RESUMEN
Amyloid-related imaging abnormalities (ARIA) in magnetic resonance imaging scans have emerged as indicators of potentially serious side effects in clinical trials of therapeutics for Alzheimer's disease. These anomalies include an edematous type (ARIA-E) that appears as hyperintense (bright) regions by T2-weighted MRI, and a type characterized by the deposition of hemosiderin (ARIA-H) that elicits a hypointense signal, especially in T2* susceptibility weighted images. ARIA in general has been linked to the presence of amyloid-ß (Aß)-type cerebral amyloid angiopathy, an accumulation of misfolded Aß protein in the vascular wall that impairs the integrity of brain blood vessels. However, the pathobiology of ARIA remains poorly understood, in part due to the absence of an animal model of the disorder that would enable a contemporaneous analysis of tissue integrity in the affected region. Here we describe both ARIA-E and ARIA-H in an aged squirrel monkey (Saimiri sciureus), a nonhuman primate model of naturally occurring cerebral amyloid angiopathy. Histopathologic examination of the anomalous region revealed reactive astrocytosis and microgliosis, infiltration of systemic inflammatory/immune cells, damage to axons and myelin, and hemosiderin deposition. The disruption of axons in particular suggests that ARIA-E could have functional consequences for affected regions. The squirrel monkey model can be useful for studying the pathogenesis and long-term effects of ARIA, and for testing the safety and efficacy of emerging therapies for Alzheimer's disease.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/metabolismo , Animales , Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Imagen de Difusión Tensora , Modelos Animales de Enfermedad , Femenino , Gliosis/diagnóstico por imagen , Gliosis/metabolismo , Gliosis/patología , Inmunohistoquímica , Imagen por Resonancia Magnética , SaimiriRESUMEN
The misfolding and aggregation of the Aß peptide - a fundamental event in the pathogenesis of Alzheimer׳s disease - can be instigated in the brains of experimental animals by the intracranial infusion of brain extracts that are rich in aggregated Aß. Recent experiments have found that the peripheral (intraperitoneal) injection of Aß seeds induces Aß deposition in the brains of APP-transgenic mice, largely in the form of cerebral amyloid angiopathy. Macrophage-type cells normally are involved in pathogen neutralization and antigen presentation, but under some circumstances, circulating monocytes have been found to act as vectors for the transport of pathogenic agents such as viruses and prions. The present study assessed the ability of peripheral monocytes to transport Aß aggregates from the peritoneal cavity to the brain. Our initial experiments showed that intravenously delivered macrophages that had previously ingested fluorescent nanobeads as tracers migrate primarily to peripheral organs such as spleen and liver, but that a small number also reach the brain parenchyma. We next injected CD45.1-expressing monocytes from donor mice intravenously into CD45.2-expressing host mice; after 24h, analysis by fluorescence-activated cell sorting (FACS) and histology confirmed that some CD45.1 monocytes enter the brain, particularly in the superficial cortex and around blood vessels. When the donor monocytes are first exposed to Aß-rich brain extracts from human AD cases, a subset of intravenously delivered Aß-containing cells migrate to the brain. These experiments indicate that, in mouse models, circulating monocytes are potential vectors by which exogenously delivered, aggregated Aß travels from periphery to brain, and more generally support the hypothesis that macrophage-type cells can participate in the dissemination of proteopathic seeds.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Monocitos/metabolismo , Animales , Transporte Biológico , Encéfalo/irrigación sanguínea , Citometría de Flujo , Humanos , Inmunohistoquímica , Antígenos Comunes de Leucocito/metabolismo , Ratones Endogámicos C57BL , Monocitos/trasplante , Bazo/metabolismoRESUMEN
Deposition of the amyloid-ß (Aß) peptide in senile plaques and cerebral Aß angiopathy (CAA) can be stimulated in Aß-precursor protein (APP)-transgenic mice by the intracerebral injection of dilute brain extracts containing aggregated Aß seeds. Growing evidence implicates a prion-like mechanism of corruptive protein templating in this phenomenon, in which aggregated Aß itself is the seed. Unlike prion disease, which can be induced de novo in animals that are unlikely to spontaneously develop the disease, previous experiments with Aß seeding have employed animal models that, as they age, eventually will generate Aß lesions in the absence of seeding. In the present study, we first established that a transgenic rat model expressing human APP (APP21 line) does not manifest endogenous deposits of Aß within the course of its median lifespan (30 months). Next, we injected 3-month-old APP21 rats intrahippocampally with dilute Alzheimer brain extracts containing aggregated Aß. After a 9-month incubation period, these rats had developed senile plaques and CAA in the injected hippocampus, whereas control rats remained free of such lesions. These findings underscore the co-dependence of agent and host in governing seeded protein aggregation, and show that cerebral Aß-amyloidosis can be induced even in animals that are relatively refractory to the spontaneous origination of parenchymal and vascular deposits of Aß.