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1.
Dement Neuropsychol ; 18: e20230108, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38933078

RESUMO

The French composer, Maurice Ravel, at the peak of his career, showed signs of a progressive disorder that affected his ability to function with verbal and musical language, as noted by the neurologist Théophile Alajouanine. The worsening of the disease led to a craniotomy, performed in 1937, which failed to reveal the cause of his illness, and he died shortly thereafter. A lack of post-mortem neuropathological evidence precluded a definitive diagnosis of the illness, which remained enigmatic. Speculations about the precise diagnosis of Ravel's neurological disease have been largely based on Alajouanine's observations, which included aphasia and amusia, mostly expressive, and ideomotor apraxia, while musical judgement, taste, and memory remained relatively intact, implying different neuroanatomical substrates. A possible subform of frontotemporal lobar degeneration complex was the diagnostic suggestion of many authors. His untimely death deprived the world of this remarkable musician, and the music that remained trapped in his mind.


O compositor francês Maurice Ravel, no ápice de sua carreira, mostrou sinais de uma desordem progressiva que afetou sua capacidade de funcionar com linguagem verbal e musical, como notado pelo neurologista Théophile Alajouanine. O agravamento de sua condição levou a uma craniotomia, efetuada em 1937, que deixou de revelar a causa de sua doença, tendo ele falecido pouco depois. A ausência de evidência neuropatológica pós-morte impediu o diagnóstico definitivo da doença, que permaneceu enigmático. Especulações sobre o diagnóstico preciso da doença neurológica de Ravel foram baseadas sobretudo nas observações de Alajouanine, que compreendiam afasia e amusia, predominantemente expressiva, e também apraxia, enquanto o julgamento, gosto e memória musicais permaneceram relativamente intactos, implicando diferentes substratos neuroanatômicos. A possibilidade de uma subforma do complexo da degenearação lobar frontotemporal foi a sugestão diagnóstica de muitos autores. A sua morte prematura privou o mundo desse notável músico e da música que permaneceu presa em sua mente.

2.
J Enzyme Inhib Med Chem ; 38(1): 2225797, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38061987

RESUMO

Cholinesterase (ChE) enzymes have been identified as diagnostic markers for Alzheimer disease (AD). Substrate-based probes have been synthesised to detect ChEs but they have not detected changes in ChE distribution associated with AD pathology. Probes are typically screened using spectrophotometric methods with pure enzyme for specificity and kinetics. However, the biochemical properties of ChEs associated with AD pathology are altered. The present work was undertaken to determine whether the Karnovsky-Roots (KR) histochemical method could be used to evaluate probes at the site of pathology. Thirty thioesters and esters were synthesised and evaluated using enzyme kinetic and KR methods. Spectrophotometric methods demonstrated all thioesters were ChE substrates, yet only a few provided staining in the brain with the KR method. Esters were ChE substrates with interactions with brain ChEs. These results suggest that the KR method may provide an efficient means to screen compounds as probes for imaging AD-associated ChEs.


Assuntos
Doença de Alzheimer , Colinesterases , Humanos , Colinesterases/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Inibidores da Colinesterase/química , Encéfalo , Acetilcolinesterase/metabolismo
3.
Antiviral Res ; 220: 105758, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38008194

RESUMO

Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle formation, viral RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two viral cysteine proteases, main protease (Mpro) and papain-like protease (PLpro), that mediate polyprotein cleavage. Using a structure-guided approach, a phenothiazine urea derivative that inhibits both SARS-CoV-2 Mpro and PLpro protease activity was identified. In silico docking studies also predicted the binding of the phenothiazine urea to the active sites of structurally similar Mpro and PLpro proteases from distantly related alphacoronavirus, HCoV-229 E (229 E), and the betacoronavirus, HCoV-OC43 (OC43). The lead phenothiazine urea derivative displayed broad antiviral activity against all three HCoVs tested in cellulo. It was further demonstrated that the compound inhibited 229 E and OC43 at an early stage of viral replication, with diminished formation of viral replication organelles, and the RNAs that are made within them, as expected following viral protease inhibition. These observations suggest that the phenothiazine urea derivative readily inhibits viral replication and may broadly inhibit proteases of diverse coronaviruses.


Assuntos
Peptídeo Hidrolases , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Papaína/química , Proteases Virais , Fenotiazinas/farmacologia , Inibidores de Proteases/química , Antivirais/farmacologia , Antivirais/química
4.
Chem Biol Interact ; 383: 110667, 2023 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-37579937

RESUMO

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that serve a wide range of physiological functions including the hydrolysis of the neurotransmitter acetylcholine and several other xenobiotics. The development of inhibitors for these enzymes has been the focus for the treatment of several conditions, such as Alzheimer's disease. Novel chemical entities are evaluated as potential inhibitors of AChE and BChE using enzyme kinetics. A common issue encountered in these studies is low aqueous solubility of the possible inhibitor. Additives such as cosolvents or detergents can be included in these studies improve the aqueous solubility. Typical cosolvents include acetonitrile or dimethyl sulfoxide while typical detergents include Polysorbate 20 (Tween 20) or 3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonate (CHAPS). When solubility is not improved, these molecules are often not evaluated further. To address this issue eleven cosolvents and six detergents that could facilitate aqueous solubility were evaluated to understand how they would affect cholinesterase enzymes using Ellman's assay. These studies show that propylene glycol, acetonitrile, methanol, Tween 20, Polysorbate 80 (Tween 80), polyoxyethylene 23 lauryl ether (Brij 35) and polyoxyethylene 10 oleoyl ether (Brij 96v) have the least inhibitory effects towards cholinesterase activity. It is concluded that these cosolvents and detergents should be considered as solubilizing agents for evaluation of potential cholinesterase inhibitors with low aqueous solubility.


Assuntos
Acetilcolinesterase , Butirilcolinesterase , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Solventes , Detergentes/farmacologia , Cinética , Polissorbatos/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Polietilenoglicóis , Éteres
5.
Sci Rep ; 12(1): 22174, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36550188

RESUMO

Neuroimaging with [2,2-dimethyl-3-[(2R,3E)-3-oxidoiminobutan-2-yl]azanidylpropyl]-[(2R,3E)-3-hydroxyiminobutan-2-yl]azanide;oxo(99Tc)technetium-99(3+) ([99mTc]HMPAO) single photon emission computed tomography (SPECT) is used in Alzheimer's disease (AD) to evaluate regional cerebral blood flow (rCBF). Hypoperfusion in select temporoparietal regions has been observed in human AD. However, it is unknown whether AD hypoperfusion signatures are also present in the 5XFAD mouse model. The current study was undertaken to compare baseline brain perfusion between 5XFAD and wild-type (WT) mice using [99mTc]HMPAO SPECT and determine whether hypoperfusion is recapitulated in 5XFAD mice. 5XFAD and WT mice underwent a 45 min SPECT scan, 20 min after [99mTc]HMPAO administration. Whole brain and regional standardized uptake values (SUV) and regional relative standardized uptake values (SUVR) with whole brain reference were compared between groups. Brain perfusion was similar between WT and 5XFAD brains. Whole brain [99mTc]HMPAO retention revealed no significant difference in SUV (5XFAD, 0.372 ± 0.762; WT, 0.640 ± 0.955; p = 0.536). Similarly, regional analysis revealed no significant differences in [99mTc]HMPAO metrics between groups (SUV: 0.357 ≤ p ≤ 0.640; SUVR: 0.595 ≤ p ≤ 0.936). These results suggest apparent discrepancies in rCBF between human AD and the 5XFAD model. Establishing baseline perfusion patterns in 5XFAD mice is essential to inform pre-clinical diagnostic and therapeutic drug discovery programs.


Assuntos
Doença de Alzheimer , Humanos , Animais , Camundongos , Doença de Alzheimer/diagnóstico por imagem , Tecnécio Tc 99m Exametazima , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Encéfalo/diagnóstico por imagem , Perfusão , Circulação Cerebrovascular/fisiologia , Compostos de Organotecnécio , Compostos Radiofarmacêuticos
6.
Chem Biol Interact ; 364: 110065, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35872043

RESUMO

A subset of octogenarians and older maintain normal cognitive function (CNOO) despite high prevalence and incidence of cognitive decline attributed to neurodegeneration or aging in the population. The rostral prefrontal cortex (rPFC) and hippocampal formation are brain regions integral to cognition, namely attention and memory, facilitated in part by cholinergic innervation. We hypothesized that preserved cholinergic neurotransmission in these regions contributes to intact cognition in the CNOO. To test this, we evaluated the burden of neuropathological and cholinesterase-associated protein aggregates in the rPFC and hippocampal formation. Tissues from age- and sex-matched CNOO and Alzheimer's disease (AD) rPFC and hippocampal formation were stained for ß-amyloid (Aß), tau, α-synuclein, phosphorylated TAR DNA-binding protein 43 (pTDP-43), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The relative abundance of neuropathological aggregates was semi-quantitatively scored. Deposition of Aß plaques, tau neurofibrillary tangles (NFT) and pTDP-43 inclusions were comparable between CNOO and AD cases. Intraneuronal Aß and tau-positive thorny astrocytes consistent with aging-related tau astrogliopathy, were also noted in the rPFC. Abundance of BChE-positive plaque pathology was significantly higher in AD than in CNOO cases in most regions of interest, followed closely by abundance of AChE-positive plaque pathology. BChE and AChE activities were also associated with varied NFT morphologies. CNOO cases maintained cognition despite a high neuropathological burden in the rPFC and hippocampal formation. BChE-positive and, to a lesser extent, AChE-positive pathologies were significantly lower in most regions in the CNOO compared to AD. This suggests a specificity of cholinesterase-associated neuropathology with AD. We conclude that while CNOO have cholinesterase-associated neuropathology in the rPFC and hippocampal formation, abundance in this population is significantly lower compared to AD which may contribute to their intact cognition.


Assuntos
Doença de Alzheimer , Butirilcolinesterase , Acetilcolinesterase/metabolismo , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Butirilcolinesterase/metabolismo , Colinérgicos , Humanos , Octogenários , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Proteínas tau/metabolismo
7.
Alzheimers Dement (N Y) ; 8(1): e12283, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35415204

RESUMO

Introduction: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aß) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Aß-mediated neurotoxicities in AD.  Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD. Results: In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aß is released as an early responder immunopeptide triggering an innate immunity cascade in which Aß exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon "self" neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Aß. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aß, leading to a chronic self-perpetuating autoimmune cycle.  AD thus emerges as a brain-centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex immunopathic-proteopathic pathogenesis. Discussion:  Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug-like analogues of these endogenous regulators represents a novel therapeutic approach for AD.

8.
J Alzheimers Dis ; 82(2): 575-592, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34057083

RESUMO

BACKGROUND: Microglia contribute to Alzheimer's disease (AD) pathogenesis by clearing amyloid-ß (Aß) and driving neuroinflammation. Domestic dogs with age-related dementia (canine cognitive dysfunction (CCD)) develop cerebral amyloidosis like humans developing AD, and studying such dogs can provide novel information about microglial response in prodromal AD. OBJECTIVE: The aim was to investigate the microglial response in the cortical grey and the subcortical white matter in dogs with CCD versus age-matched cognitively normal dogs. METHODS: Brains from aged dogs with CCD and age-matched controls without dementia were studied. Cases were defined by dementia rating score. Brain sections were stained for Aß, thioflavin S, hyperphosphorylated tau, and the microglial-macrophage ionized calcium binding adaptor molecule 1 (Iba1). Results were correlated to dementia rating score and tissue levels of Aß. RESULTS: Microglial numbers were higher in the Aß plaque-loaded deep cortical layers in CCD versus control dogs, while the coverage by microglial processes were comparable. Aß plaques were of the diffuse type and without microglial aggregation. However, a correlation was found between the %Iba1 area and insoluble Aß 42 and N-terminal pyroglutamate modified Aß(N3pE)-42. The %Iba1 area was higher in white matter, showing phosphorylation of S396 tau, versus grey matter. Perivascular macrophage infiltrates were abundant in the white matter particularly in CDD dogs. CONCLUSION: The results from this study of the microglial-macrophage response in dogs with CCD are suggestive of relatively mild microglial responses in the Aß plaque-loaded deep cortical layers and perivascular macrophage infiltrates in the subcortical white matter, in prodromal AD.


Assuntos
Envelhecimento , Doença de Alzheimer , Macrófagos , Transtornos da Memória , Microglia , Substância Branca , Envelhecimento/patologia , Envelhecimento/fisiologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Cães , Sistema Glinfático/patologia , Macrófagos/imunologia , Macrófagos/patologia , Transtornos da Memória/imunologia , Transtornos da Memória/patologia , Microglia/patologia , Microglia/fisiologia , Neuroimunomodulação , Placa Amiloide/patologia , Sintomas Prodrômicos , Prognóstico , Substância Branca/imunologia , Substância Branca/patologia
9.
Neurobiol Aging ; 103: 31-41, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33789210

RESUMO

In sporadic Alzheimer's disease (SpAD), acetylcholinesterase and butyrylcholinesterase, co-regulators of acetylcholine, are associated with ß-amyloid plaques and tau neurofibrillary tangles in patterns suggesting a contribution to neurotoxicity. This association has not been explored in early-onset familial Alzheimer's disease (FAD). We investigated whether cholinesterases are observed in the neuropathological hallmarks in FAD expressing the presenilin 1 Leu235Pro mutation. Brain tissues from three FAD cases and one early-onset SpAD case were stained and analyzed for ß-amyloid, tau, α-synuclein, acetylcholinesterase and butyrylcholinesterase. AD pathology was prominent throughout the rostrocaudal extent of all 4 brains but α-synuclein-positive neurites were present in only one familial case. In FAD and SpAD cases, cholinergic activity was associated with plaques and tangles but not with α-synuclein pathology. Both cholinesterases showed similar or decreased plaque staining than detected with ß-amyloid immunostaining but greater plaque deposition than observed with thioflavin-S histofluorescence. Acetylcholinesterase and butyrylcholinesterase are highly associated with AD pathology in inherited disease and both may represent specific diagnostic and therapeutic targets for all AD forms.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Colinesterases/genética , Colinesterases/metabolismo , Expressão Gênica , Mutação/genética , Presenilina-1/genética , Adulto , Fatores Etários , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Amiloide/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Proteínas tau/toxicidade
10.
Neurobiol Aging ; 101: 298.e1-298.e10, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33612310

RESUMO

Mutations in the microtubule-associated protein tau gene are known to cause progressive neurodegenerative disorders with variable clinical and neuropathological phenotypes, including the intronic 10 + 14 (IVS10 + 14) splice site mutation. Three families have been reported with the IVS10 + 14 microtubule-associated protein tau mutation. Here, we describe the clinical and neuropathological data from an additional family. Neuropathological data were available for 2 of the 3 cases, III-4, and III-5. While III-5 had widespread tau deposition and atrophy, III-4 exhibited more mild neuropathological changes except for the substantia nigra. The previously reported families that express the IVS10 + 14 mutation exhibited significant interfamilial heterogeneity, with symptoms including amyotrophy, dementia, disinhibition, parkinsonism, and breathing problems. In addition to expressing many of these symptoms, members of this fourth family experienced profound sensory abnormalities and sleep disturbance. Although there were probable clinicopathological correlates for the symptoms expressed by the earlier families and III-5 from our cohort, pathology in III-4 did not appear sufficient to explain symptom severity. This indicates the need to explore alternate mechanisms of tau-induced brain dysfunction.


Assuntos
Mutação/genética , Doenças Neurodegenerativas/genética , Proteínas tau/genética , Adulto , Feminino , Demência Frontotemporal/genética , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Masculino , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Fenótipo , Sítios de Splice de RNA/genética , Transtornos de Sensação/genética , Transtornos do Sono-Vigília/genética , Substância Negra/patologia
11.
J Comp Neurol ; 529(5): 1029-1051, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32779183

RESUMO

The cetacean hippocampal formation has been noted to be one of the smallest relative to brain size of all mammals studied. This region, comprised of the dentate gyrus, hippocampus proper, subiculum, presubiculum, parasubiculum and the entorhinal cortex, is important in learning, memory, and navigation. There have been a number of studies detailing the distribution of acetylcholinesterase (AChE) in the hippocampal formation of terrestrial mammals with the goal of gaining a greater understanding of some aspects of the cholinergic innervation to this region, as well as its parcellation. The present study was undertaken to describe the organization, cytoarchitecture, and distribution of AChE in the hippocampal formation of the Atlantic white-sided dolphin (AWSD) with the view to understand similarities and differences between this aquatic mammal and terrestrial mammals. Nissl-staining demonstrated cytoarchitecture of the hippocampal formation in the AWSD comparable to that reported in other cetaceans. In addition, the AWSD had a rich pattern of AChE staining that distinctly varied between regions and laminae. A number of differences in the distribution of AChE staining in areas comparable to those of terrestrial species reported suggested possible alterations in connectivity of this region. Overall, however, AChE-staining suggested that cholinergic innervation, neural pathways and function of the hippocampal formation of the AWSD is conserved, similar to other mammals.


Assuntos
Acetilcolinesterase/análise , Golfinhos/fisiologia , Hipocampo/enzimologia , Proteínas do Tecido Nervoso/análise , Animais , Giro Denteado/enzimologia , Córtex Entorrinal/enzimologia , Feminino , Hipocampo/ultraestrutura , Masculino
12.
Chem Biol Interact ; 335: 109348, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33278462

RESUMO

The disease, COVID-19, is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) for which there is currently no treatment. The SARS-CoV-2 main protease (Mpro) is an important enzyme for viral replication. Small molecules that inhibit this protease could lead to an effective COVID-19 treatment. The 2-pyridone scaffold was previously identified as a possible key pharmacophore to inhibit SARS-CoV-2 Mpro. A search for natural, antimicrobial products with the 2-pyridone moiety was undertaken herein, and their calculated potency as inhibitors of SARS-CoV-2 Mpro was investigated. Thirty-three natural products containing the 2-pyridone scaffold were identified from the literature. An in silico methodology using AutoDock was employed to predict the binding energies and inhibition constants (Ki values) for each 2-pyridone-containing compound with SARS-CoV-2 Mpro. This consisted of molecular optimization of the 2-pyridone compound, docking of the compound with a crystal structure of SARS-CoV-2 Mpro, and evaluation of the predicted interactions and ligand-enzyme conformations. All compounds investigated bound to the active site of SARS-CoV-2 Mpro, close to the catalytic dyad (His-41 and Cys-145). Thirteen molecules had predicted Ki values <1 µM. Glu-166 formed a key hydrogen bond in the majority of the predicted complexes, while Met-165 had some involvement in the complex binding as a close contact to the ligand. Prominent 2-pyridone compounds were further evaluated for their ADMET properties. This work has identified 2-pyridone natural products with calculated potent inhibitory activity against SARS-CoV-2 Mpro and with desirable drug-like properties, which may lead to the rapid discovery of a treatment for COVID-19.


Assuntos
Antivirais/metabolismo , Produtos Biológicos/metabolismo , Proteases 3C de Coronavírus/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , Piridonas/metabolismo , SARS-CoV-2/enzimologia , Antivirais/química , Antivirais/farmacocinética , Produtos Biológicos/química , Produtos Biológicos/farmacocinética , Células CACO-2 , Domínio Catalítico , Proteases 3C de Coronavírus/química , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacocinética , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Piridonas/química , Piridonas/farmacocinética
13.
Biomolecules ; 10(12)2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33260981

RESUMO

Kinetic studies and molecular modeling of human acetylcholinesterase (AChE) inhibition by a fluorinated acetophenone derivative, 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK), were performed. Fast reversible inhibition of AChE by TFK is of competitive type with Ki = 5.15 nM. However, steady state of inhibition is reached slowly. Kinetic analysis showed that TFK is a slow-binding inhibitor (SBI) of type B with Ki* = 0.53 nM. Reversible binding of TFK provides a long residence time, τ = 20 min, on AChE. After binding, TFK acylates the active serine, forming an hemiketal. Then, disruption of hemiketal (deacylation) is slow. AChE recovers full activity in approximately 40 min. Molecular docking and MD simulations depicted the different steps. It was shown that TFK binds first to the peripheral anionic site. Then, subsequent slow induced-fit step enlarged the gorge, allowing tight adjustment into the catalytic active site. Modeling of interactions between TFK and AChE active site by QM/MM showed that the "isomerization" step of enzyme-inhibitor complex leads to a complex similar to substrate tetrahedral intermediate, a so-called "transition state analog", followed by a labile covalent intermediate. SBIs of AChE show prolonged pharmacological efficacy. Thus, this fluoroalkylketone intended for neuroimaging, could be of interest in palliative therapy of Alzheimer's disease and protection of central AChE against organophosphorus compounds.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Teoria da Densidade Funcional , Inibidores da Colinesterase/química , Humanos , Modelos Moleculares , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Proteínas Recombinantes/metabolismo
14.
Neurology ; 95(24): e3269-e3279, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-32989103

RESUMO

OBJECTIVE: To test the hypothesis that degree of frailty and neuropathologic burden independently contribute to global cognition and odds of dementia. METHODS: This was a secondary analysis of a prospective cohort study of older adults living in Illinois. Participants underwent an annual neuropsychological and clinical evaluation. We included 625 participants (mean age 89.7 ± 6.1 years; 67.5% female) who died and underwent autopsy. We quantified neuropathology using an index measure of 10 neuropathologic features: ß-amyloid deposition, hippocampal sclerosis, Lewy bodies, tangle density, TDP-43, cerebral amyloid angiopathy, arteriolosclerosis, atherosclerosis, and gross and chronic cerebral infarcts. Clinical consensus determined dementia status, which we coded as no cognitive impairment, mild cognitive impairment, or dementia. A battery of 19 tests spanning multiple domains quantified global cognition. We operationalized frailty using a 41-item frailty index. We employed regression analyses to model relationships between neuropathology, frailty, and dementia. RESULTS: Both frailty and a neuropathology index were independently associated with global cognition and dementia status. These results held after controlling for traditional pathologic measures in a sample of participants with Alzheimer clinical syndrome. Frailty improved the fit of the model for dementia status (χ2[2] 72.64; p < 0.0001) and explained an additional 11%-12% of the variance in the outcomes. CONCLUSION: Dementia is a multiply determined condition, to which both general health, as captured by frailty, and neuropathology significantly contribute. This integrative view of dementia and health has implications for prevention and therapy; specifically, future research should evaluate frailty as a means of dementia risk reduction.


Assuntos
Transtornos Cognitivos/fisiopatologia , Demência/patologia , Demência/fisiopatologia , Fragilidade/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Transtornos Cognitivos/epidemiologia , Comorbidade , Demência/epidemiologia , Feminino , Fragilidade/epidemiologia , Humanos , Illinois/epidemiologia , Masculino , Estudos Prospectivos , Análise de Regressão
15.
Front Cell Neurosci ; 13: 538, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31866830

RESUMO

Sections from the middle frontal gyrus (Brodmann area 46) of autopsy-confirmed Alzheimer's disease (AD) patients and non-demented subjects were examined for the prevalence of hallmark AD pathology, including amyloid-ß (Aß) plaques, phosphorylated tau (pTau) tangles, neuroinflammation and synaptic loss (n = 7 subjects/group). Dense-core deposits of Aß were present in all AD patients (7/7) and some non-demented subjects (3/7), as evidenced by 6E10 immunohistochemistry. Levels of Aß immunoreactivity were higher in AD vs. non-AD cases. For pTau, AT8-positive neurofibrillary tangles and threads were exclusively observed in AD patient tissue. Levels of [3H]PK11195 binding to the translocator protein (TSPO), a marker of inflammatory processes, were elevated in the gray matter of AD patients compared to non-demented subjects. Levels of [3H]UCB-J binding to synaptic vesicle glycoprotein 2A (SV2A), a marker of synaptic density, were not different between groups. In AD patients, pTau immunoreactivity was positively correlated with [3H]PK11195, and negatively correlated with [3H]UCB-J binding levels. No correlation was observed between Aß immunoreactivity and markers of neuroinflammation or synaptic density. These data demonstrate a close interplay between tau pathology, inflammation and SV2A density in AD, and provide useful information on the ability of neuroimaging biomarkers to diagnose AD dementia.

16.
Sci Rep ; 9(1): 15758, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673052

RESUMO

Despite compelling evidence that the accumulation of amyloid-beta (Aß) promotes neocortical MAPT (tau) aggregation in familial and idiopathic Alzheimer's disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. In the present study, we show that tau can accumulate spontaneously in aged transgenic APPswe/PS1ΔE9 mice. Tau pathology is abundant around Aß deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the APPswe/PS1ΔE9 brain at 18 months of age. Age-dependent increases in argyrophilia correlated positively with binding levels of the paired helical filament (PHF) tracer [18F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Quantitative proteomics identified sequences of hyperphosphorylated and three-repeat tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Tissue from the frontal gyrus of human subjects was used to validate these findings, revealing primarily quantitative differences between the tau pathology observed in AD patient vs. transgenic mouse tissue. As physiological levels of endogenous, 'wild-type' tau aggregate secondarily to Aß in APPswe/PS1ΔE9 mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.


Assuntos
Envelhecimento , Doença de Alzheimer , Peptídeos beta-Amiloides , Amiloidose , Proteínas tau , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Amiloidose/genética , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Proteínas tau/genética , Proteínas tau/metabolismo
17.
Can J Neurol Sci ; 46(2): 174-183, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30819267

RESUMO

BACKGROUND: Primary Progressive Aphasia (PPA) is a syndrome characterized by an isolated impairment of language function at disease onset. The cholinergic system is implicated in language function and cholinergic deficits are seen in the brains of individuals with PPA. One major source of cholinergic innervation of the cerebral cortex is the nucleus basalis of Meynert (NBM) within which lies the nucleus subputaminalis (NSP). This nucleus is postulated to be involved in language function. We compared the abundance of cholinergic neurons in the NBM and NSP of controls and individuals with PPA. Also explored was whether the individuals presenting with PPA, who subsequently developed different clinical and neuropathological profiles, showed similar cholinergic deficits in the NSP. METHODS: Cytoarchitecture of the basal forebrain was studied using Nissl staining in control (n = 5) and PPA (n = 5) brains. Choline acetyltransferase (ChAT) immunohistochemical staining labeled cholinergic neurons were quantified using Neurolucida software. RESULTS: In comparison to matched controls, PPA showed reduction of cholinergic neurons in the NBM (t(8) = 4.04, p = 0.0037; Cohen's effect size value d = 2.62) and the NSP (t(6) = 4.62, p = 0.0042; Cohen's d effect size d = 2.92). The average percent of cholinergic neuronal loss was relatively higher in the NSP (64.7%) compared to the NBM (47.7%). CONCLUSION: Regardless of underlying pathology, all cases presenting with PPA showed a marked loss of cholinergic neurons in the NSP, providing further evidence for the importance of this nucleus in language function.


Assuntos
Afasia Primária Progressiva/patologia , Núcleo Basal de Meynert/patologia , Neurônios Colinérgicos/patologia , Idoso , Idoso de 80 Anos ou mais , Afasia Primária Progressiva/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Clin Neuropsychol ; 33(5): 817-830, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29985104

RESUMO

Objective: The Clock Drawing Test (CDT) is commonly used as a screening tool for the assessment of dementia. The association between the CDT in acute stroke and long-term functional and cognitive outcomes in this population is unknown. The present prospective study is the first to examine if CDT scores in the acute stage after stroke are related to long-term outcomes and to compare the predictive ability of two scoring systems in a large sample of stroke patients. Method: A total of 340 patients admitted to an acute stroke unit were included in the present study. Separate stepwise multiple linear regression analyses were performed with eight independent variables (demographic/pre-stroke variables - age, sex, premorbid functioning; stroke-related variables - stroke severity, localization; cognitive variables - Orientation Test, CDT [2 scoring systems]), and four dependent variables administered one year post-stroke (Barthel Index, modified Rankin Scale, Reintegration to Normal Living index, Global Deterioration Scale). Results: Although both CDT scoring methods were related to all long-term outcome measures, the more comprehensive scoring system was the only baseline variable that significantly explained the variance in outcome measures in all four multiple regression models. Conclusion: Performance on the CDT in acute stroke is related to long-term outcomes including patients' degree of independence in performing activities of daily living, the degree to which they achieved reintegration into daily occupations, and the degree of cognitive decline observed one-year post-stroke. Future studies are needed to clarify the nature of the relationship between different CDT scoring systems and post-stroke outcomes.


Assuntos
Disfunção Cognitiva/diagnóstico , Testes Neuropsicológicos/normas , Acidente Vascular Cerebral/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Acidente Vascular Cerebral/patologia , Adulto Jovem
20.
Front Cell Neurosci ; 12: 397, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30459560

RESUMO

Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer's disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1ΔE9 transgenic mice with E. coli lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b+ microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68+ microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APPSWE/PS1ΔE9 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD.

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