An emerging role of astrocytes in vascular contributions to cognitive impairment and dementia

Abstract

Vascular contributions to cognitive impairment and dementia (VCID) is understood to be the second most common cause of dementia after Alzheimer's disease, and is also a frequent comorbidity with Alzheimer's disease. While VCID is widely acknowledged as a key contributor to dementia, the mechanistic underpinnings of VCID remain poorly understood. In this review, we address the potential role of astrocytes in the pathophysiology of VCID. The vast majority of the blood vessels in the brain are surrounded by astrocytic end-feet. Given that astrocytes make up a significant proportion of the cells in the brain, and that astrocytes are usually passively connected to one another through gap junctions, we hypothesize that astrocytes are key mediators of cognitive impairment because of cerebrovascular disease. In this review, we discuss the existing body of literature regarding the role of astrocytes at the vasculature in the brain, and the known consequences of their dysfunction, as well as our hypotheses regarding the role astrocytes play in VCID.

Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

“…Moreover, it is believed that astrocytes in AD are seriously compromised through the altered expressions of connexin 43, a hemichannel fundamental in astrocytic gap junctions, which is fundamental for astrocytes connections to neurons [270][271][272][273][274], through widespread modifications of energy metabolism and due to altered response to oxidative stress [274][275][276]. In SVD, there are some data [277] that concern the cerebral amyloid angiopathy. There is a decrease in the number of astrocytic processes contacting the vasculature in the cerebral cortex and hippocampus, which are even degenerated and undergo to the clasmatodendrosis process [278].…”

“…There is a decrease in the number of astrocytic processes contacting the vasculature in the cerebral cortex and hippocampus, which are even degenerated and undergo to the clasmatodendrosis process [278]. Price et al [277] examined the end-foot changes of astrocytes in cerebral amyloid angiopathy and found out that there is a significant reduction of aquaporin-4-positive staining associated with the blood vessels, without any modification of the total protein or gene-expression [277]. Moreover, end-feet inward rectifying potassium channel, K ir 4.1 and BK calcium-dependent potassium channel, being tightly co-anchored to aquaporin-4-water channels, have been found significantly decreased in mice with high levels of cerebral amyloid angiopathy [279,280].…”

“…Moreover, end-feet inward rectifying potassium channel, K ir 4.1 and BK calcium-dependent potassium channel, being tightly co-anchored to aquaporin-4-water channels, have been found significantly decreased in mice with high levels of cerebral amyloid angiopathy [279,280]. Even though that these alterations are not indicative of a global decrease in potassium, as a whole, they can be considered as being a fundamental cause of altered astrocytic excitability, therefore causing an alteration in the neurovascular coupling [277,280]. Specific models of astrocytes impairment in hyperhomocysteinemic (HHcy)mice, which mimic small vessel disease, have been developed, with a three-step investigation (at 6, 10, and 14 weeks of B6, B9, and B12 detrimental diet in wild type HHcy mouse) [281,282].…”

The many faces of vascular cognitive impairment

“…These aspects are explained by Dr. Wilcock and collaborators in their review article (Price et al . ).…”

“…Astrocytes may play a key role in the development of vascular dementia as they are strategically localized between neurons and cerebral blood vessels, which are completely surrounded by astrocytic endfeet. These aspects are explained by Dr. Wilcock and collaborators in their review article (Price et al 2018).…”