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1.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371878

RESUMO

Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3ß (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPß, and the concentration of Aß40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-ß expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.


Assuntos
Doença de Alzheimer/prevenção & controle , Encéfalo/efeitos dos fármacos , Suplementos Nutricionais , Plasma , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ração Animal , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Quinase 5 Dependente de Ciclina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fragmentos de Peptídeos/metabolismo , Fosforilação , Transdução de Sinais , Secagem por Atomização , Sus scrofa , Proteínas tau/metabolismo
2.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202125

RESUMO

Alzheimer's disease is a neurodegenerative disorder associated with age, and is characterized by pathological markers such as amyloid-beta plaques and neurofibrillary tangles. Symptoms of AD include cognitive impairments, anxiety and depression. It has also been shown that individuals with AD have impaired neurotransmission, which may result from the accumulation of amyloid plaques and neurofibrillary tangles. Preclinical studies showed that melatonin, a monoaminergic neurotransmitter released from the pineal gland, is able to ameliorate AD pathologies and restore cognitive impairments. Theoretically, inhibition of the pathological progression of AD by melatonin treatment should also restore the impaired neurotransmission. This review aims to explore the impact of AD on neurotransmission, and whether and how melatonin can enhance neurotransmission via improving AD pathology.


Assuntos
Doença de Alzheimer/metabolismo , Melatonina/metabolismo , Neurotransmissores/metabolismo , Transmissão Sináptica , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Monoaminas Biogênicas/metabolismo , Suscetibilidade a Doenças , Humanos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Proteínas tau/metabolismo
3.
Med Hypotheses ; 154: 110645, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34315048

RESUMO

Alzheimer's disease (AD) is a progressive incurable neurodegenerative disease of the brain afflicting a third of the population aged 85 and older. Pathologic hallmarks include extracellular plaques of amyloid-beta (Aß), intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein, synaptic destruction, neuronal death, and brain atrophy. Neuroinflammation, mediated by microglia, is a central component of the disease, and is intricately connected with peripheral inflammation. The clinical manifestations include progressive memory loss and eventual death. The present treatment of AD is largely ineffective. Nearly all AD is late-onset and presents age 65 or older, and the most common genetic risk factor is carriage of an apolipoprotein (APO) E4 allele, seen in about 25% of the general population. Individuals carrying an APOE4 allele produce more Aß and clear it less efficiently from the brain throughout life. There has been accumulating pathologic and clinical evidence that microbes, particularly the herpes simplex virus (HSV), is a causative factor for AD, most notable in carriers of the APOE4 allele. Eighty percent of the adult population harbors HSV and it resides in the trigeminal ganglion in latent state throughout life, but periodically reactivates, traveling antegrade resulting in herpes labialis and traveling retrograde into the brain leading to neuroinflammation. Functioning as an antimicrobial peptide, Aß inactivates HSV and the recurring process culminates in a buildup of Aß plaque and other hallmarks of AD over time. Periodontal disease exists in 20-50% of the adult population and is also a causative factor for AD. Accordingly, bacteria causing periodontal disease and their byproducts can enter the brain directly via the trigeminal nerve or indirectly through the bloodstream, resulting in AD pathology over time. There are many other promoters of AD, particularly inflammatory conditions outside of the brain, that can be mitigated. Small trials are finally in progress testing antimicrobial drugs for the prevention and treatment of AD. In the meantime, a more proactive approach to the prevention and treatment of AD is posited, with an emphasis on prevention, since the pathologic underpinnings of the disease start decades before the clinical manifestations. Individuals can be stratified in risk categories using family history, periodontal disease presence, APOE4 carriage, and HSV IgG positivity. Moderate- and high-risk individuals can be treated safely with various preventive measures and appropriate antimicrobial agents as discussed. Importantly, the proposed treatments are concordant with the accepted practice of medicine, and if utilized, could significantly decrease AD prevalence.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Idoso , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Humanos , Emaranhados Neurofibrilares/metabolismo , Placa Amiloide
4.
ACS Chem Neurosci ; 12(11): 1983-1988, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33978396

RESUMO

Self-assembly of hyperphosphorylated tau proteins into neurofibrillary tangles (NFT) is a hallmark of Alzheimer's disease. Previous studies suggest that the tau monomer may play an important role in NFTs formation in two general categories: inert (Mi) monomer and seed-competent (Ms) monomer. In the current study, replica-exchange molecular dynamics (REMD) were performed to investigate the effect of histidine tautomerism on the structures of a key fragment (R3) of tau protein and the transformation between different conformations. Based on the simulation results, we propose the histidine tautomerism hypothesis for tau protein misfolding. Histidine tautomerism greatly expands the conformational library, which triggers the emergence of conformations with higher aggregation tendency. Moreover, the conversions existing in both isomers and conformations may cause protein misfolding to occur more readily.


Assuntos
Doença de Alzheimer , Proteínas tau , Histidina , Humanos , Simulação de Dinâmica Molecular , Emaranhados Neurofibrilares/metabolismo , Proteínas tau/metabolismo
5.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915734

RESUMO

MicroRNAs have been demonstrated as key regulators of gene expression in the etiology of a range of diseases including Alzheimer's disease (AD). Recently, we identified miR-483-5p as the most upregulated miRNA amongst a panel of miRNAs in blood plasma specific to prodromal, early-stage Alzheimer's disease patients. Here, we investigated the functional role of miR-483-5p in AD pathology. Using TargetScan and miRTarBase, we identified the microtubule-associated protein MAPT, often referred to as TAU, and the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), known to phosphorylate TAU, as predicted direct targets of miR-483-5p. Employing several functional assays, we found that miR-483-5p regulates ERK1 and ERK2 at both mRNA and protein levels, resulting in lower levels of phosphorylated forms of both kinases. Moreover, miR-483-5p-mediated repression of ERK1/2 resulted in reduced phosphorylation of TAU protein at epitopes associated with TAU neurofibrillary pathology in AD. These results indicate that upregulation of miR-483-5p can decrease phosphorylation of TAU via ERK pathway, representing a compensatory neuroprotective mechanism in AD pathology. This miR-483-5p/ERK1/TAU axis thus represents a novel target for intervention in AD.


Assuntos
Doença de Alzheimer/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MicroRNAs/metabolismo , Proteínas tau/metabolismo , Biomarcadores/metabolismo , Células HEK293 , Humanos , Emaranhados Neurofibrilares/metabolismo , Fosforilação
6.
ACS Chem Neurosci ; 12(9): 1621-1631, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33877805

RESUMO

Taupathies involve the deposition of abnormal tau protein into neurofibrillary tangles (NFTs) in the human brain. The abnormally hyperphosphorylated tau dissociates from microtubules and forms insoluble aggregates known as paired helical filaments (PHFs), highlighting the importance of post-translational modifications in taupathies. The present study examines the factors responsible for the structural stability of PHFs in native as well as in phosphorylated and O-GlcNAcylated tau. We carried out molecular dynamics simulations on the R3-R4 repeat domains of the human tau protein to gain atomic insights into the key noncovalent interactions responsible for their unique dimeric C-shaped structure. The structural effects upon post-translational modification were found to be prominent for phosphorylation when compared with O-GlcNAcylation. O-GlcNAcylated tau was found to retain the "C conformation" observed in the native tau PHF, whereas upon phosphorylation, we observed a conformational transition to a more opened "H conformation". We found that this conformational transition is brought about by the loss of a key salt bridge between Lys353 and Asp358 due to the phosphorylation at Ser356 that results in the reorganization of the dimeric interface.


Assuntos
Doença de Alzheimer , Proteínas tau , Doença de Alzheimer/metabolismo , Humanos , Emaranhados Neurofibrilares/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas tau/metabolismo
7.
Nat Commun ; 12(1): 2311, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33875655

RESUMO

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.


Assuntos
Doença de Alzheimer/genética , Córtex Cerebral/metabolismo , Perfilação da Expressão Gênica/métodos , Hipocampo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Autopsia , Córtex Cerebral/patologia , Feminino , Hipocampo/patologia , Humanos , Aprendizado de Máquina , Masculino , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Inibidor da Proteína C/genética , Inibidor da Proteína C/metabolismo , RNA-Seq/métodos , Proteínas tau/genética , Proteínas tau/metabolismo
8.
ACS Chem Neurosci ; 12(11): 1885-1893, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33689290

RESUMO

Aggregated tau protein is a core pathology present in several neurodegenerative diseases. Therefore, the development and application of positron emission tomography (PET) imaging radiotracers that selectively bind to aggregated tau in fibril form is of importance in furthering the understanding of these disorders. While radiotracers used in human PET studies offer invaluable insight, radiotracers that are also capable of visualizing tau fibrils in animal models are important tools for translational research into these diseases. Herein, we report the synthesis and characterization of a novel library of compounds based on the phenyl/pyridinylbutadienylbenzothiazoles/benzothiazolium (PBB3) backbone developed for this application. From this library, we selected the compound LM229, which binds to recombinant tau fibrils with high affinity (Kd = 3.6 nM) and detects with high specificity (a) pathological 4R tau aggregates in living cultured neurons and mouse brain sections from transgenic human P301S tau mice, (b) truncated human 151-351 3R (SHR24) and 4R (SHR72) tau aggregates in transgenic rat brain sections, and (c) tau neurofibrillary tangles in brain sections from Alzheimer's disease (3R/4R tau) and progressive supranuclear palsy (4R tau). With LM229 also shown to cross the blood-brain barrier in vivo and its effective radiolabeling with the radioisotope carbon-11, we have established a novel platform for PET translational studies using rodent transgenic tau models.


Assuntos
Doença de Alzheimer , Proteínas tau , Doença de Alzheimer/diagnóstico por imagem , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Tomografia por Emissão de Pósitrons , Ratos , Ratos Transgênicos , Proteínas tau/metabolismo
9.
ACS Chem Neurosci ; 12(6): 1039-1048, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33663205

RESUMO

Microtubule-associated protein tau is abnormally phosphorylated and forms the aggregates of paired helical filaments in Alzheimer's disease (AD) and other tauopathies. So far, the relationship and mechanism between the abnormal phosphorylation of tau and fibril formation is still unclear. Therefore, studying the effect of phosphorylation on the structure of tau protein is helpful to elucidate the pathogenic mechanism of tauopathies. It has been shown that pS202/pT205/pS208 triple phosphorylations located in the proline-rich region can promote tau aggregation. In this work, the effect of triple phosphorylations on tau structure was investigated by molecular dynamics simulations combined with multiple analytical methods of trajectories. The results showed that the conformational diversity of G192-T212 fragments decreased after phosphorylation compared with that of the wild-type. Moreover, the dynamic network and hydrogen bond analyses showed that the addition of pS208 phosphorylation can destroy the key hydrogen bonds and the network structure formed centered on pT205 at the C-terminal of the pS202/pT205 double phosphorylated peptide and then destroy the turn structure formed in the region of G207-R211. The destruction of this turn structure is considered to be the main reason for the aggregation of pS202/pT205/pS208 triple phosphorylations. For the pS202/pT205/pS208 triple phosphorylated system, the G207-R211 region is a coil structure, which is more extended and prone to aggregation. In a word, our results reveal the mechanism that pS202/pT205/pS208 triple phosphorylations promote tau aggregation at the atomic level, which can provide useful theoretical guidance for the rational design of effective therapeutic drugs against AD and other tauopathies.


Assuntos
Doença de Alzheimer , Proteínas tau , Doença de Alzheimer/metabolismo , Humanos , Simulação de Dinâmica Molecular , Emaranhados Neurofibrilares/metabolismo , Fosforilação , Proteínas tau/metabolismo
10.
J Cereb Blood Flow Metab ; 41(8): 1821-1841, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557692

RESUMO

Alzheimer's disease (AD) is a devastating neurological degenerative disorder and is the most common cause of dementia in the elderly. Clinically, AD manifests with memory and cognitive decline associated with deposition of hallmark amyloid beta (Aß) plaques and neurofibrillary tangles (NFTs). Although the mechanisms underlying AD remains unclear, two hypotheses have been proposed. The established amyloid hypothesis states that Aß accumulation is the basis of AD and leads to formation of NFTs. In contrast, the two-hit vascular hypothesis suggests that early vascular damage leads to increased accumulation of Aß deposits in the brain. Multiple studies have reported significant morphological changes of the cerebrovasculature which can result in severe functional deficits. In this review, we delve into known structural and functional vascular alterations in various mouse models of AD and the cellular and molecular constituents that influence these changes to further disease progression. Many studies shed light on the direct impact of Aß on the cerebrovasculature and how it is disrupted during the progression of AD. However, more research directed towards an improved understanding of how the cerebrovasculature is modified over the time course of AD is needed prior to developing future interventional strategies.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Angiopatia Amiloide Cerebral/metabolismo , Angiopatia Amiloide Cerebral/patologia , Circulação Cerebrovascular , Modelos Animais de Doenças , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Fenótipo
11.
Neurosci Lett ; 747: 135708, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33548407

RESUMO

BACKGROUND: Dementia with Lewy bodies (DLB) is one of the major neurodegenerative diseases and a clinical diagnosis is made based on the fourth consensus report on DLB. However, clinicopathological features of DLB are variable among cases. METHODS: We analyzed three autopsy-proven cases of DLB (patients 1-3). Their clinical features were variable in spite of their pathological commonality. The entire hemispheric sections were stained for phosphorylated alpha-synuclein (aS), digitized, and each aS positive lesion was mapped using a virtual slide system. RESULTS: The three patients were clinically diagnosed as having DLB. However, patient 1 exhibited amnesia and misrecognition, while patient 3 exhibited abnormal behavior in addition to dementia. Therefore, both patients 1 and 3 did not fulfill the clinical criteria of DLB, in contrast to patient 2. In spite of the clinical heterogeneity, Lewy pathology was similar in patients 1, 2, and 3. Additionally, patient 1 exhibited less frequent Lewy neurites of the amygdala and entorhinal cortex, and less frequent neurofibrillary tangles and senile plaque as compared to patient 2. On the other hand, the Lewy pathology of patient 3 extended far beyond those of patients 1 and 2, wherein the superior to middle frontal cortices, insular cortex, and lentiform nucleus were severely affected by Lewy pathology. CONCLUSIONS: Clinical features could be variable among autopsy-proven cases of DLB. Furthermore, we show that the accent of Lewy pathology differs according to the variability of the clinical symptoms. This method will provide a comprehensive strategy to analyze wide-spread aS lesions scattered throughout the entire cerebral hemisphere and help determine the corresponding pathological lesions responsible for the clinical variability of neurodegenerative disorders, including DLB.


Assuntos
Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Neuritos/patologia , Emaranhados Neurofibrilares/patologia , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebral/metabolismo , Feminino , Humanos , Masculino , Neuritos/metabolismo , Emaranhados Neurofibrilares/metabolismo , Projetos Piloto
12.
J Alzheimers Dis ; 79(4): 1517-1531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33459640

RESUMO

BACKGROUND: Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) are examples of neurodegenerative diseases, characterized by abnormal tau inclusions, that are called tauopathies. AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. PSP is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with repeated microtubule-binding domains of three (3R) or four (4R) repeats. In AD, the 4R:3R ratio is 1:1. In PSP, the 4R isoform predominates. The lesions in PSP brains contain phosphorylated tau aggregates in both neurons and glial cells. OBJECTIVE: Our objective was to evaluate and compare the processing of pathological tau in PSP and AD. METHODS: Double and triple immunofluorescent labeling with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) staining were carried out and analyzed by confocal microscopy. RESULTS: Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Tau truncated at either Glu391 or Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR in the absence of intact or phosphorylated tau. CONCLUSION: Phosphorylated tau was as abundant in PSP as in AD. The development of eNFTs from both glial cells and neuronal bodies suggests that truncated tau species, different from those observed in AD, could be present in PSP. Additional studies on truncated tau within PSP lesions could improve our understanding of the pathological processing of tau and help identify a discriminatory biomarker for AD and PSP.


Assuntos
Emaranhados Neurofibrilares/metabolismo , Neuroglia/patologia , Neurônios/patologia , Paralisia Supranuclear Progressiva/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Humanos , Emaranhados Neurofibrilares/patologia , Neuroglia/metabolismo , Neurônios/metabolismo , Paralisia Supranuclear Progressiva/patologia
13.
Neurobiol Aging ; 99: 28-43, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33422892

RESUMO

Vascular contributions to early cognitive decline are increasingly recognized, prompting further investigation into the nature of related changes in perivascular spaces (PVS). Using magnetic resonance imaging, we show that, compared to a cognitively normal sample, individuals with early cognitive dysfunction have altered PVS presence and distribution, irrespective of Amyloid-ß. Surprisingly, we noted lower PVS presence in the anterosuperior medial temporal lobe (asMTL) (1.29 times lower PVS volume fraction in cognitively impaired individuals, p < 0.0001), which was associated with entorhinal neurofibrillary tau tangle deposition (beta (standard error) = -0.98 (0.4); p = 0.014), one of the hallmarks of early Alzheimer's disease pathology. We also observed higher PVS volume fraction in centrum semi-ovale of the white matter, but only in female participants (1.47 times higher PVS volume fraction in cognitively impaired individuals, p = 0.0011). We also observed PVS changes in participants with history of hypertension (higher in the white matter and lower in the asMTL). Our results suggest that anatomically specific alteration of the PVS is an early neuroimaging feature of cognitive impairment in aging adults, which is differentially manifested in female.


Assuntos
Disfunção Cognitiva/patologia , Sistema Glinfático/patologia , Envelhecimento/patologia , Amiloide/metabolismo , Feminino , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/metabolismo , Humanos , Hipertensão/patologia , Imageamento por Ressonância Magnética , Masculino , Emaranhados Neurofibrilares/metabolismo , Neuroimagem , Tamanho do Órgão , Caracteres Sexuais , Substância Branca/patologia , Proteínas tau/metabolismo
14.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33431651

RESUMO

Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3ß (GSK3ß). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cistationina gama-Liase/genética , Glicogênio Sintase Quinase 3 beta/genética , Sulfeto de Hidrogênio/farmacologia , Morfolinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Compostos Organotiofosforados/farmacologia , Proteínas tau/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Ligação Proteica , Processamento de Proteína Pós-Traducional , Sulfatos/metabolismo , Proteínas tau/metabolismo
15.
Nat Neurosci ; 24(2): 276-287, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432193

RESUMO

Alzheimer's disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus-brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively-from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.


Assuntos
Doença de Alzheimer/metabolismo , Córtex Entorrinal/metabolismo , Lobo Frontal/metabolismo , Neurônios/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Córtex Entorrinal/patologia , Feminino , Lobo Frontal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Neurônios/patologia , Proteínas tau/metabolismo
16.
J Neurochem ; 156(5): 563-588, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32770783

RESUMO

Since aggregates of the microtubule-binding protein tau were found to be the main component of neurofibrillary tangles more than 30 years ago, their contribution to neurodegeneration in Alzheimer's disease (AD) and tauopathies has become well established. Recent work shows that both tau load and its distribution in the brain of AD patients correlate with cognitive decline more closely compared to amyloid plaque deposition. In addition, the amyloid cascade hypothesis has been recently challenged because of disappointing results of clinical trials designed to treat AD by reducing beta-amyloid levels, thus fuelling a renewed interest in tau. There is now robust evidence to indicate that tau pathology can spread within the central nervous system via a prion-like mechanism following a stereotypical pattern, which can be explained by the trans-synaptic inter-neuronal transfer of pathological tau. In the receiving neuron, tau has been shown to take multiple routes of internalisation, which are partially dependent on its conformation and aggregation status. Here, we review the emerging mechanisms proposed for the uptake of extracellular tau in neurons and the requirements for the propagation of its pathological conformers, addressing how they gain access to physiological tau monomers in the cytosol. Furthermore, we highlight some of the key mechanistic gaps of the field, which urgently need to be addressed to expand our understanding of tau propagation and lead to the identification of new therapeutic strategies for tauopathies.


Assuntos
Encéfalo/metabolismo , Emaranhados Neurofibrilares/metabolismo , Neurônios/metabolismo , Tauopatias/metabolismo , Proteínas tau/metabolismo , Animais , Transporte Biológico/fisiologia , Encéfalo/patologia , Humanos , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/patologia , Neurônios/patologia , Tauopatias/genética , Tauopatias/patologia , Proteínas tau/genética
17.
Eur J Nucl Med Mol Imaging ; 48(4): 1093-1102, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32970217

RESUMO

PURPOSE: MK6240 is a second-generation tau PET tracer designed to detect the neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). The aim of the study was to characterize 3H-MK6240 in AD and control brain tissue and to compare its binding properties with those of first-generation tau PET tracers. METHODS: Saturation binding assays with 3H-MK6240 were carried out in the temporal and parietal cortices of AD brains to determine the maximum number of binding sites (Bmax) and the dissociation constants (Kd) at these sites. Competitive binding assays were carried out between 3H-MK6240 and unlabelled MK6240, AV-1451 (aka T807, flortaucipir) and THK5117, and between 3H-THK5351 and unlabelled MK6240. Regional binding studies with 3H-MK6240 were carried out in homogenates from six AD and seven control brains and, using autoradiography, on large frozen sections from two AD brains and one control brain. RESULTS: The saturation binding assays gave Bmax and Kd values of 59.2 fmol/mg and 0.32 nM in the temporal cortex and 154.7 fmol/mg and 0.15 nM in the parietal cortex. The competitive binding assays revealed two binding sites with affinities in the picomolar and nanomolar range shared by 3H-MK6240 and all the tested unlabelled compounds. There were no binding sites in common between 3H-THK5351 and unlabelled MK6240. Regional binding of 3H-MK6240 was significantly higher in AD brain tissue than in controls. Binding in brain tissue from AD patients with early-onset AD was significantly higher than in brain tissue from patients with late-onset AD. Binding of 3H-MK6240 was not observed in off-target regions. Autoradiography showed high regional cortical binding in the two AD brains and very low binding in the control brain. CONCLUSIONS: 3H-MK6240 has a high binding affinity for tau deposits in AD brain tissue but also has different binding characteristics from those of the first-generation tau tracers. This confirms the complexity of tau tracer binding on tau deposits with different binding affinities for different binding sites.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico por imagem , Autopsia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Humanos , Emaranhados Neurofibrilares/metabolismo , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo
18.
Eur J Med Chem ; 209: 112915, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33139110

RESUMO

Alzheimer's disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Currently there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Fármacos Neuroprotetores/química , Proteínas tau/metabolismo , Animais , Benzodioxóis/farmacologia , Inibidores da Colinesterase/farmacologia , Colinesterases/metabolismo , Curcumina/farmacologia , Humanos , Terapia de Alvo Molecular , Emaranhados Neurofibrilares/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosforilação , Placa Amiloide/metabolismo , Agregação Patológica de Proteínas/prevenção & controle , Processamento de Proteína Pós-Traducional , Quinazolinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tiadiazóis/farmacologia
19.
Int J Biol Macromol ; 167: 382-394, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33278431

RESUMO

It is reported that approximately 40 million people are suffering from dementia, globally. Dementia is a group of symptoms that affect neurons and cause some mental disorders, such as losing memory. Alzheimer's disease (AD) which is known as the most common cause of dementia, is one of the top medical care concerns across the world. Although the exact sources of the disease are not understood, is it believed that aggregation of amyloid-beta (Aß) outside of neuron cells and tau aggregation or neurofibrillary tangles (NFTs) formation inside the cell may play crucial roles. In this paper, we are going to review studies that targeted inhibition of amyloid plaque and tau protein tangle formation, to suppress or postpone AD.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/metabolismo , Suscetibilidade a Doenças , Humanos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Agregados Proteicos , Agregação Patológica de Proteínas , Dobramento de Proteína , Proteínas tau/antagonistas & inibidores , Proteínas tau/genética
20.
J Neuropathol Exp Neurol ; 80(2): 102-111, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33367843

RESUMO

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-ß (Aß) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aß pathology in AD and PART.


Assuntos
Envelhecimento/patologia , Região CA2 Hipocampal/patologia , Neurônios/patologia , Tauopatias/patologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Peptídeos beta-Amiloides/metabolismo , Região CA2 Hipocampal/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Neurônios/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Tauopatias/metabolismo , Proteínas tau/metabolismo
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