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1.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206089

RESUMO

Amyloid-ß (Aß) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer's disease (AD). Whereas in AD, Aß is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aß aggregated species, soluble oligomers are suggested to be responsible for most of Aß's toxic effects. Aß oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aß deposition and facilitate neurodegeneration, resulting in an Aß-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aß induces on synaptic dysfunction and network disorganization.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Sinapses/genética , Transmissão Sináptica/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/efeitos adversos , Peptídeos beta-Amiloides/ultraestrutura , Proteínas Amiloidogênicas/efeitos adversos , Proteínas Amiloidogênicas/genética , Animais , Humanos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Multimerização Proteica/genética , Sinapses/metabolismo
2.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207264

RESUMO

Despite not being utilized as considerably as other antidepressants in the therapy of depression, the monoamine oxidase inhibitors (MAOIs) proceed to hold a place in neurodegeneration and to have a somewhat broad spectrum in respect of the treatment of neurological and psychiatric conditions. Preclinical and clinical studies on MAOIs have been developing in recent times, especially on account of rousing discoveries manifesting that these drugs possess neuroprotective activities. The altered brain levels of monoamine neurotransmitters due to monoamine oxidase (MAO) are directly associated with various neuropsychiatric conditions like Alzheimer's disease (AD). Activated MAO induces the amyloid-beta (Aß) deposition via abnormal cleavage of the amyloid precursor protein (APP). Additionally, activated MAO contributes to the generation of neurofibrillary tangles and cognitive impairment due to neuronal loss. No matter the attention of researchers on the participation of MAOIs in neuroprotection has been on monoamine oxidase-B (MAO-B) inhibitors, there is a developing frame of proof indicating that monoamine oxidase-A (MAO-A) inhibitors may also play a role in neuroprotection. The therapeutic potential of MAOIs alongside the complete understanding of the enzyme's physiology may lead to the future advancement of these drugs.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/metabolismo , Animais , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Neurotransmissores/metabolismo
3.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209586

RESUMO

Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer's disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Alzheimer/metabolismo , Animais , Coronavirus/patogenicidade , Humanos , Imunidade Inata , Microglia/metabolismo , Viroses/imunologia , Viroses/patologia
4.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: covidwho-1295856

RESUMO

Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer's disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Alzheimer/metabolismo , Animais , Coronavirus/patogenicidade , Humanos , Imunidade Inata , Microglia/metabolismo , Viroses/imunologia , Viroses/patologia
5.
Biochemistry (Mosc) ; 86(6): 667-679, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225590

RESUMO

Alzheimer's disease is the most common age-related neurodegenerative disease. Understanding of its etiology and pathogenesis is constantly expanding. Thus, the increasing attention of researchers is directed to the study of the role of mitochondrial disorders. In addition, in recent years, the concept of Alzheimer's disease as a stress-induced disease has begun to form more and more actively. The stress-induced damage to the neuronal system can trigger a vicious circle of pathological processes, among which mitochondrial dysfunctions have a significant place, since mitochondria represent a substantial component in the anti-stress activity of the cell. The study of mitochondrial disorders in Alzheimer's disease is relevant for at least two reasons: first, as important pathogenetic component in this disease; second, due to vital role of mitochondria in formation of the body resistance to various conditions, including stressful ones, throughout the life. This literature review analyzes the results of a number of recent studies assessing potential significance of the mitochondrial disorders in Alzheimer's disease. The probable mechanisms of mitochondrial disorders associated with the development of this disease are considered: bioenergetic dysfunctions, changes in mitochondrial DNA (including assessment of the significance of its haplogroup features), disorders in the dynamics of these organelles, oxidative damage to calcium channels, damage to MAM complexes (membranes associated with mitochondria; mitochondria-associated membranes), disruptions of the mitochondrial quality control system, mitochondrial permeability, etc. The issues of the "primary" or "secondary" mitochondrial damage in Alzheimer's disease are discussed. Potentials for the development of new methods for diagnosis and therapy of mitochondrial disorders in Alzheimer's disease are considered.


Assuntos
Doença de Alzheimer/metabolismo , Doenças Mitocondriais/metabolismo , Doença de Alzheimer/complicações , Animais , DNA Mitocondrial/química , Metabolismo Energético , Feminino , Humanos , Masculino , Mitocôndrias/metabolismo , Doenças Mitocondriais/complicações , Estresse Oxidativo
6.
Biochemistry (Mosc) ; 86(6): 680-692, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225591

RESUMO

The incidence of Alzheimer's disease (AD) increases significantly following chronic stress and brain ischemia which, over the years, cause accumulation of toxic amyloid species and brain damage. The effects of global 15-min ischemia and 120-min reperfusion on the levels of expression of the amyloid precursor protein (APP) and its processing were investigated in the brain cortex (Cx) of male Wistar rats. Additionally, the levels of expression of the amyloid-degrading enzymes neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1), and insulin-degrading enzyme (IDE), as well as of some markers of oxidative damage were assessed. It was shown that the APP mRNA and protein levels in the rat Cx were significantly increased after the ischemic insult. Protein levels of the soluble APP fragments, especially of sAPPß produced by ß-secretase, (BACE-1) and the levels of BACE-1 mRNA and protein expression itself were also increased after ischemia. The protein levels of APP and BACE-1 in the Cx returned to the control values after 120-min reperfusion. The levels of NEP and ECE-1 mRNA also decreased after ischemia, which correlated with the decreased protein levels of these enzymes. However, we have not observed any changes in the protein levels of insulin-degrading enzyme. Contents of the markers of oxidative damage (di-tyrosine and lysine conjugates with lipid peroxidation products) were also increased after ischemia. The obtained data suggest that ischemia shifts APP processing towards the amyloidogenic ß-secretase pathway and accumulation of the neurotoxic Aß peptide as well as triggers oxidative stress in the cells. These results are discussed in the context of the role of stress and ischemia in initiation and progression of AD.


Assuntos
Doença de Alzheimer/etiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Isquemia Encefálica/metabolismo , Córtex Cerebral/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/enzimologia , Córtex Cerebral/enzimologia , Enzimas Conversoras de Endotelina/genética , Enzimas Conversoras de Endotelina/metabolismo , Regulação da Expressão Gênica , Insulisina/genética , Insulisina/metabolismo , Masculino , Neprilisina/genética , Neprilisina/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo
7.
Biochemistry (Mosc) ; 86(6): 737-745, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225596

RESUMO

The review summarizes the results of studies on the cellular and molecular mechanisms mediating the impact of stress on the pathogenesis of neurodegenerative brain pathologies (Alzheimer's disease, Parkinson's disease, etc.) and presents current information on the role of stress in the hyperphosphorylation of tau protein, aggregation of beta-amyloid, and hyperactivation of the hypothalamic-pituitary-adrenal axis involved in the hyperproduction of factors that contribute to the pathogenetic role of stress in neurodegeneration. The data on the participation of microglia in the effects of stress on the pathogenesis of neurodegenerative diseases are presented.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Psicológico , Proteínas tau/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Demência/etiologia , Demência/metabolismo , Demência/fisiopatologia , Humanos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Fosforilação , Agregação Patológica de Proteínas , Processamento de Proteína Pós-Traducional
8.
Int J Nanomedicine ; 16: 4373-4390, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234432

RESUMO

Current treatments for Alzheimer's disease (AD) attenuate the progression of symptoms and aim to improve the patient's quality of life. Licensed medicines are mostly for oral administration and are limited by the difficulty in crossing the blood-brain barrier (BBB). Here in, the nasal route has been explored as an alternative pathway that allows drugs to be directly delivered to the brain via the nasal cavity. However, clearance mechanisms in the nasal cavity impair the delivery of drugs to the brain and limit their bioavailability. To optimize nose-to-brain delivery, formulations of lipid-based nanosystems, namely nanoemulsions and nanostructured lipid carriers (NLC), formulated in situ gelling hydrogels have been proposed as approaches for nose-to-brain delivery. These formulations possess characteristics that facilitate drug transport directly to the brain, minimizing side effects and maximizing therapeutic benefits. It has been recommended that the manufacture of these drug delivery systems follows the quality by design (QbD) approach based on nasal administration requirements. This review provides an insight into the current knowledge of the AD, highlighting the need for an effective drug delivery to the brain. Considering the mounting interest in the use of nanoemulsions and NLC for nose-to-brain delivery, a description of drug transport pathways in the nasal cavity and the application of these nanosystems and their in situ hydrogels through the intranasal route are presented. Relevant preclinical studies are summarised, and the future prospects for the use of lipid-based nanosystems in the treatment of AD are emphasized.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Portadores de Fármacos/química , Hidrogéis/química , Lipídeos/química , Nanoestruturas/química , Nariz , Doença de Alzheimer/tratamento farmacológico , Animais , Emulsões , Humanos
9.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206322

RESUMO

Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer's disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/-) AD mouse model. Memory and spatial learning of male hAPP23+/- and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/- brains, amyloid-beta (Aß) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/- mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/- animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/- mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/- mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD.


Assuntos
Doença de Alzheimer/sangue , Biomarcadores/sangue , Disfunção Cognitiva , Corticosterona/sangue , Resistência à Insulina , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Síndrome de Cushing/complicações , Modelos Animais de Doenças , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
10.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065168

RESUMO

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aß) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aß plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1ß in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.


Assuntos
Doença de Alzheimer/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Doenças Metabólicas/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Polipeptídeo Inibidor Gástrico/metabolismo , Grelina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Resistina/metabolismo
11.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070553

RESUMO

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia. Metabolic disorders including obesity and type 2 diabetes mellitus (T2DM) may stimulate amyloid ß (Aß) aggregate formation. AD, obesity, and T2DM share similar features such as chronic inflammation, increased oxidative stress, insulin resistance, and impaired energy metabolism. Adiposity is associated with the pro-inflammatory phenotype. Adiposity-related inflammatory factors lead to the formation of inflammasome complexes, which are responsible for the activation, maturation, and release of the pro-inflammatory cytokines including interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). Activation of the inflammasome complex, particularly NLRP3, has a crucial role in obesity-induced inflammation, insulin resistance, and T2DM. The abnormal activation of the NLRP3 signaling pathway influences neuroinflammatory processes. NLRP3/IL-1ß signaling could underlie the association between adiposity and cognitive impairment in humans. The review includes a broadened approach to the role of obesity-related diseases (obesity, low-grade chronic inflammation, type 2 diabetes, insulin resistance, and enhanced NLRP3 activity) in AD. Moreover, we also discuss the mechanisms by which the NLRP3 activation potentially links inflammation, peripheral and central insulin resistance, and metabolic changes with AD.


Assuntos
Doença de Alzheimer/metabolismo , Inflamassomos/metabolismo , Resistência à Insulina , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Obesidade/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Doença de Alzheimer/patologia , Animais , Humanos , Obesidade/patologia , Síndrome de Resposta Inflamatória Sistêmica/patologia
12.
Nat Commun ; 12(1): 3291, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078905

RESUMO

The formation of hyperphosphorylated intracellular Tau tangles in the brain is a hallmark of Alzheimer's disease (AD). Tau hyperphosphorylation destabilizes microtubules, promoting neurodegeneration in AD patients. To identify suppressors of tau-mediated AD, we perform a screen using a microRNA (miR) library in Drosophila and identify the miR-9 family as suppressors of human tau overexpression phenotypes. CG11070, a miR-9a target gene, and its mammalian orthologue UBE4B, an E3/E4 ubiquitin ligase, alleviate eye neurodegeneration, synaptic bouton defects, and crawling phenotypes in Drosophila human tau overexpression models. Total and phosphorylated Tau levels also decrease upon CG11070 or UBE4B overexpression. In mammalian neuroblastoma cells, overexpression of UBE4B and STUB1, which encodes the E3 ligase CHIP, increases the ubiquitination and degradation of Tau. In the Tau-BiFC mouse model, UBE4B and STUB1 overexpression also increase oligomeric Tau degradation. Inhibitor assays of the autophagy and proteasome systems reveal that the autophagy-lysosome system is the major pathway for Tau degradation in this context. These results demonstrate that UBE4B, a miR-9 target gene, promotes autophagy-mediated Tau degradation together with STUB1, and is thus an innovative therapeutic approach for AD.


Assuntos
Doença de Alzheimer/genética , Proteínas de Drosophila/genética , MicroRNAs/genética , Ubiquitina-Proteína Ligases/genética , Proteínas tau/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Autofagia/genética , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Olho/metabolismo , Olho/patologia , Humanos , Lisossomos/metabolismo , Camundongos , MicroRNAs/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Proteínas tau/metabolismo
13.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071254

RESUMO

A central characteristic of Alzheimer's disease (AD) and other tauopathies is the accumulation of aggregated and misfolded Tau deposits in the brain. Tau-targeting therapies for AD have been unsuccessful in patients to date. Here we show that human polymerase δ-interacting protein 2 (PolDIP2) interacts with Tau. With a set of complementary methods, including thioflavin-T-based aggregation kinetic assays, Tau oligomer-specific dot-blot analysis, and single oligomer/fibril analysis by atomic force microscopy, we demonstrate that PolDIP2 inhibits Tau aggregation and amyloid fibril growth in vitro. The identification of PolDIP2 as a potential regulator of cellular Tau aggregation should be considered for future Tau-targeting therapeutics.


Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Proteínas Nucleares/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Benzotiazóis , Encéfalo/metabolismo , Humanos , Proteínas Nucleares/genética , Tauopatias
14.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071270

RESUMO

The peroxisome proliferator-activated receptor co-activator-1α (PGC1α) belongs to a family of transcriptional regulators, which act as co-activators for a number of transcription factors, including PPARs, NRFs, oestrogen receptors, etc. PGC1α has been implicated in the control of mitochondrial biogenesis, the regulation of the synthesis of ROS and inflammatory cytokines, as well as genes controlling metabolic processes. The levels of PGC1α have been shown to be altered in neurodegenerative disorders. In the brains of Alzheimer's disease (AD) patients and animal models of amyloidosis, PGC1α expression was reduced compared with healthy individuals. Recently, it was shown that overexpression of PGC1α resulted in reduced amyloid-ß (Aß) generation, particularly by regulating the expression of BACE1, the rate-limiting enzyme involved in the production of Aß. These results provide evidence pointing toward PGC1α activation as a new therapeutic avenue for AD, which has been supported by the promising observations of treatments with drugs that enhance the expression of PGC1α and gene therapy studies in animal models of AD. This review summarizes the different ways and mechanisms whereby PGC1α can be neuroprotective in AD and the pre-clinical treatments that have been explored so far.


Assuntos
Doença de Alzheimer/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Regulação da Expressão Gênica , Terapia Genética , Humanos , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fatores de Transcrição/metabolismo
15.
Aging (Albany NY) ; 13(11): 14552-14556, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: covidwho-1267005

RESUMO

SARS-CoV-2 more readily affects the elderly, especially as they present co-morbidities. In the COVID-19 pathogeny, ACE2 appears to be the key cell receptor for SARS-CoV-2 to infect humans. The level of ACE2 gene expression influences the susceptibility of contracting SARS-CoV-2. In circumstances in which the ACE2 level is low, the incidence of Covid-19 seems to be fewer. Two clinical patterns illustrate this observation, i. e., in infants and in Alzheimer's disease (AD). Very young children and AD patients get little COVID-19, in part probably due to decreased expression of ACE2. The determination of the nasal level of ACE2 gene expression could provide a useful scale to predict the susceptibility to contract the SARS-CoV-2 infection.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/etiologia , SARS-CoV-2/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , COVID-19/metabolismo , Cérebro/metabolismo , Suscetibilidade a Doenças , Expressão Gênica , Humanos , Lactente , Mucosa Nasal/metabolismo
16.
Adv Food Nutr Res ; 96: 251-310, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1240122

RESUMO

Since the discovery of manifest Zn deficiency in 1961, the increasing number of studies demonstrated the association between altered Zn status and multiple diseases. In this chapter, we provide a review of the most recent advances on the role of Zn in health and disease (2010-20), with a special focus on the role of Zn in neurodegenerative and neurodevelopmental disorders, diabetes and obesity, male and female reproduction, as well as COVID-19. In parallel with the revealed tight association between ASD risk and severity and Zn status, the particular mechanisms linking Zn2+ and ASD pathogenesis like modulation of synaptic plasticity through ProSAP/Shank scaffold, neurotransmitter metabolism, and gut microbiota, have been elucidated. The increasing body of data indicate the potential involvement of Zn2+ metabolism in neurodegeneration. Systemic Zn levels in Alzheimer's and Parkinson's disease were found to be reduced, whereas its sequestration in brain may result in modulation of amyloid ß and α-synuclein processing with subsequent toxic effects. Zn2+ was shown to possess adipotropic effects through the role of zinc transporters, zinc finger proteins, and Zn-α2-glycoprotein in adipose tissue physiology, underlying its particular role in pathogenesis of obesity and diabetes mellitus type 2. Recent findings also contribute to further understanding of the role of Zn2+ in spermatogenesis and sperm functioning, as well as oocyte development and fertilization. Finally, Zn2+ was shown to be the potential adjuvant therapy in management of novel coronavirus infection (COVID-19), underlining the perspectives of zinc in management of old and new threats.


Assuntos
Transtorno do Espectro Autista/metabolismo , COVID-19/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Doenças Neurodegenerativas/metabolismo , Obesidade/metabolismo , Reprodução , Zinco/metabolismo , Doença de Alzheimer/metabolismo , Animais , COVID-19/tratamento farmacológico , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/metabolismo , Estado Nutricional , Doença de Parkinson/metabolismo , Zinco/deficiência , Zinco/uso terapêutico
17.
Clin Interv Aging ; 16: 1185-1191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34188461

RESUMO

Aim: High glucose (HG)-induced activation of mTOR promotes tau phosphorylation and leads to diabetes-associated dementia. This study aimed to explore the role of metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) in HG-induced neuronal cell injury. Methods: Hippocampus cells were isolated from C57BL/6J mice. After 6 days of culture, the cells were incubated with 5.5 mM glucose in normal medium or 75 mM glucose for 4 days. Cells were transfected with miR-144 mimic, miR-144 inhibitor, siRNA for MALAT1 or corresponding controls. Gene expression was detected by PCR and Western blot analysis. Results: HG increased the levels of MALAT1 and p-tau in hippocampal cells. Knockdown of MALAT1 partially reversed the effects of HG on mTOR activity and p-tau protein levels. MALAT1 functioned as competing endogenous RNA (ceRNA) for miR-144, and pre-treatment with MALAT1 siRNA decreased mTOR activity and p-tau protein level in HG-treated hippocampal cells, which was significantly attenuated by miR-144 mimics. Moreover, miR-144 negatively regulated the expression of mTOR and knockdown of MALAT1 suppressed mTOR, while overexpression of mTOR abrogated protective effects of MALAT1 knockdown in HG-treated hippocampal cells. Conclusion: MALAT1 knockdown prevented HG-induced mTOR activation and inhibited tau phosphorylation. MALAT1 may be a therapy target for diabetes associated dementia.


Assuntos
Doença de Alzheimer/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , RNA Longo não Codificante/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Doença de Alzheimer/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Diabetes Mellitus Tipo 2/genética , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , RNA Longo não Codificante/genética , Serina-Treonina Quinases TOR/genética
18.
Adv Food Nutr Res ; 96: 251-310, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34112355

RESUMO

Since the discovery of manifest Zn deficiency in 1961, the increasing number of studies demonstrated the association between altered Zn status and multiple diseases. In this chapter, we provide a review of the most recent advances on the role of Zn in health and disease (2010-20), with a special focus on the role of Zn in neurodegenerative and neurodevelopmental disorders, diabetes and obesity, male and female reproduction, as well as COVID-19. In parallel with the revealed tight association between ASD risk and severity and Zn status, the particular mechanisms linking Zn2+ and ASD pathogenesis like modulation of synaptic plasticity through ProSAP/Shank scaffold, neurotransmitter metabolism, and gut microbiota, have been elucidated. The increasing body of data indicate the potential involvement of Zn2+ metabolism in neurodegeneration. Systemic Zn levels in Alzheimer's and Parkinson's disease were found to be reduced, whereas its sequestration in brain may result in modulation of amyloid ß and α-synuclein processing with subsequent toxic effects. Zn2+ was shown to possess adipotropic effects through the role of zinc transporters, zinc finger proteins, and Zn-α2-glycoprotein in adipose tissue physiology, underlying its particular role in pathogenesis of obesity and diabetes mellitus type 2. Recent findings also contribute to further understanding of the role of Zn2+ in spermatogenesis and sperm functioning, as well as oocyte development and fertilization. Finally, Zn2+ was shown to be the potential adjuvant therapy in management of novel coronavirus infection (COVID-19), underlining the perspectives of zinc in management of old and new threats.


Assuntos
Transtorno do Espectro Autista/metabolismo , COVID-19/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Doenças Neurodegenerativas/metabolismo , Obesidade/metabolismo , Reprodução , Zinco/metabolismo , Doença de Alzheimer/metabolismo , Animais , COVID-19/tratamento farmacológico , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/metabolismo , Estado Nutricional , Doença de Parkinson/metabolismo , Zinco/deficiência , Zinco/uso terapêutico
19.
Nat Commun ; 12(1): 3825, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158479

RESUMO

Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Glucuronidase/metabolismo , Transtornos da Memória/metabolismo , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Expressão Gênica , Glucuronidase/genética , Heterozigoto , Humanos , Masculino , Transtornos da Memória/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica
20.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064208

RESUMO

In Parkinson's disease, aggregates of α-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary α-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational modifications such as phosphorylation, ubiquitination, nitration, glycation, and SUMOylation affect α-synuclein conformation along with its aggregation propensity and neurotoxic profiles. In addition, proteolytic cleavage of α-synuclein by specific proteases results in the formation of a broad spectrum of fragments with consecutively altered and not fully understood physiological and/or pathological properties. In the present review, we summarize the current knowledge on proteolytical α-synuclein cleavage by neurosin, calpain-1, cathepsin D, and matrix metalloproteinase-3 in health and disease. We also shed light on the contribution of the same enzymes to proteolytical processing of pathogenic proteins in Alzheimer's disease and report potential cross-disease mechanisms of pathogenic protein aggregation.


Assuntos
alfa-Sinucleína/metabolismo , Doença de Alzheimer/metabolismo , Animais , Humanos , Doença de Parkinson/metabolismo , Peptídeo Hidrolases/metabolismo , Agregados Proteicos/fisiologia , Proteólise
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