RESUMO
The amyloid C-terminal fragment (ßCTF) of the amyloid precursor protein (APP) is the cleaved component of APP by beta secretase-1 (BACE1), which shows similar neurotoxicity as amyloid beta (Aß) in many ways. Evidence suggested that in addition to Aß, ßCTF might also participate in the pathogenesis of Alzheimer's disease (AD). In recent years, the relationship between ßCTF processing and hyperphosphorylated tau has attracted increasing research attention. In this study, we established an animal model of tau hyperphosphorylation with okadaic acid (OA) treatment, and analyzed ßCTF processing in vivo. The ßCTF level was found to increase in neurons, which was most likely caused by the induction of OA and BACE1 overexpression. Furthermore, these results provide the first evidence that ßCTF can predominately accumulate in the axons of neurons in a hyperphosphorylated tau state in vivo, and suggested that the redistribution of ßCTF is involved in the pathogenesis of AD. These results indicate that BACE1 could be a therapeutic target of AD by affecting the processing of ßCTF.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Neurônios/metabolismo , Inibidores de Proteases/farmacologia , Tauopatias/genética , Proteínas tau/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ácido Okadáico , Fosforilação , Ratos , Ratos Sprague-Dawley , Técnicas Estereotáxicas , Tauopatias/induzido quimicamente , Tauopatias/tratamento farmacológico , Tauopatias/patologia , Proteínas tau/genéticaRESUMO
STUDY OBJECTIVE: To describe sleep characteristics and rapid eye movement (REM) sleep behavior disorder in patients with Guadeloupean atypical parkinsonism (Gd-PSP), a tauopathy resembling progressive supranuclear palsy that mainly affects the midbrain. It is possibly caused by the ingestion of sour sop (corossol), a tropical fruit containing acetogenins, which are mitochondrial poisons. DESIGN: Sleep interview, motor and cognitive tests, and overnight videopolysomnography. PATIENTS: Thirty-six age-, sex-, disease-duration- and disability-matched patients with Gd-PSP (n = 9), progressive supranuclear palsy (a tauopathy, n = 9), Parkinson disease (a synucleinopathy, n = 9) and controls (n = 9). SETTINGS: Tertiary-care academic hospital. RESULTS: REM sleep behavior disorder was found in 78% patients with Gd-PSP (43% of patients reported having this disorder several years before the onset of parkinsonism), 44% of patients with idiopathic Parkinson disease, 33% of patients with progressive supranuclear palsy, and no controls. The percentage of muscle activity during REM sleep was greater in patients with Gd-PSP than in controls (limb muscle activity, 8.3%+/-8.7% vs 0.1%+/- 0.2%; chin muscle activity, 24.3%+/- 23.7% vs 0.7%+/-2.0%) but similar to that of other patient groups. The latency and percentage of REM sleep were similar in patients with Gd-PSP, patients with Parkinson disease, and controls, whereas patients with progressive supranuclear palsy had delayed and shortened REM sleep. CONCLUSION: Although Gd-PSP is a tauopathy, most patients experience REM sleep behavior disorder. This suggests that the location of neuronal loss or dysfunction in the midbrain, rather than the protein comprising the histologic lesions (synuclein versus tau aggregation), is responsible for suppressing muscle atonia during REM sleep. Subjects with idiopathic REM sleep behavior disorder should avoid eating sour sop.
Assuntos
Álcoois Graxos/toxicidade , Frutas/toxicidade , Lactonas/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtorno do Comportamento do Sono REM/induzido quimicamente , Tauopatias/induzido quimicamente , Acetogeninas , Idoso , Demência/induzido quimicamente , Demência/diagnóstico , Diagnóstico Diferencial , Avaliação da Deficiência , Sonhos/efeitos dos fármacos , Feminino , Guadalupe , Humanos , Masculino , Mesencéfalo/efeitos dos fármacos , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Exame Neurológico/efeitos dos fármacos , Doença de Parkinson/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Polissonografia/efeitos dos fármacos , Estudos Prospectivos , Transtorno do Comportamento do Sono REM/diagnóstico , Transtornos da Transição Sono-Vigília/induzido quimicamente , Transtornos da Transição Sono-Vigília/diagnóstico , Paralisia Supranuclear Progressiva/induzido quimicamente , Paralisia Supranuclear Progressiva/diagnóstico , Tauopatias/diagnósticoRESUMO
Over the last 60 years an abnormally high prevalence of atypical Parkinsonism has been reported in 5 different geographic isolates. It was first described on Guam, later in New Guinea and in the Kii peninsula, on Guadeloupe, and in New Caledonia. We investigated the phenotype of atypical Parkinsonism in three of these foci and observed several similarities with dementia in most and amyotrophic lateral sclerosis in some. This disappearance of this disease in two places--Guam and New Guinea--suggested an environmental origin which has not been clarified before the disease ended. The exposure to annonaceae acetogenins and/or rotenone has been documented in four of these places, and experimental studies in animals demonstrated annonaceae acetogenins neurotoxicity, which is similar to rotenone neurotoxicity. Simultaneous exposure to acetogenins and rotenone could produce a synergistic toxicity on neurons.