RESUMEN
Amyloid beta-peptide (Abeta) accumulation in specific brain regions is a pathological hallmark of Alzheimer's disease (AD). We have previously reported that a well-characterized acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, CP-113,818, inhibits Abeta production in cell-based experiments. Here, we assessed the efficacy of CP-113,818 in reducing AD-like pathology in the brains of transgenic mice expressing human APP(751) containing the London (V717I) and Swedish (K670M/N671L) mutations. Two months of treatment with CP-113,818 reduced the accumulation of amyloid plaques by 88%-99% and membrane/insoluble Abeta levels by 83%-96%, while also decreasing brain cholesteryl-esters by 86%. Additionally, soluble Abeta(42) was reduced by 34% in brain homogenates. Spatial learning was slightly improved and correlated with decreased Abeta levels. In nontransgenic littermates, CP-113,818 also reduced ectodomain shedding of endogenous APP in the brain. Our results suggest that ACAT inhibition may be effective in the prevention and treatment of AD by inhibiting generation of the Abeta peptide.
Asunto(s)
Péptidos beta-Amiloides/efectos de los fármacos , Encéfalo/patología , Inhibidores Enzimáticos/uso terapéutico , Piridinas/uso terapéutico , Esterol O-Aciltransferasa/efectos de los fármacos , Glándulas Suprarrenales/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/metabolismo , Animales , Western Blotting , Encéfalo/efectos de los fármacos , Ésteres del Colesterol/análisis , Ésteres del Colesterol/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/efectos adversos , Femenino , Humanos , Aprendizaje/efectos de los fármacos , Masculino , Ratones , Ratones Transgénicos , Placa Amiloide/metabolismo , Piridinas/efectos adversos , Factores Sexuales , Esterol O-Aciltransferasa/metabolismoRESUMEN
Cerebral amyloid angiopathy (CAA), the deposition of cerebrovascular beta-amyloid (Abeta) in the walls of arterial vessels, has been implicated in hemorrhagic stroke and is present in most cases of Alzheimer disease. Previous studies of the progression of CAA in humans and animal models have been limited to the comparison of pathological tissue from different brains at single time points. Our objective was to visualize in real time the initiation and progression of CAA in Tg2576 mice by multiphoton microscopy through cranial windows. Affected vessels were labeled by methoxy-X04, a fluorescent dye that selectively binds cerebrovascular beta-amyloid and plaques. With serial imaging sessions spaced at weekly intervals, we were able to observe the earliest appearance of CAA in leptomeningeal arteries as multifocal deposits of band-like Abeta. Over subsequent imaging sessions, we were able to identify growth of these deposits (propagation), as well as appearance of new bands (additional initiation events). Statistical modeling of the data suggested that as the extent of CAA progressed in this vascular bed, there was increased prevalence of propagation over initiation. During the early phases of CAA development, the overall pathology burden progressed at a rate of 0.35% of total available vessel area per day (95% confidence interval, 0.3-0.4%). The consistent rate of disease progression implies that this model is amenable to investigations of therapeutic interventions.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/análisis , Angiopatía Amiloide Cerebral/patología , Alquenos/análisis , Animales , Derivados del Benceno/análisis , Angiopatía Amiloide Cerebral/genética , Craneotomía , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Colorantes Fluorescentes/análisis , Humanos , Procesamiento de Imagen Asistido por Computador , Cinética , Meninges/irrigación sanguínea , Meninges/patología , Ratones , Ratones Transgénicos , Placa Amiloide/patología , Técnica de Ventana Cutánea , EstilbenosRESUMEN
Cerebral amyloid angiopathy (CAA), the deposition of beta-amyloid (Abeta3) in cerebral vessels, has been implicated as a common cause of hemorrhagic stroke and other forms of vascular disease. CAA is also a frequent concomitant of Alzheimer disease (AD). While the longterm consequences of CAA are well recognized from clinical and pathologic studies, numerous questions remain unanswered regarding the progression of the disease. Examination of CAA in traditional histologic sections does not easily allow for characterization of CAA, particularly in leptomeningeal vessels. In order to approach this topic, we used low magnification imaging of intact, postmortem brains from transgenic mouse models of AD-like pathology to define the spatial and temporal characteristics of CAA in leptomeningeal vessels. Imaging of brains from 10- to 26-month-old animals demonstrated a stereotypical pattern to the development of CAA, with vessels over the dorsal surface of the brain showing an anterior-to-posterior and large-to-small vessel gradient of involvement. High magnification imaging revealed that CAA deposition began with a banding pattern determined by the organization of the vascular smooth muscle cells. Further analysis of the pattern of amyloid deposits showed shrinkage and disappearance of the gaps between clusters of amyloid bands, gradually reaching a confluent pattern. These data led to a classification system to describe the severity of CAA deposition and demonstrate the potential of using intact brains to generate maps defining the progression and kinetics of CAA. This approach should lead to more informed analysis of the consequences of evolving therapeutic options for AD on this related form of vascular pathology.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Factores de Edad , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/irrigación sanguínea , Angiopatía Amiloide Cerebral/metabolismo , Diagnóstico por Imagen , Modelos Animales de Enfermedad , Humanos , Meninges/irrigación sanguínea , Meninges/patología , Ratones , Ratones TransgénicosRESUMEN
Mitotic centromere-associated kinesin (MCAK) is a microtubule-depolymerizing kinesin-13 member that can track with polymerizing microtubule tips (hereafter referred to as tip tracking) during both interphase and mitosis. MCAK tracks with microtubule tips by binding to end-binding proteins (EBs) through the microtubule tip localization signal SKIP, which lies N terminal to MCAK's neck and motor domain. The functional significance of MCAK's tip-tracking behavior during mitosis has never been explained. In this paper, we identify and define a mitotic function specific to the microtubule tip-associated population of MCAK: negative regulation of microtubule length within the assembling bipolar spindle. This function depends on MCAK's ability to bind EBs and track with polymerizing nonkinetochore microtubule tips. Although this activity antagonizes centrosome separation during bipolarization, it ultimately benefits the dividing cell by promoting robust kinetochore attachments to the spindle microtubules.