Cholesterol as a modifying agent of the neurovascular unit structure and function under physiological and pathological conditions

Abstract

The brain, demanding constant level of cholesterol, precisely controls its synthesis and homeostasis. The brain cholesterol pool is almost completely separated from the rest of the body by the functional blood-brain barrier (BBB). Only a part of cholesterol pool can be exchanged with the blood circulation in the form of the oxysterol metabolites such, as 27-hydroxycholesterol (27-OHC) and 24S–hydroxycholesterol (24S–OHC). Not only neurons but also blood vessels and neuroglia, constituting neurovascular unit (NVU), are crucial for the brain cholesterol metabolism and undergo precise regulation by numerous modulators, metabolites and signal molecules. In physiological conditions maintaining the optimal cholesterol concentration is important for the energetic metabolism, composition of cell membranes and myelination. However, a growing body of evidence indicates the consequences of the cholesterol homeostasis dysregulation in several pathophysiological processes. There is a causal relationship between hypercholesterolemia and 1) development of type 2 diabetes due to long-term high-fat diet consumption, 2) significance of the oxidative stress consequences for cerebral amyloid angiopathy and neurodegenerative diseases, 3) insulin resistance on progression of the neurodegenerative brain diseases. In this review, we summarize the current state of knowledge concerning the cholesterol influence upon functioning of the NVU under physiological and pathological conditions.

Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

“…The brain represents 2% of the total body weight of an adult but contains about 25% of all cholesterol, mostly within myelin . This makes it the richest cholesterol‐containing organ, with approximately 23 mg of cholesterol per gram of brain matter .…”

“…Cholesterol homoeostasis, in the adult brain, is regulated by the interaction between components of the neurovascular unit, consisting of neurons, cerebral blood vessels, astrocytes and perivascular macrophages . Furthermore, the cerebral cholesterol pool is separated from the periphery by the blood–brain barrier (BBB), which cholesterol cannot cross.…”

“…They are autonomous from their systemic counterparts and share important interconnections with each other and with the amyloidogenic and nonamyloidogenic pathways . Moreover, those two systems are involved in central glucose metabolism, cerebral blood flow regulation, neuroinflammation and oxidative stress . The brain RAS participates in memory, although its effects are poorly understood, and overactivation of the central RAS has been demonstrated in early stages of cognitive decline .…”

Increased Levels of 27‐Hydroxycholesterol Induced by Dietary Cholesterol in Brain Contribute to Learning and Memory Impairment in Rats

“…Recent evidences have indicated that oxysterols which act as a link between cholesterol metabolism and hypercholesterolemia play important roles in the development of AD . The oxysterols that are likely to contribute to pathogenesis of AD are 24‐hydroxychosterol (24S‐OHC) and 27‐hydroxycholesterol (27‐OHC), which can freely cross the blood–brain barrier . The high level of 27‐OHC in brain and increased level of neurodegeneration have been observed with a high‐cholesterol diet (CD) feeding rabbits .…”

“…[6][7][8] The oxysterols that are likely to contribute to pathogenesis of AD are 24-hydroxychosterol (24S-OHC) and , which can freely cross the blood-brain barrier. [9] The high level of 27-OHC in brain and increased level of neurodegeneration have been observed with a high-cholesterol diet (CD) feeding rabbits. [10] In the early stages of AD, the elevated level of 27-OHC was observed in brains of AD patients with increased Aβ production and accumulation.…”