Aged blood inhibits hippocampal neurogenesis and activates microglia through VCAM1 at the blood-brain barrier

Abstract

An aged circulatory environment can promote brain dysfunction and we hypothesized that the blood-brain barrier (BBB) mediates at least some of these effects. We observe brain endothelial cells (BECs) in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of Vascular Cell Adhesion Molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, the shed, soluble form of VCAM1 is prominently increased in the aged circulation of humans and mice, and aged plasma is sufficient to increase VCAM1 expression in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic ablation of VCAM1 in BECs counteracts the detrimental effects of aged plasma on young brains and reverses aging aspects in old mouse brains. Thus, VCAM1 is a negative regulator of adult neurogenesis and inducer of microglial reactivity, establishing VCAM1 and the luminal side of the BBB as possible targets to treat age-related neurodegeneration.Brain structure and function deteriorate with age, steadily driving cognitive impairments and susceptibility to neurodegenerative disorders in humans 1 . How aging leads to these manifestations is poorly understood but two cellular hallmarks of brain aging are particularly noticeable. The first is an increase in activation of innate immune pathways and an increase in the activation state of microglia and astrocytes, frequently referred to as "neuroinflammation" 2-4 . The second aging hallmark is the precipitous loss of stem cell numbers and activity in the dentate gyrus (DG) of the hippocampus, one of two neurogenic regions of the adult mammalian brain 5 . The hippocampus is crucial for learning and memory, and is particularly vulnerable to age-related neurodegeneration and diseases such as Alzheimer's disease (AD) 6 . Hippocampal neurogenesis is important for some aspects of learning and memory, especially as it relates to spatial navigation and pattern separation 7 .While many of these age-related changes in the brain may be the consequences of cellintrinsic and brain-localized mechanisms of aging, we asked if changes in secreted signaling proteins, dubbed the communicome 8 , could be used to understand, characterize, and quantify aspects of brain aging and cognitive impairment. Indeed, such changes in plasma or CSF proteomes are not only abundant with aging and disease 9,10 , but factors in young blood or

Aged blood inhibits hippocampal function through VCAM1 at blood brain barrier

“…However, aged plasma depleted of sVCAM1 did not display obviously less detrimental effects on young brain, indicating that sVCAM1 is not the driving factor of aging phenotype. (Yousef et al, 2018) explained the high quantity of sVCAM1 as a result of high membrane bound Vascular Cell Adhesion Molecule 1 (VCAM1) because of the constitutive shedding of VCAM1 from BBB to plasma (Garton et al, 2003;SINGH et al, 2005)(SINGH et al, 2005. This is in line with the higher expression level of VCAM1, according to higher Vcam1 mRNA concentration detected in aged BECs compared to young ones.…”

“…A recent research carried out by Yousef et al (2018) in Stanford University also observed sufficient capacity of aged plasma to trigger aging phenotypes in young brains, primarily in neurogenesis suppression and microglia activation of the hippocampus. Activated microglia is known to be a chronic source of diverse neurotoxins that leads to neuronal function loss, particularly in aged brain and neurodegenerative diseases (Lull and Block, 2010).…”

“…These two phenomena are considered to be cellular hallmarks of brain aging. Yousef et al (2018) hypothesized that deterioration of hippocampus function in aged circulatory environment is mediated by blood-brain barrier (BBB). Because BBB separates brain from blood and protects brain parenchyma from harmful factors in the circulating milieu.…”

“…Because BBB separates brain from blood and protects brain parenchyma from harmful factors in the circulating milieu. In their paper, Yousef et al (2018)explained that factors in blood affect brain cells through behaviour of brain endothelial cells (BECs) constituting the BBB.…”

“…To determine the proteins involved in age-related changes in BECs, Yousef et al (2018) compared the plasma proteomic differences between healthy aging control groups and identified 31 protein factors related significantly with age. Among them soluble form of Vascular Cell Adhesion Molecule 1 (sVCAM1) has performed the most strongly positive correlation with age.…”