RESUMEN
Reduction of amyloid beta (Aß) has been shown to be effective in treating Alzheimer's disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aß is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aß in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aß production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aß production could be a promising therapeutic strategy for treating AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Modelos Animales de Enfermedad , Ratones Transgénicos , Neuronas , Oligodendroglía , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Técnicas de Sustitución del Gen , Neuronas/metabolismo , Oligodendroglía/metabolismoRESUMEN
AIMS: The objective of this study was to elucidate the early white matter changes in CADASIL small vessel disease. METHODS: We used high-pressure freezing and freeze substitution (HPF/FS) in combination with high-resolution electron microscopy (EM), immunohistochemistry and confocal microscopy of brain specimens from control and CADASIL (TgNotch3R169C ) mice aged 4-15 months to study white matter lesions in the corpus callosum. RESULTS: We first optimised the HPF/FS protocol in which samples were chemically prefixed, frozen in a sample carrier filled with 20% polyvinylpyrrolidone and freeze-substituted in a cocktail of tannic acid, osmium tetroxide and uranyl acetate dissolved in acetone. EM analysis showed that CADASIL mice exhibit significant splitting of myelin layers and enlargement of the inner tongue of small calibre axons from the age of 6 months, then vesiculation of the inner tongue and myelin sheath thinning at 15 months of age. Immunohistochemistry revealed an increased number of oligodendrocyte precursor cells, although only in older mice, but no reduction in the number of mature oligodendrocytes at any age. The number of Iba1 positive microglial cells was increased in older but not in younger CADASIL mice, but the number of activated microglial cells (Iba1 and CD68 positive) was unchanged at any age. CONCLUSION: We conclude that early WM lesions in CADASIL affect first and foremost the myelin sheath and the inner tongue, suggestive of a primary myelin injury. We propose that those defects are consistent with a hypoxic/ischaemic mechanism.
Asunto(s)
CADASIL/patología , Cuerpo Calloso/ultraestructura , Substitución por Congelación , Vaina de Mielina/ultraestructura , Animales , Cuerpo Calloso/patología , Substitución por Congelación/métodos , Ratones , Vaina de Mielina/patología , Sustancia Blanca/patologíaRESUMEN
The blood vessels of the brain are lined with endothelial cells and it has been long known that these help to regulate blood flow to the brain. However, there is increasing evidence that these cells also interact with the surrounding brain tissue. These interactions change when the endothelial cells become dysfunctional and have an impact in diseases such as cerebral small vessel disease, the leading cause of vascular dementia. In this review, we focus on what endothelial dysfunction is, what causes it, how it leads to surrounding brain pathology, how researchers can investigate it with current models, and where this might lead in the future for dementia therapies.
Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales , Células Endoteliales , Encéfalo , Hemodinámica , HumanosRESUMEN
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. White matter (WM) lesions (WMLs) are the earliest and most frequent abnormalities, and can be associated with lacunar infarcts and enlarged perivascular spaces (ePVS). The prevailing view is that blood brain barrier (BBB) leakage, possibly mediated by pericyte deficiency, plays a pivotal role in the formation of WMLs. Herein, we investigated the involvement of BBB leakage and pericyte loss in CADASIL WMLs. Using post-mortem brain tissue from 12 CADASIL patients and 10 age-matched controls, we found that WMLs are heterogeneous, and that BBB leakage reflects the heterogeneity. Specifically, while fibrinogen extravasation was significantly increased in WMLs surrounding ePVS and lacunes, levels of fibrinogen leakage were comparable in WMLs without other pathology ("pure" WMLs) to those seen in the normal appearing WM of patients and controls. In a mouse model of CADASIL, which develops WMLs but no lacunes or ePVS, we detected no extravasation of endogenous fibrinogen, nor of injected small or large tracers in WMLs. Moreover, there was no evidence of pericyte coverage modification in any type of WML in either CADASIL patients or mice. These data together indicate that WMLs in CADASIL encompass distinct classes of WM changes and argue against the prevailing hypothesis that pericyte coverage loss and BBB leakage are the primary drivers of WMLs. Our results also have important implications for the interpretation of studies on the BBB in living patients, which may misinterpret evidence of BBB leakage within WM hyperintensities as suggesting a BBB related mechanism for all WMLs, when in fact this may only apply to a subset of these lesions.
Asunto(s)
Barrera Hematoencefálica/patología , Encéfalo/patología , CADASIL/patología , Sustancia Blanca/patología , Anciano , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , CADASIL/metabolismo , Permeabilidad Capilar/fisiología , Estudios de Cohortes , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Sustancia Blanca/irrigación sanguínea , Sustancia Blanca/metabolismoRESUMEN
Dementia is a major social and economic problem for our aging population. One of the most common of dementia in the elderly is cerebral small vessel disease (SVD). Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause. In a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90α, which blocks oligodendroglial differentiation, contributing to impaired myelination. Treatment with EC-stabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B, which caused the EC dysfunction in the rat SVD model, and a single-nucleotide polymorphism in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model, which may also be of relevance to human SVD.
Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales/patología , Enfermedades de los Pequeños Vasos Cerebrales/fisiopatología , Endotelio Vascular/fisiopatología , Sustancia Blanca/patología , Adenosina Trifosfatasas/genética , Animales , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/fisiopatología , Proliferación Celular , Modelos Animales de Enfermedad , Células Endoteliales/patología , Endotelio Vascular/patología , Proteínas HSP90 de Choque Térmico/metabolismo , Homocigoto , Humanos , Hipertensión/patología , Hipertensión/fisiopatología , Proteínas de Transporte de Membrana/genética , Persona de Mediana Edad , Células Precursoras de Oligodendrocitos/metabolismo , Polimorfismo de Nucleótido Simple/genética , Ratas , Sustancia Blanca/fisiopatologíaRESUMEN
Cerebral small vessel disease (SVD) is a prevalent, neurological disease that significantly increases the risk of stroke and dementia. The main pathological changes are vascular, in the form of lipohyalinosis and arteriosclerosis, and in the white matter (WM), in the form of WM lesions. Despite this, it is unclear to what extent the key cell types involved-the endothelial cells (ECs) of the vasculature and the oligodendrocytes of the WM-interact. Here, we describe the work that has so far been carried out suggesting an interaction between ECs and oligodendrocytes in SVD. As these interactions have been studied in more detail in other disease states and in development, we explore these systems and discuss the role these mechanisms may play in SVD.