Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Abstract

Our results show that pericytes are the first cells affected by Notch3 aggregation in CADASIL mice. Pericyte pathology causes opening of the BBB and microvascular dysfunction. Therefore, protecting pericytes may represent a novel therapeutic strategy for vascular dementia.

RETRACTED ARTICLE: Pericyte degeneration causes white matter dysfunction in the mouse central nervous system

“…We show that pericyte degeneration leads to phenotypic changes in mice similar to those described in the white matter disease associated with small vessel disease contributing to dementia in humans 1–4 . Additionally, neurological disorders associated with cognitive impairment, cerebrovascular dysfunction, and white matter lesions, including AD 23–26 , mild dementia 27 , stroke 14,16 , and CADASIL 28 , exhibit pericyte degeneration including loss of pericyte coverage in the white matter, as we show in AD. Therefore, the present findings may have important implications for the pathogenesis and treatment of small vessel disease and age-related white matter disease, and suggest pericytes as a trigger, and potential therapeutic target, for white matter disease.…”

“…Pericytes control microvascular functions in neuron-dense grey matter regions including blood-brain barrier (BBB) permeability 15–17 and cerebral blood flow 18–22 . They die in AD 10,23–26 mild dementia 27 , stroke 19,20 and cerebral autosomal dominant arteriopathy with subcortical infarcts (CADASIL), the most common genetic ischemic small vessel disease associated with cognitive impairment 28 . Nonetheless, the role of pericytes in the pathogenesis of these disorders, particularly the white matter lesions, is still poorly understood.…”

Pericytes of the neurovascular unit: key functions and signaling pathways

“…Pericytes degenerate and likely play a role in cerebrovascular dysfunction in complex neurological diseases such as AD 26,49,50 , amyotrophic lateral sclerosis (ALS) 51 , and type 2 diabetes mellitus (T2DM)-related microangiopathy and retinopathy 52–54 . Pericyte dysfunction has been also associated with human immunodeficiency virus (HIV)-related dementia 55 , epilepsy 56 , cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) 57 , and brain cancer 58,59 .…”

Dynamic Remodeling of Pericytes In Vivo Maintains Capillary Coverage in the Adult Mouse Brain

“…Critically, there is growing evidence that pericyte loss or dysfunction is involved in diseases that affect the adult human brain. For example, recent studies have shown reduced pericyte numbers in Alzheimer’s disease (AD) (Miners et al, 2017; Sengillo et al, 2013) and CADASIL (Dziewulska and Lewandowska, 2012; Ghosh et al, 2015). In these diseases, the presumption is that pericytes develop normally, but accelerated pericyte loss with aging and pathology worsens BBB dysfunction and contributes to neurodegeneration.…”