المصدر: Neurobiology of Disease, Vol 22, Iss 3, Pp 651-656 (2006)

مصطلحات موضوعية: Aβ40, Aβ42, Alzheimer's disease, Amyloidosis, Brain, Hyperhomocysteinemia, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms are unknown. We tested the hypothesis that high serum homocysteine concentration may increase amyloid beta-peptide (Aβ) levels in the brain and could therefore accelerate AD neuropathology. For this purpose, we mated a hyperhomocysteinemic CBStm1Unc mouse carrying a heterozygous dominant mutation in cystathionine-beta-synthase (CBS*) with the APP*/PS1* mouse model of brain amyloidosis. The APP*/PS1*/CBS* mice showed significant elevations of serum homocysteine levels compared to the double transgenic APP*/PS1* model of amyloidosis. Results showed that female (but not male) APP*/PS1*/CBS* mice exhibited significant elevations of Aβ40 and Aβ42 levels in the brain. Correlations between homocysteine levels in serum and brain Aβ levels were statistically significant. No increases in beta secretase activity or evidence of neuronal cell loss in the hyperhomocysteinemic mice were found.The causes of neuronal dysfunction and degeneration in AD are not fully understood, but increased production of Aβ seems to be of major importance. By unveiling a link between homocysteine and Aβ levels, these findings advance our understanding on the mechanisms involved in hyperhomocysteinemia as a risk factor for AD.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0969996106000076Test; https://doaj.org/toc/1095-953XTest

الوصول الحر: https://doaj.org/article/282f5459dc554f98b11b1f747eb62abcTest

المؤلفون: Eliza Barnwell, Vasudevaraju Padmaraju, Robert Baranello, Javier Pacheco-Quinto, Craig Crosson, Zsolt Ablonczy, Elizabeth Eckman, Christopher B Eckman, Viswanathan Ramakrishnan, Nigel H Greig, Miguel A Pappolla, Kumar Sambamurti

المصدر: PLoS ONE, Vol 9, Iss 3, p e91531 (2014)

مصطلحات موضوعية: Medicine, Science

الوصف: BACE1 (β-secretase) and α-secretase cleave the Alzheimer's amyloid β protein (Aβ) precursor (APP) to C-terminal fragments of 99 aa (CTFβ) and 83 aa (CTFα), respectively, which are further cleaved by γ-secretase to eventually secrete Aβ and Aα (a.k.a. P3) that terminate predominantly at residues 40 and 42. A number of γ-secretase inhibitors (GSIs), such as N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), have been developed with the goal of reducing Aβ to treat Alzheimer's disease (AD). Although most studies show that DAPT inhibits Aβ in a dose-dependent manner several studies have also detected a biphasic effect with an unexpected increase at low doses of DAPT in cell cultures, animal models and clinical trials. In this article, we confirm the increase in Aβ40 and Aβ42 in SH-SY5Y human neuroblastoma cells treated with low doses of DAPT and identify one of the mechanisms for this paradox. We studied the pathway by first demonstrating that stimulation of Aβ, a product of γ-secretase, was accompanied by a parallel increase of its substrate CTFβ, thereby demonstrating that the inhibitor was not anomalously stimulating enzyme activity at low levels. Secondly, we have demonstrated that inhibition of an Aβ degrading activity, endothelin converting enzyme (ECE), yielded more Aβ, but abolished the DAPT-induced stimulation. Finally, we have demonstrated that Aα, which is generated in the secretory pathway before endocytosis, is not subject to the DAPT-mediated stimulation. We therefore conclude that impairment of γ-secretase can paradoxically increase Aβ by transiently skirting Aβ degradation in the endosome. This study adds to the growing body of literature suggesting that preserving γ-secretase activity, rather than inhibiting it, is important for prevention of neurodegeneration.

وصف الملف: electronic resource

العلاقة: http://europepmc.org/articles/PMC3962361?pdf=renderTest; https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/3e3c856aacf8479196377dffa67b13e4Test

المؤلفون: Lorenzo M. Refolo, Miguel A. Pappolla, Brian Malester, John LaFrancois, Tara Bryant-Thomas, Rong Wang, G.Stephen Tint, Kumar Sambamurti, Karen Duff

المصدر: Neurobiology of Disease, Vol 7, Iss 4, Pp 321-331 (2000)

مصطلحات موضوعية: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571

الوصف: Recent data suggest that cholesterol metabolism is linked to susceptibility to Alzheimer's disease (AD). However, no direct evidence has been reported linking cholesterol metabolism and the pathogenesis of AD. To test the hypothesis that amyloid β-peptide (Aβ) deposition can be modulated by diet-induced hypercholesterolemia, we used a transgenic-mouse model for AD amyloidosis and examined the effects of a high-fat/high-cholesterol diet on central nervous system (CNS) Aβ accumulation. Our data showed that diet-induced hypercholesterolemia resulted in significantly increased levels of formic acid-extractable Aβ peptides in the CNS. Furthermore, the levels of total Aβ were strongly correlated with the levels of both plasma and CNS total cholesterol. Biochemical analysis revealed that, compared with control, the hypercholesterolemic mice had significantly decreased levels of sAPPα and increased levels of C-terminal fragments (β-CTFs), suggesting alterations in amyloid precursor protein processing in response to hypercholesterolemia. Neuropathological analysis indicated that the hypercholesterolemic diet significantly increased β-amyloid load by increasing both deposit number and size. These data demonstrate that high dietary cholesterol increases Aβ accumulation and accelerates the AD-related pathology observed in this animal model. Thus, we propose that diet can be used to modulate the risk of developing AD.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0969996100903048Test; https://doaj.org/toc/1095-953XTest

الوصول الحر: https://doaj.org/article/63c83aa9944e4c6aa4e4629a93bf4f54Test