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AIM: This study aimed to analyze two cases of marked hypo-high-density lipoprotein (HDL) cholesterolemia to identify mutations in ATP-binding cassette transporter A1 (ABCA1) and elucidate the molecular mechanism by which these novel pathological mutations contribute to hypo-HDL cholesterolemia in Tangier disease. METHODS: Wild type and mutant expression plasmids containing a FLAG tag inserted at the C-terminus of the human ABCA1 gene were generated and transfected into HEK293T cells. ABCA1 protein expression and cholesterol efflux were evaluated via Western blotting and efflux assay. The difference in the rate of change in protein expression was evaluated when proteolytic and protein-producing systems were inhibited. RESULTS: In case 1, a 20-year-old woman presented with a chief complaint of gait disturbance. Her HDL-C level was only 6.2 mg/dL. Tangier disease was suspected because of muscle weakness, decreased nerve conduction velocity, and splenomegaly. Whole-exome analysis showed compound heterozygosity for a W484* nonsense mutation and S1343I missense mutation, which confirmed Tangier disease. Cholesterol efflux decreased by a mixture of W484* and S1343I mutations. The S1343I mutation decreased the protein production rate but increased the degradation rate, decreasing the protein levels. This patient also had Krabbe disease. The endogenous ABCA1 protein level of macrophage cell decreased by knocking down its internal galactocerebrosidase.Case 2, a 51-year-old woman who underwent tonsillectomy presented with peripheral neuropathy, corneal opacity, and HDL-C of 3.4 mg/dL. Whole-exome analysis revealed compound heterozygosity for R579* and R1572* nonsense mutations, which confirmed Tangier disease. CONCLUSION: Case 1 is a new ABCA1 mutation with complex pathogenicity, namely, a W484*/S1343I compound heterozygote with marked hypo-HDL cholesterolemia. Analyses of the compound heterozygous mutations indicated that decreases in ABCA1 protein levels and cholesterol efflux activity caused by the novel S1343I mutation combined with loss of W484* protein activity could lead to marked hypo-HDL cholesterolemia. Galactocerebrosidase dysfunction could also be a potential confounding factor for ABCA1 protein function.
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GDF-15, a member of the transforming growth factor beta superfamily, regulates inflammatory and apoptotic pathways in various diseases, such as heart failure, kidney dysfunction, and cancer. We aimed to clarify potentially confounding variables affecting GDF-15 and demonstrate its utility as a mitochondrial biomarker using serum samples from 15 patients with mitochondrial diseases (MD), 15 patients with limbic encephalitis (LE), 10 patients with multiple sclerosis/neuromyelitis optica spectrum disorders (MS/NMOSD), and 19 patients with amyotrophic lateral sclerosis (ALS). GDF-15 and FGF-21 were significantly elevated in MD. GDF-15 and FGF-21 showed a good correlation in MD but not in LE, MS, and ALS. GDF-15 was potentially influenced by age in LE, MS/NMOSD, and ALS but not in MD. FGF-21 was not correlated with age in MS/NMOSD, ALS, LE, and MD. GDF-15 was not correlated with clinical features in LE or BMI or body weight in ALS. GDF-15 positively correlated with the Expanded Disability Status Scale (EDSS) in MS/NMOSD, while EDSS showed no correlation with age. In conclusion, the results revealed that GDF-15 may be influenced by EDSS in MS/NMOPSD and by age in LE, MS/NMOSD, and ALS but not in MD. Mitochondrial damage in MS/NMOSD is a potentially confounding variable affecting GDF-15.
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Fatores de Crescimento de Fibroblastos/sangue , Fator 15 de Diferenciação de Crescimento/sangue , Doenças Mitocondriais/sangue , Esclerose Múltipla/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/sangue , Biomarcadores/sangue , Avaliação da Deficiência , Feminino , Humanos , Encefalite Límbica/sangue , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/sangue , Adulto JovemRESUMO
RATIONALE: Neurological complications of varicella-zoster virus (VZV) infection include cerebral infarction, meningoencephalitis, segmental sensory disturbance, facial nerve palsy, and myelitis. Chronic myelitis is rarely reported. Diagnosis of VZV infection can be confirmed by elevated anti-VZV immunoglobulin G (IgG) antibody or detection of VZV DNA in the cerebrospinal fluid (CSF), the former reported to be superior. The detection rate of VZV DNA is generally thought to decrease with time after the onset of the condition. The utility of VZV DNA polymerase chain reaction (PCR) is thus thought to be limited to the acute phase of the disease. The presence of skin lesions also helps to render a diagnosis; however, cases of zoster sine herpete (ZSH), the occurrence of segmental symptoms without skin lesions, renders the diagnosis of VZV infection more difficult. Antiviral drugs, such as acyclovir, are the treatment of choice to resolve VZV infections. PATIENT CONCERNS: A 65-year-old Japanese man felt heaviness and a throbbing pain on the ulnar side of the right forearm. He was previously diagnosed with cervical spondylosis, and received nonsteroidal anti-inflammatory drugs with little improvement. Contrast cervical magnetic resonance imaging showed a swelling and an increased signal intensity of the spinal cord, and an enhancing lesion, all of which were suggestive of myelitis. DIAGNOSIS: We found no evidence for diagnoses of sarcoidosis, Behçet disease, multiple sclerosis, or neuromyelitis optica spectrum disorder. The CSF analysis revealed an elevation of the total protein concentration and that the patient was positive for VZV DNA, while anti-VZV IgG was not elevated. The patient was therefore diagnosed with ZSH myelitis. INTERVENTIONS: We administered acyclovir and valaciclovir as the first therapy. At the time of recurrence, we used high-dose acyclovir, vidarabine, and high-dose methylprednisolone pulse therapy. OUTCOMES: The patient's dysesthetic pain in the right upper limb improved following the first antiviral therapy. Two months later, he suffered a recurrence, but the second therapy significantly relieved his symptoms. LESSONS: VZV infection should be regarded as an important differential diagnosis of chronic myelitis. VZV DNA PCR should be performed even in the chronic phase of the condition to introduce the possibility of antiviral therapy as a treatment option.
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Mielite/etiologia , Zoster Sine Herpete/complicações , Zoster Sine Herpete/diagnóstico , Idoso , Antivirais/uso terapêutico , DNA Viral/análise , Antebraço , Herpesvirus Humano 3/isolamento & purificação , Humanos , Imageamento por Ressonância Magnética , Masculino , Mielite/diagnóstico por imagem , Reação em Cadeia da Polimerase , Recidiva , Zoster Sine Herpete/líquido cefalorraquidiano , Zoster Sine Herpete/tratamento farmacológicoRESUMO
RATIONALE: Intravascular large B-cell lymphoma (IVLBCL) is a type of malignant lymphoma in which neoplastic B cells proliferate selectively within the lumina of small- and medium-sized vessels. Patients with IVLBCL frequently develop neurological manifestations during their disease course. Patients are known to often develop various neurological manifestations, but there are only a few reports of IVLBCL whose initial symptoms are deafness and/or disequilibrium. PATIENT CONCERNS: A 66-year-old Japanese man was provisionally diagnosed with sudden sensorineural hearing loss. Administration of prednisolone did not improve his symptoms, and then he experienced amaurosis fugax. Magnetic resonance imaging (MRI) showed multiple brain infarcts, so he was administered antithrombotic drugs. Nevertheless, he experienced recurrent strokes, became irritable, and had visual hallucinations. He was emergently admitted to our hospital with disturbance of consciousness. DIAGNOSIS: Blood tests showed elevation of lactose dehydrogenase and soluble interleukin-2 receptor. Cranial MR diffusion-weighted imaging showed multiple lesions bilaterally in the cerebral white matter and cortex, posterior limbs of the internal capsule, and cerebellar hemispheres, which were hypointense on apparent diffusion coefficient maps. Hyperintense lesions were detected bilaterally in the cerebral white matter and basal ganglia on both T2-weighted imaging and fluid-attenuated inversion recovery imaging. Contrast-enhanced brain MRI demonstrated contrast-enhancing high-signal lesions along the cerebral cortex. Brain biopsy revealed a diagnosis of IVLBCL. INTERVENTIONS: The patient could not receive chemotherapy because of his poor general condition. Therefore, we administered high-dose methylprednisolone (mPSL) pulse therapy. OUTCOMES: There was little improvement in consciousness levels after the high-dose mPSL pulse therapy. On the forty-ninth day of hospitalization, he was transferred to another hospital to receive supportive care. LESSONS: IVLBCL should be regarded as an important differential diagnosis of hearing loss and dizziness. Most importantly, if the symptoms are fluctuant and steroid therapy is not effective, biopsy should be considered as early as possible.
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Tontura/etiologia , Perda Auditiva/etiologia , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/fisiopatologia , Idoso , Imagem de Difusão por Ressonância Magnética , Humanos , Masculino , Oxirredutases/sangue , Receptores de Interleucina-2/sangue , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologiaRESUMO
OBJECTIVE: To evaluate effectiveness of random skin biopsies for intravascular large B-cell lymphoma (IVLBCL) with or without central nervous system (CNS) involvement. METHODS: Data from 21 patients with suspected IVLBCL (7 with CNS involvement and 14 without CNS involvement) who underwent single (4 patients), double (1 patient), and random (16 patients) skin biopsies were retrospectively analyzed. RESULTS: IVLBCL was diagnosed in 16 patients (including 6 with CNS involvement). Sensitivity, specificity, and positive predictive value of random skin biopsies were 75%, 100%, and 100%. Ratio of tumor-positive biopsy samples to plasma soluble interleukin-2 receptor (sIL-2R) values was significantly correlated in cases with data on both variables. sIL-2R values in the 6 tumor-negative skin samples (median, 1415 U/mL; range, 487-3200 U/mL) were significantly lower than in tumor-positive skin samples (median, 3550 U/mL; range, 595-8700 U/mL) with at least 1 skin specimen obtained. Mean ratio of tumor-positive biopsy samples in IVLBCL cases with low sIL-2R (<3000 U/mL) was only 45%, indicating a requirement for 3-site multiple sampling. No differences in median sIL-2 values between cases of IVLBCL with and without CNS involvement were found (2795 U/mL vs. 3550 U/mL). Steroids administered before diagnosis yielded false-negative results in 3 of 5 IVLBCL cases (all false-negative cases were IVLBCL with CNS involvement), whereas none of 11 IVLBCL cases without steroid administration yielded false-negative results. CONCLUSIONS: Random skin biopsies before brain biopsy are recommended in patients with suspected IVLBCL regardless of CNS involvement, but low sIL-2R values and steroids may yield false-negative results.
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Neoplasias Encefálicas/patologia , Encéfalo/patologia , Linfoma Difuso de Grandes Células B/patologia , Neoplasias Cutâneas/patologia , Pele/patologia , Adolescente , Adulto , Idoso , Antígenos CD20/metabolismo , Biópsia/métodos , Encéfalo/efeitos dos fármacos , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/sangue , Estudos RetrospectivosRESUMO
The present study aimed to assess whether our newly developed redox nanoparticle (RNPN) that has antioxidant potential decreases Aß levels or prevents Aß aggregation associated with oxidative stress. The transgenic Tg2576 Alzheimer's disease (AD) mice were used to investigate the effect of chronic ad libitum drinking of RNPN solution for 6 months, including memory and learning functions, antioxidant activity, and amyloid plaque aggregation. The results showed that RNPN-treated mice had significantly attenuated cognitive deficits of both spatial and non-spatial memories, reduced oxidative stress of lipid peroxide, and DNA oxidation. RNPN treatment increased the percent inhibition of superoxide anion and glutathione peroxidase activity, neuronal densities in the cortex and hippocampus, decreased Aß(1-40), Aß(1-42) and gamma (γ)-secretase levels, and reduced Aß plaque observed using immunohistochemistry analysis and thioflavin S staining. Our results suggest that RNPN may be a promising candidate for AD therapy because of its antioxidant properties and reduction in Aß aggregation, thereby suppressing its adverse side effect.
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Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/farmacologia , Hipocampo/metabolismo , Nanopartículas/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Modelos Animais de Doenças , Feminino , Hipocampo/patologia , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/genéticaRESUMO
A chronic inflammatory condition may underlie neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease (AD). For example, both PD and AD patients show an increase in transforming growth factor-ß1 (TGF-ß1) levels in their cerebrospinal fluid (CSF). TGF-ß1 is a cytokine that inhibits inflammation. In the present study, using an enzyme-linked immunosorbent assay, we tested the hypothesis that the level of TGF-ß1 in the CSF of patients with amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration (SCD), or multiple system atrophy-cerebellar subtype (MSA-C) would be elevated compared with that of normal controls. We found that TGF-ß1 levels in the CSF were not significantly different between these patients and normal controls. Our data suggest that the level of TGF-ß1 in the CSF is an unreliable biomarker of ALS, SCD, and MSA-C.
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Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Ataxias Espinocerebelares/líquido cefalorraquidiano , Fator de Crescimento Transformador beta1/líquido cefalorraquidiano , Adulto , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Esclerose Lateral Amiotrófica/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/diagnóstico , Ataxias Espinocerebelares/diagnóstico , Adulto JovemRESUMO
Nivolumab, an anti-programmed death-1-specific monoclonal antibody, has demonstrated a durable response and effect on overall survival and has become one of the standard treatments for patients with advanced melanoma. Reported herein is a case of nivolumab-induced chronic inflammatory demyelinating polyradiculoneuropathy, in which an 85-year-old woman with stage IV melanoma developed grade 1 paresthesia 2 weeks after the initial dose of nivolumab was administered. With continued treatment, the neurological deficiency deteriorated rapidly, mimicking Guillain-Barré syndrome, causing such a dramatic decrease in her activities of daily living that she could no longer function in daily life. Thus, nivolumab treatment was discontinued. A course of intravenous immunoglobulin infusion yielded a dramatic clinical improvement; in particular, improved motor control was observed within a few days. Her initial presentation was suggestive of acute inflammatory demyelinating polyradiculoneuropathy, a subtype of Guillain-Barré syndrome; however, the good response to steroids and exacerbation 8 weeks after the onset were suggestive of chronic inflammatory demyelinating polyradiculoneuropathy induced by nivolumab. This is the first case of Guillain-Barré syndrome-like autoimmune polyradiculoneuropathy induced by programmed death-1/programmed death-ligand 1 inhibitors. Although neurological adverse events related to nivolumab are rare, they can become severe, requiring early diagnosis and intervention. Intravenous immunoglobulin may be considered as an effective initial treatment for patients who develop acute autoimmune nervous system disorders due to nivolumab.
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Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Atividades Cotidianas , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Medula Cervical/diagnóstico por imagem , Feminino , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Infusões Intravenosas , Imageamento por Ressonância Magnética , Melanoma/tratamento farmacológico , Nivolumabe , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/etiologia , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
The misfolding and accumulation of the protein fragment ß-amyloid (Aß) is an early and essential event in the pathogenesis of Alzheimer's disease (AD). Despite close biological similarities among primates, humans appear to be uniquely susceptible to the profound neurodegeneration and dementia that characterize AD, even though nonhuman primates deposit copious Aß in senile plaques and cerebral amyloid-ß angiopathy as they grow old. Because the amino acid sequence of Aß is identical in all primates studied to date, we asked whether differences in the properties of aggregated Aß might underlie the vulnerability of humans and the resistance of other primates to AD. In a comparison of aged squirrel monkeys (Saimiri sciureus) and humans with AD, immunochemical and mass spectrometric analyses indicate that the populations of Aß fragments are largely similar in the 2 species. In addition, Aß-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of Aß in a transgenic mouse model. However, the epitope exposure of aggregated Aß differs in sodium dodecyl sulfate-stable oligomeric Aß from the 2 species. In addition, the high-affinity binding of (3)H Pittsburgh Compound B to Aß is significantly diminished in tissue extracts from squirrel monkeys compared with AD patients. These findings support the hypothesis that differences in the pathobiology of aggregated Aß among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors.
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Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Suscetibilidade a Doenças , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos Transgênicos , Saimiri , Tauopatias/etiologia , Tauopatias/metabolismo , Tauopatias/patologiaRESUMO
A 68-year-old man, with a history of type 2 diabetes mellitus and chronic kidney impairment, had been suffering from progressive knee joint contracture and dysesthesia of the lower extremities for 4 years. When he walked, his knees remained bent owing to contracture of the knee joints. There was no evidence of muscle pseudohypertrophy, intramuscular nodules, or muscle weakness. Clinical examination revealed IgA λ M-protein, reticular high-signal intensity lesions demonstrated by magnetic resonance T2-short TI IR(STIR) imaging of the lower extremity muscles, and a mixture of neurogenic and myogenic changes demonstrated by needle electromyography. A biopsy specimen from the vastus lateralis muscle identified Aλ amyloid deposits around the vessels, establishing a diagnosis of amyloid myopathy based on systemic AL amyloidosis. This case demonstrated that joint contracture and reticular lesions shown by magnetic resonance STIR imaging of the muscles can alert the physician to consider muscle biopsy to investigate deposition of amyloid in the skeletal muscles even in the absence of muscle pseudohypertrophy or weakness, both of which are characteristic of amyloid myopathy.
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Amiloidose/complicações , Amiloidose/patologia , Contratura/etiologia , Músculo Esquelético/patologia , Idoso , Amiloide/análise , Humanos , Articulação do Joelho , Masculino , Parestesia/etiologiaRESUMO
We herein report the first case of glossopharyngeal nerve and vagus nerve palsies that appeared after an influenza vaccination. A 15-year-old boy developed dysphagia and dysarthria seven days after receiving an inoculation of the inactivated influenza vaccine. Massive intravenous immunoglobulin (IVIg) treatment was applied, as the patient's symptoms were considered to be immunological adverse effects of the influenza vaccine. He responded well to IVIg, and the symptoms immediately diminished. The mechanisms underlying the development of neurologic symptoms following vaccination are difficult to determine; however, providing immediate immunological treatment, such as IVIg, is effective and beneficial in countering these symptoms.
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Traumatismos do Nervo Glossofaríngeo/diagnóstico , Vacinas contra Influenza/efeitos adversos , Paralisia/diagnóstico , Vacinação/efeitos adversos , Traumatismos do Nervo Vago/diagnóstico , Adolescente , Traumatismos do Nervo Glossofaríngeo/induzido quimicamente , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Paralisia/induzido quimicamente , Traumatismos do Nervo Vago/induzido quimicamenteRESUMO
Background. Neuroleptic malignant syndrome (NMS) is a rare but life-threatening complication of neuroleptic drugs, which are used widely in head and neck cancer (HANC) patients who develop delirium. Methods and Results. Postoperative delirium in a 39-year-old man with tongue cancer was treated with haloperidol and chlorpromazine. Three days after the first administration of antipsychotics, the patient exhibited elevated body temperature, autonomic and extrapyramidal symptoms, and impaired consciousness. A definitive diagnosis was made using the research diagnostic criteria for NMS in the DSM-IV, and the antipsychotics were immediately discontinued. The patient was given dantrolene and bromocriptine to treat the NMS. The patient's hyperthermia, elevated creatinin kinase (CK), and muscle rigidity improved gradually, with all symptoms of NMS resolving completely by 13 days after the diagnosis. Conclusions. HANC surgeons must be alert for early signs of NMS and use antipsychotics conservatively to avoid NMS and its potentially fatal outcome.
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Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been reported to attenuate amyloid-ß peptide (Aß) production in various cellular models. However, the mechanisms by which statins affect neuronal Aß production have not yet been clarified. Here, we investigated this issue in rat primary cortical neurons using two statins, pitavastatin (PV) and atorvastatin (AV). Treatment of neurons with 0.2-2.5 µM PV or AV for 4 days induced a concentration- and time-dependent reduction in the secretion of both Aß40 and Aß42. Moreover, Western blot analyses of cell lysates showed that treatment with PV or AV significantly reduced expression levels of the mature form of amyloid precursor protein (APP) and Thr668-phosphorylated APP (P-APP), but not immature form of APP; the decreases in P-APP levels were more notable than those of mature APP levels. The statin treatment did not alter expression of BACE1 (ß-site APP-cleaving enzyme 1) or γ-secretase complex proteins (presenilin 1, nicastrin, APH-1, and PEN-2). In neurons overexpressing APP via recombinant adenoviruses, PV or AV similarly reduced Aß secretion and the levels of mature APP and P-APP. Statins also markedly reduced cellular cholesterol content in neurons in a concentration-dependent manner. Co-treatment with mevalonate reversed the statin-induced decreases in Aß secretion and mature APP and P-APP levels, whereas co-treatment with cholesterol did not, despite recovery of cellular cholesterol levels. Finally, cell-surface biotinylation experiments revealed that both statins significantly reduced the levels of cell-surface P-APP without changing those of cell surface mature APP. These results suggest that statins reduce Aß production by selectively modulating APP maturation and phosphorylation through a mechanism independent of cholesterol reduction in cultured neurons.
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Peptídeos beta-Amiloides/biossíntese , Precursor de Proteína beta-Amiloide/biossíntese , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neurônios/efeitos dos fármacos , Pirróis/farmacologia , Quinolinas/farmacologia , Animais , Atorvastatina , Colesterol , Ácido Mevalônico/farmacologia , Neurônios/metabolismo , Fragmentos de Peptídeos/biossíntese , Fosforilação , RatosAssuntos
Antagonistas Muscarínicos/uso terapêutico , Pescoço , Triexifenidil/uso terapêutico , Idoso , Distonia , Humanos , MasculinoRESUMO
Cerebral amyloid angiopathy (CAA) is increasingly recognized as a major contributor of Alzheimer's disease (AD) pathogenesis. To date, vascular deposits and not parenchymal plaques appear more sensitive predictors of dementia. Amyloid deposition in and around cerebral blood vessels plays a central role in a series of response mechanisms that lead to changes in the integrity of the blood-brain barrier, extravasations of plasma proteins, edema formation, release of inflammatory mediators and matrix metalloproteases which, in turn, produce partial degradation of the basal lamina with the potential to develop hemorrhagic complications. The progressive buildup of amyloid deposits in and around blood vessels chronically limits blood supply and causes focal deprivation of oxygen, triggering a secondary cascade of metabolic events several of which involve the generation of nitrogen and oxygen free radicals with consequent oxidative stress and cell toxicity. Many aspects of CAA in early- and late-onset AD -the special preference of Aß40 to deposit in the vessel walls, the favored vascular compromise associated with many Aß genetic variants, the puzzling observation that some of these vasculotropic variants solely manifest with recurrent hemorrhagic episodes while others are mainly associated with dementia- await clarification. Non-Aß cerebral amyloidoses reinforce the viewpoint that plaque burden is not indicative of dementia while highlighting the relevance of nonfibrillar lesions and vascular involvement in the disease pathogenesis. The lessons learned from the comparative study of Aß and non-Aß cerebral amyloidosis provide new avenues and alternative models to study the role of amyloid in the molecular basis of neurodegeneration.
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Amyloid molecules harboring pyroglutamate (pGlu) residue at the N-termini are considered to be important for the development of cerebral amyloidosis such as Alzheimer's disease and thought to be either spontaneously generated or being catalyzed by glutaminyl cyclase. Familial British dementia (FBD) is an autosomal dominant form of dementia neuropathologically characterized by parenchymal amyloid and preamyloid deposits, extensive cerebral amyloid angiopathy, and neurofibrillary tangles. FBD is caused by a stop to Arg mutation in the BRI2 gene, generating de novo created amyloid molecule ABri which accumulates in FBD brains but is not present in the normal population. Soluble ABri molecules present in the circulation of carriers of the BRI2 mutation are 34 amino acids long exclusively harboring Glu residue at the N-termini (ABri1-34E), whereas water- and formic acid-soluble ABri molecules extracted from FBD brains have abundant ABri species bearing pGlu residue (ABri1-34pE), suggesting that pyroglutamate formation occurs at the site of deposition. In order to further clarify the mechanism (s) of ABri deposition, we studied whether pyroglutamate formation indeed occurs outside the central nervous system taking advantage that FBD is also a systemic amyloidosis. Soluble and fibrillar ABri molecules extracted from systemic organs and analyzed biochemically using a combination of immunoprecipitation, mass spectrometry, and western blot analysis were oligomeric in size and contained a large proportion of ABri1-34pE. The data indicate that pyroglutamate formation at the N-termini of ABri molecules is an early step in the process of FBD amyloid deposition, and its formation is not restricted to the central nervous system.
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The anomalous folding and polymerization of the beta-amyloid (Abeta) peptide is thought to initiate the neurodegenerative cascade in Alzheimer's disease pathogenesis(1). Abeta is predominantly a 40- or 42-amino acid peptide that is prone to self-aggregation into beta-sheet-rich amyloid fibrils that are found in the cores of cerebral senile plaques in Alzheimer's disease. Increasing evidence suggests that low molecular weight, soluble Abeta multimers are more toxic than fibrillar Abeta amyloid(2). The identification and quantification of low- and high-molecular weight multimeric Abeta species in brain tissue is an essential objective in Alzheimer's disease research, and the methods employed also can be applied to the identification and characterization of toxic multimers in other proteopathies(3). Naturally occurring Abeta multimers can be detected by SDS-polyacrylamide gel electrophoresis followed by immunoblotting with Abeta-specific antibodies. However, the separation and detection of multimeric Abeta requires the use of highly concentrated cortical homogenates and antigen retrieval in small pore-size nitrocellulose membranes. Here we describe a technique for the preparation of clarified human cortical homogenates, separation of proteins by SDS-PAGE, and antigen-epitope retrieval/Western blotting with antibody 6E10 to the N-terminal region of the Abeta peptide. Using this protocol, we consistently detect Abeta monomers, dimers, trimers, tetramers, and higher molecular weight multimers in cortical tissue from humans with Alzheimer's pathology.
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Peptídeos beta-Amiloides/análise , Western Blotting/métodos , Córtex Cerebral/química , Eletroforese em Gel de Poliacrilamida/métodos , Fragmentos de Peptídeos/análise , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/imunologia , Epitopos/análise , Epitopos/imunologia , Humanos , Fragmentos de Peptídeos/imunologiaRESUMO
Mutations within the amyloid-beta (Abeta) sequence, especially those clustered at residues 21-23, which are linked to early onset familial Alzheimer's disease (AD), are primarily associated with cerebral amyloid angiopathy (CAA). The basis for this predominant vascular amyloid burden and the differential clinical phenotypes of cerebral hemorrhage/stroke in some patients and dementia in others remain unknown. The AbetaD23N Iowa mutation is associated with progressive AD-like dementia, often without clinically manifested intracerebral hemorrhage. Neuropathologically, the disease is characterized by predominant preamyloid deposits, severe CAA, and abundant neurofibrillary tangles in the presence of remarkably few mature plaques. Biochemical analyses using a combination of immunoprecipitation, mass spectrometry, amino acid sequence, and Western blot analysis performed after sequential tissue extractions to separately isolate soluble components, preamyloid, and fibrillar amyloid species indicated that the Iowa deposits are complex mixtures of mutated and nonmutated Abeta molecules. These molecules exhibited various degrees of solubility, were highly heterogeneous at both the N- and C-termini, and showed partial aspartate isomerization at positions 1, 7, and 23. This collection of Abeta species-the Iowa brain Abeta peptidome-contained clear imprints of amyloid clearance mechanisms yet highlighted the unique neuropathological features shared by a non-Abeta cerebral amyloidosis, familial Danish dementia, in which neurofibrillary tangles coexist with extensive pre-amyloid deposition in the virtual absence of fibrillar lesions. These data therefore challenge the importance of neuritic plaques as the sole contributors for the development of dementia.