RESUMO
The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer's disease. Previous studies showed that NPT088 treatment reduced ß-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer's disease. Patients were treated with 4 dose levels of NPT088 for 6 months to evaluate its safety and tolerability. Exploratory measurements included measurement of change in ß-amyloid plaque and tau burden utilizing Positron Emission Tomography imaging as well as measures of Alzheimer's disease symptoms. At endpoint NPT088 was generally safe and well-tolerated with the most prominent finding being infusion reactions in a minority of patients. No effect of NPT088 on brain plaques, tau aggregates or Alzheimer's disease symptoms was observed.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Bacteriófago M13/genética , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Etilenoglicóis , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Masculino , Pessoa de Meia-Idade , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismoRESUMO
In this review we address the idea that conservation of epigenetic mechanisms for information storage represents a unifying model in biology, with epigenetic mechanisms being utilized for cellular memory at levels from behavioral memory to development to cellular differentiation. Epigenetic mechanisms typically involve alterations in chromatin structure, which in turn regulate gene expression. An emerging idea is that the regulation of chromatin structure through histone acetylation and DNA methylation may mediate long-lasting behavioral change in the context of learning and memory. We find this idea fascinating because similar mechanisms are used for triggering and storing long-term 'memory' at the cellular level, for example when cells differentiate. An additional intriguing aspect of the hypothesis of a role for epigenetic mechanisms in information storage is that lifelong behavioral memory storage may involve lasting changes in the physical, three-dimensional structure of DNA itself.
Assuntos
Epigênese Genética , Memória/fisiologia , Modelos Neurológicos , Plasticidade Neuronal/genética , Animais , Cromatina/genética , Hipocampo/metabolismo , Sistema Nervoso/metabolismoRESUMO
Systemic arterial compliance was measured in 22 patients with permanent essential hypertension and compared with 11 sex- and age-matched normal normal subjects. Determinations were made from analysis of the monoexponential blood pressure-time curve during diastole, according to a simple visco-elastic model. Arterial compliance was significantly decreased (P less than 0.001) in hypertensives. In the overall population, arterial compliance was negatively correlated to age (P less than 0.005) and blood pressure (P less than 0.001), suggesting that the changes in compliance could be attributable to the level of blood pressure per se and/or to the rigidity of the arterial wall. Administration of vasoactive substances (angiotensin and sodium nitroprusside) enabled a strong negative relationship (P less than 0.01) between arterial compliance and diastolic blood pressure to be demonstrated in each individual. The slope of the curve was not dependent on age and represented the ability to decrease compliance per unit rise in pressure. The slope was steeper in hypertensives, suggesting a change reactivity of the arterial wall in these patients.
