Blood-Brain Barrier Dysfunction and the Potential Mechanisms in Chronic Cerebral Hypoperfusion Induced Cognitive Impairment

Abstract

Chronic cerebral hypoperfusion (CCH) is a major cause of vascular cognitive impairment and dementia (VCID). Although the underlying mechanisms have not been fully elucidated, the emerging data suggest that blood-brain barrier (BBB) dysfunction is one of the pivotal pathological changes in CCH. BBB dysfunction appears early in CCH, contributing to the deterioration of white matter and the development of cognitive impairment. In this review, we summarize the latest experimental and clinical evidence implicating BBB disruption as a major cause of VCID. We discuss the mechanisms of BBB dysfunction in CCH, focusing on the cell interactions within the BBB, as well as the potential role of APOE genotype. In summary, we provide novel insights into the pathophysiological mechanisms underlying BBB dysfunction and the potential clinical benefits of therapeutic interventions targeting BBB in CCH.

Keywords: blood–brain barrier; chronic cerebral hypoperfusion; normal appearing white matter; vascular cognitive impairment and dementia; white matter hyperintensity.

FIGURE 1

Blood–brain barrier (BBB) damage in chronic cerebral hypoperfusion (CCH). The composition of the BBB mainly includes endothelial cells, pericytes, astrocytes, and microglia, all of which are indispensable in the maintenance of normal BBB integrity and functions. Endothelial cells form a seamless barrier that confines solute exchange between the CNS and the systemic vasculature, attributed to intercellular junction molecules (e.g., ZO-1, occluding, claudin-5), while the loss of barrier in CCH gives rise to BBB leakage and leads to more frequent substance exchange like albumin and IgG entering CNS. Pericytes, wrapping most endothelial cells, protect BBB completeness via nurturing endothelial cells and controlling substance transportation. In CCH, diminishing and malfunction of pericytes cause BBB dysfunction. Reduced pericyte marker PDGFRβ in situ and elevated sPDGFRβ in the cerebral spinal fluid are hallmarks of CCH. The function or metabolism of the pericyte is also vital in regulating BBB damage. For example, energy imbalance resulting from mitochondria degeneration causes the malfunction of pericytes in CCH. Furthermore, astrocytes excrete cytokines that might either be protective (e.g., sonic hedgehog, glutamate, and apoE) or toxic (e.g., VEGFA, TSP1, and MMP9). The environmental changes in CCH trigger off harmful factors release and lead to increased BBB permeability. Also, microglia exert dual effects on BBB physiologically, while in CCH, in general, pro-inflammatory subtypes worsen BBB damage.