Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats

Abstract

One Sentence Summary: In cerebral small vessel disease, endothelial dysfunction leads to white matter vulnerability which is reversible in a rat model with endothelial stabilizing drugs.Abstract: Dementia is a major social and economic problem for our ageing population. One of the commonest causes 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. Here, 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 90-alpha, which blocks oligodendroglial differentiation, contributing to impaired myelination. Treatment with ECstabilizing 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 (SNP) 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.

Nicotinamide riboside rescues angiotensin II–induced cerebral small vessel disease in mice

“…42,43 The decreased expression of claudin-5, the key tight junction protein of the BBB, has been reported in a CSVD model. 38 In addition, growing evidence has indicated that limited caveolae-mediated transcytosis maintains BBB integrity in the CNS, 44 and BBB disruption due to increased vesicle transport has been confirmed in many models. 27,45 Cav-1 is a major structural component of caveolae and is mainly expressed in the vessels of the CNS.…”

“…The mechanism of CSVD has also been evaluated in animal models. Rajani et al reported that mature oligodendrocytes are decreased, which implies abnormal myelination. In the CNS, MBP and NF200 are the critical components of myelin and axons, and their integrity plays an important role in maintaining the conduction of nerve fiber bundles .…”

“…Previous studies of BBB permeability in CSVD have focused on tight junction proteins, such as zonula occludens‐1 (ZO‐1), occludin, and claudin‐5 . The decreased expression of claudin‐5, the key tight junction protein of the BBB, has been reported in a CSVD model . In addition, growing evidence has indicated that limited caveolae‐mediated transcytosis maintains BBB integrity in the CNS, and BBB disruption due to increased vesicle transport has been confirmed in many models .…”

“…4 The mechanism of CSVD has also been evaluated in animal models. Rajani et al 38 of myelin and axons, and their integrity plays an important role in maintaining the conduction of nerve fiber bundles. 39 In our study, cognitive decline and myelin degeneration were observed after mice were infused with Ang Ⅱ for 28 days.…”

VEGF receptor‐1 modulates amyloid β 1–42 oligomer‐induced senescence in brain endothelial cells

“…Senescent cells accumulate in tissues and organs, where they play a detrimental role in the aging process (48)(49)(50)(51). Senescent ECs could contribute to cerebrovascular dysfunction by: 1) inhibiting EC replacement and regeneration in response to ageing and aberrant angiogenic signals; 2) inducing changes in tight junction protein expression and coverage (52), leading to blood-brain barrier alterations and leakiness; and 3) inducing local inflammatory responses and secreting proinflammatory cytokines (28) to cause further damage to the neurovascular unit or secrete other factors, such as HSP90a, which was recently shown to inhibit oligodendrocyte maturation in a rat model of cerebral small vessel disease (53). All of these pathogenic responses by dysfunctional ECs could cause further collateral damage to the neurovascular unit, ultimately leading to neurodegeneration and cognitive deficits in the AD brain.…”